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3.A.1 The ATP-binding Cassette (ABC) Superfamily

The ABC superfamily contains both uptake and efflux transport systems, and the members of these two porter groups generally cluster loosely together with just a few exceptions (Saurin et al., 1999). ATP hydrolysis without protein phosphorylation energizes transport. There are dozens of families within the ABC superfamily, and family generally correlates with substrate specificity. However there are exceptions. The high resolution X-ray structures of several ABC transporters, both uptake and efflux systems, have been determined, and specific details of the transport mechanisms have been proposed (Davidson and Maloney, 2007; Lee et al., 2007). Several multidrug resistance (MDR) transporters catalyze lipid, lipopolysaccharide, and/or lipoprotein export. This can occur by a 'flip-flop' mechanism or a 'projection' mechanism (Nagao et al., 2010). Pagès et al. (2011) have described several classes of efflux pump inhibitors that counteract MDR. Known structures have been discussed by Zolnerciks et al. (2011) and by Wilkens 2015. Mechanistic models for the transport cycle have been compared (Szöllősi et al. 2017). Transporters can be modified posttranslationally by phsophorylation, ubiquitination, glycosylation and/or palmitoylation (Czuba et al. 2018). Ford and Beis 2019 reviewed  progress on structural determination of eukaryotic and bacterial ABC transporters as well as novel proposed mechanisms.  There are 48 genes encoding ABC transporters in humans (Sakamoto et al. 2019).

Switch and constant contact models have been presented (George and Jones, 2012).  The prevailing paradigm for the ABC transport mechanism is the Switch Model, in which the nucleotide binding domains are proposed to dimerise upon binding of two ATP molecules, and thence dissociate upon sequential hydrolysis of the ATP. This idea appears consistent with crystal structures of both isolated subunits and whole transporters, as well as with the biochemical data. Nonetheless, an alternative Constant Contact Model has been proposed, in which the nucleotide binding domains do not fully dissociate, and ATP hydrolysis occurs alternately at each of the two active sites (Jones and George 2012).  In this model, one of the sites remains closed and contains an occluded nucleotide at all times. The cassettes remain in contact, and the active sites swing open in an alternately seesawing motion. Whilst the concept of NBD association/dissociation in the Switch Model is naturally compatible with a single alternating-access channel, the asymmetric functioning proposed by the Constant Contact model suggests an alternating or reciprocating function in the TMDs. A new model for the function of ABC transporters has been proposed by Jones and George 2014 in which the sequence of ATP binding, hydrolysis, and product release in each active site is directly coupled to the analogous sequence of substrate binding, translocation and release in one of two functionally separate substrate translocation pathways. Each translocation pathway functions 180 degrees out of phase.

As noted above, the porters of the ABC superfamily consist of two integral membrane domains/proteins and two cytoplasmic domains/proteins. The uptake systems (but not the efflux systems) usually possess extracytoplasmic solute-binding receptors (one or more per system) which in Gram-negative bacteria are found in the periplasm, and in Gram-positive bacteria is present either as a lipoprotein, tethered to the external surface of the cytoplasmic membrane, or as a cell surface-associated protein, bound to the external membrane surface via electrostatic interactions. For those systems with two or more extracytoplasmic solute binding receptors, the receptors may interact in a cooperative fashion (Biemans-Oldehinkel and Poolman, 2003). These binding proteins fall into six phylogenetic clusters (Berntsson et al., 2010). Both the integral membrane channel constituent(s) and the cytoplasmic ATP-hydrolyzing constituent(s) may be present as homodimers or heterodimers. Two families of ABC transporters have members in which one or two receptors are fused to either the N- or C-terminus of the translocating membrane protein. This suggests that two or even four substrate-binding sites may function in the complex. Possibly multiple receptors in proximity to the translocator enhances the transport rate. Multiple receptors may also broaden the substrate specificity of the system (van der Heide and Poolman, 2002). These systems with covalent receptor domains linked to the transmembrane translocators are found in the PAAT family (TC #3.A.1.3) and the QAT family (TC #3.A.1.12) (van der Heide and Poolman, 2002). Some high affinity ABC uptake systems specific for vitamins, minerals and other small molecules, called ECF systems, lack an extracytoplasm receptor and function by a mechanisms as discussed by Slotboom 2014.

ABC transporters always have two nucleotide binding domains (NBDs). ATP-bound NBDs dimerize in a head-to-tail arrangement, with two nucleotides sandwiched at the dimer interface. Upon the binding of ATP molecules to nucleotide binding domains (NBDs), ATP-binding cassette (ABC) exporters undergo a conformational transition from an inward-facing (IF) to an outward-facing (OF) state via chemo-mechanical coupling. The ATP binding energy is converted into distortion energy of several transmembrane helices (Arai et al. 2017). Both NBDs contribute residues to each of the two nucleotide-binding sites (NBSs) in the dimer. The prototypical NBD MJ0796 from Methanocaldococcus jannaschii forms ATP-bound dimers that dissociate completely following hydrolysis of one of the two bound ATP molecules.  ATP hydrolysis at one nucleotide-binding site drives NBD dissociation, but two binding sites are required to form the ATP-sandwich NBD dimer necessary for hydrolysis (Zoghbi and Altenberg 2013).

Kinases can affect the activities of ABC transporters as do protein-protein interactions. Crawford et al. 2018 reviewed the effects of such interactions on the ABC transporters ABCB1, ABCB11, ABCC1, ABCC4, and ABCG2 of humans, showing how kinases and protein-protein interactions regulate these transporters. Yeast have all of these types of ABC transporters, and a comprehensive overview of these proteins of the drug-resistant human fungal pathogen, Candida glabrata (Kumari et al. 2018). A comprehensive review of the classes of efflux pump inhibitors from various sources, highlighting their structure-activity relationships, which can be useful for medicinal chemists in the pursuit of novel efflux pump inhibitors has appeared (Durães et al. 2018). Protein expression and functional relevance of various primary and secondary drug efflux and uptake porters at the Blood-Brain Barrier of human brain and glioblastoma have been investigated (Bao et al. 2019).

The TC system of classification uses the integral membrane proteins, not the energy coupling proteins, receptor, or auxiliary subunits to classify the system into families (Saier, 1994; 2000). The exception to this rule was the ABC superfamily which by engrained tradition was classified based on the use of an ATP-binding cassette (ABC) ATPase for energy coupling before the TC system was designed. Since then it has become known that the membrane proteins of ABC export systems fall into three evolutionarily distinct families that followed three different pathways of origin (Wang et al., 2009). These have been designated ABC1, ABC2 and ABC3. ABC1 porters arose by triplication of a primordial 2 TMS element; ABC2 porters arose by duplication of a 3 TMS element, and ABC3 porters arose from a 4 TMS precursor that either remained as two 4 TMS proteins (a homo or hetero dimer) or internally duplicated to give 8 or 10 proteins, the extra two appear to be in the center between the two 4 TMS repeat units (Khwaja et al. 2005). The ABC functional superfamily therefore consists of three true superfamilies. The ABC subfamiies or clusters that belong to each of these three superfamilies are listed below. 

ABC1:
3.A.1.106 The Lipid Exporter (LipidE) Family
3.A.1.108 The β-Glucan Exporter (GlucanE) Family
3.A.1.109 The Protein-1 Exporter (Prot1E) Family
3.A.1.110 The Protein-2 Exporter (Prot2E) Family
3.A.1.111 The Peptide-1 Exporter (Pep1E) Family
3.A.1.112 The Peptide-2 Exporter (Pep2E) Family
3.A.1.113 The Peptide-3 Exporter (Pep3E) Family
3.A.1.117 The Drug Exporter-2 (DrugE2) Family
3.A.1.118 The Microcin J25 Exporter (McjD) Family
3.A.1.119 The Drug/Siderophore Exporter-3 (DrugE3) Family
3.A.1.123 The Peptide-4 Exporter (Pep4E) Family
3.A.1.127 The AmfS Peptide Exporter (AmfS-E) Family
3.A.1.129 The CydDC Cysteine Exporter (CydDC-E) Family
3.A.1.135 The Drug Exporter-4 (DrugE4) Family
3.A.1.139 The UDP-Glucose Exporter (U-GlcE) Family (UPF0014 Family)
3.A.1.201 The Multidrug Resistance Exporter (MDR) Family (ABCB)
3.A.1.202 The Cystic Fibrosis Transmembrane Conductance Exporter (CFTR) Family (ABCC)
3.A.1.203 The Peroxysomal Fatty Acyl CoA Transporter (P-FAT) Family (ABCD)
3.A.1.206 The a-Factor Sex Pheromone Exporter (STE) Family (ABCB)
3.A.1.208 The Drug Conjugate Transporter (DCT) Family (ABCC) (Dębska et al., 2011)
3.A.1.209 The MHC Peptide Transporter (TAP) Family (ABCB)
3.A.1.210 The Heavy Metal Transporter (HMT) Family (ABCB)
3.A.1.212 The Mitochondrial Peptide Exporter (MPE) Family (ABCB)
3.A.1.21   The Siderophore-Fe3+ Uptake Transporter (SIUT) Family

ABC2:
3.A.1.101 The Capsular Polysaccharide Exporter (CPSE) Family
3.A.1.102 The Lipooligosaccharide Exporter (LOSE) Family
3.A.1.103 The Lipopolysaccharide Exporter (LPSE) Family
3.A.1.104 The Teichoic Acid Exporter (TAE) Family
3.A.1.105 The Drug Exporter-1 (DrugE1) Family
3.A.1.107 The Putative Heme Exporter (HemeE) Family
3.A.1.115 The Na+ Exporter (NatE) Family
3.A.1.116 The Microcin B17 Exporter (McbE) Family
3.A.1.124 The 3-component Peptide-5 Exporter (Pep5E) Family
3.A.1.126 The β-Exotoxin I Exporter (βETE) Family
3.A.1.128 The SkfA Peptide Exporter (SkfA-E) Family
3.A.1.130 The Multidrug/Hemolysin Exporter (MHE) Family
3.A.1.131 The Bacitracin Resistance (Bcr) Family
3.A.1.132 The Gliding Motility ABC Transporter (Gld) Family
3.A.1.133 The Peptide-6 Exporter (Pep6E) Family
3.A.1.138 The Unknown ABC-2-type (ABC2-1) Family
3.A.1.141 The Ethyl Viologen Exporter (EVE) Family (DUF990 Family)
3.A.1.142 The Glycolipid Flippase (G.L.Flippase) Family
3.A.1.143 The Exoprotein Secretion System (EcsAB(C))
3.A.1.144:  Functionally Uncharacterized ABC2-1 (ABC2-1) Family
3.A.1.145:  Peptidase Fused Functionally Uncharacterized ABC2-2 (ABC2-2) Family
3.A.1.146:  The actinorhodin (ACT) and undecylprodigiosin (RED) exporter (ARE) family
3.A.1.147:  Functionally Uncharacterized ABC2-2 (ABC2-2) Family
3.A.1.148:  Functionally Uncharacterized ABC2-3 (ABC2-3) Family
3.A.1.149:  Functionally Uncharacterized ABC2-4 (ABC2-4) Family
3.A.1.150:  Functionally Uncharacterized ABC2-5 (ABC2-5) Family
3.A.1.151:  Functionally Uncharacterized ABC2-6 (ABC2-6) Family
3.A.1.152:  The lipopolysaccharide export (LptBFG) Family
3.A.1.204 The Eye Pigment Precursor Transporter (EPP) Family (ABCG)
3.A.1.205 The Pleiotropic Drug Resistance (PDR) Family (ABCG)
3.A.1.211 The Cholesterol/Phospholipid/Retinal (CPR) Flippase Family (ABCA)
9.B.74      The Phage Infection Protein (PIP) Family
all uptake systems (3.A.1.1 - 3.A.1.34 except 3.A.1.21) 

ABC3:
3.A.1.114 The Probable Glycolipid Exporter (DevE) Family
3.A.1.122 The Macrolide Exporter (MacB) Family
3.A.1.125 The Lipoprotein Translocase (LPT) Family
3.A.1.134 The Peptide-7 Exporter (Pep7E) Family
3.A.1.136 The Uncharacterized ABC-3-type (U-ABC3-1) Family
3.A.1.137 The Uncharacterized ABC-3-type (U-ABC3-2) Family
3.A.1.140 The FtsX/FtsE Septation (FtsX/FtsE) Family
3.A.1.207 The Eukaryotic ABC3 (E-ABC3) Family

Uptake systems are believed to be almost exclusively of the ABC2 type, but they have undergone extensive sequence and topological diversification. The only exception is ABC family 3.A.1.21, the Siderophore-Fe3+ Uptake Transporter (SIUT) Family which is of the ABC1 type. It has no extracytoplasmic receptor as well. 

ABC importers have been divided into two classes: type I importers follow an alternating access mechanism driven by the presence of the substrate, while type II importers accept substrates in a nucleotide-free state, with hydrolysis driving an inward-facing conformation.  RbsABC2 (TC#3.A.1.2.1) seems to share functional traits with both type I and type II importers, as well as possessing unique features, and may employ a distinct mechanism relative to other ABC transporters (Clifton et al. 2014).

Unlike most uptake systems which have one or two functionally equivalent membrane subunits that form a homo- or hetero-dimer and an extracytoplasmic receptor, a subset of these porters have two functionally dissimilar membrane subunits, called S (substrate recognition) and T (transducer) that are very divergent in sequence, and they lack extracytoplasmic receptors (Erkens et al. 2012). This group of ABC2 porters represent a subfamily within the ABC2 uptake systems. This subfamily includes:

ECF:
3.A.1.18 The Cobalt Uptake Transporter (CoT) Family 
3.A.1.22 The Nickel Uptake Transporter (NiT) Family
3.A.1.23 The Nickel/Cobalt Uptake Transporter (NiCoT) Family
3.A.1.25 The Biotin Uptake Transporter (BioMNY) Family
3.A.1.26 The Putative Thiamine Uptake Transporter (ThiW) Family
3.A.1.28 The Queuosine (Queuosine) Family
3.A.1.29 The Methionine Precursor (Met-P) Family
3.A.1.30 The Thiamin Precursor (Thi-P) Family
3.A.1.31 The Unknown-ABC1 (U-ABC1) Family
3.A.1.32 The Cobalamin Precursor (B12-P) Family
3.A.1.33 The Methylthioadenosine (MTA) Family
S-subunits are homologous to:
2.A.87 The Prokaryotic Riboflavin Transporter (P-RFT) Family
2.A.88 The Vitamin Uptake Transporter (VUT or ECF) Family

Karpowich and Wang (2013) characterized the ECF transporters from Thermotoga maritima and Streptococcus thermophilus and determined a subunit stoichiometry of 2S:2T:1A:1A'.  They concluded that S subunits for different substrates can be incorporated into the same transporter complex simultaneously. In the crystal structure of the A-A' heterodimer, each subunit contains a novel motif called the Q-helix that plays a role in subunit coupling with the T subunits. A mechanism for coupling ATP binding and hydrolysis to transmembrane transport by ECF transporters was proposed.

The maltose import transporter is composed of two TM subunits, MalF and MalG, and two subunits of a cytoplasmic ATPase, MalK. Like many uptake systems in Gram-negative bacteria, the periplasmic maltose-binding protein (MBP), is required to stimulate the ATPase activity of the transporter. In the absence of maltose, MBP exists in equilibrium between an open and closed conformation, and binding of maltose stabilizes the closed conformation. Two structures of MalFGK2 have been determined by x-ray crystallography. In the absence of MBP, MalFGK2 forms an inward-facing conformation with the TM maltose-binding site exposed to the cytoplasm. An outward-facing conformation, crystallized in complex with open MBP and ATP, shows that closure of the NBDs of MalK is concomitant with transfer of maltose from MBP to the TM subunits. These structures capture two states in the transport cycle: The inward-facing conformation represents the resting state where the transporter has a very low ATPase activity, and the outward-facing conformation represents a catalytic intermediate where ATP is poised for hydrolysis. Because MBP stimulates ATP hydrolysis and initiates the transport process, it must interact with the resting state conformation to form a 'pretranslocation' complex that is metastable in order to advance to the outward-facing conformation in the presence of ATP (25). Oldham and Chen (2011) presented the crystal structure of the initial complex formed between closed MBP and MalFGK2. As an essential intermediate between the inward- and outward-facing conformations, this structure suggests a mechanism by which substrate bound on the periplasmic surface influences the conformation of the NBDs at the intracellular surface. The same investigators suggested that ABC transporters catalyze ATP hydrolysis via a general base mechanism (Oldham and Chen, 2011).

The homodimeric LmrA drug efflux pump (TC #3.A.1.117.1) of Lactococcus lactis appears to function by an alternating site (half of sites) type mechanism. In many of these porters, the various domains are fused in a variety of combinations. Uptake porters generally have their constituents as distinct polypeptide chains, while efflux systems usually have them fused. ABC-type uptake systems have not been identified in eukaryotes, but ABC-type efflux systems abound in both prokaryotes and eukaryotes. The eukaryotic efflux systems often have the four domains (two cytoplasmic domains and two integral membrane domains) fused into either one or two polypeptide chains. The integral membrane porter domains each usually possesses 5 (uptake) or 6 (efflux) transmembrane spanners, but exceptions exist. For example, the MntB protein (TC #3.A.1.15.1) exhibits 9 established TMSs. The 3-dimensional structure of the E. coli MsbA protein (TC #3.A.1.106.1) has been solved to a resolution of 3.7 Å (Ward et al., 2007), that of the Staphylococcus aureus Sav1866 protein (TC #3.A.1.106.2) has been solved to a resolution of 3.0 Å (Dawson and Locher, 2006), that of the Archaeoglobus fulgidus ModABC complex has been solved at 3.1 Å resolution (Hollenstein et al., 2007), that of the E. coli BtuCDF Vitamin B12 transporter was solved at 2.6 Å resolution (Hvorup et al., 2007), and the maltose transporter has been solved at 2.8 Å resolution (Oldham et al., 2007). These structures are very different, but the two transmembrane domains form a single barrel 5-6 nm in diameter and about 5 nm deep with an entral pore open either to the external or internal surface spanning much of the membrane (Rosenberg et al., 2003). A model has been proposed allowing the channel to open up to the lipid bilayer. A half of sites model in which the two nucleotide binding domains interact in a fashion controlled by substrate binding has also been proposed (Hou et al., 2003; Loo et al., 2003).

Hollenstein et al. (2007) presented the 3.1 Å crystal structure of a putative molybdate transporter (ModB2C2) from Archaeoglobus fulgidus in complex with its binding protein (ModA). Twelve transmembrane helices of the ModB subunits provide an inward-facing conformation, with a closed gate near the external membrane boundary. The ATP-hydrolyzing ModC subunits reveal a nucleotide-free, open conformation, whereas the attached binding protein aligns the substrate-binding cleft with the entrance to the presumed translocation pathway. Structural comparison of ModB2C2A with Sav1866 suggests a common alternating access and release mechanism, with binding of ATP promoting an outward-facing conformation and dissociation of the hydrolysis products promoting an inward-facing conformation. ATP hydrolysis at one of the two sites in ABC transporters initiates transport-related conformational transitions (Gyimesi et al., 2011).

Smriti et al., 2009 mapped residues proximal to the daunorubicin (DNR)-binding site in MsbA (TC#3.A.1.106.1) using site-specific, ATP-dependent quenching of DNR intrinsic fluorescence by spin labels. In the nucleotide-free MsbA intermediate, DNR-binding residues cluster at the cytoplasmic end of helices 3 and 6 at a site accessible from the membrane/water interface and extending into an aqueous chamber formed at the interface between the two transmembrane domains. Binding of a nonhydrolyzable ATP analog inverts the transporter to an outward-facing conformation. DNR may thus enter near an elbow helix parallel to the water/membrane interface, partitioning into the open chamber, and then translocating toward the periplasm upon ATP binding.

The turnover rates of some transporters are inhibited by their substrates in a process termed trans-inhibition. Gerber et al. (2008) presented the crystal structure of a molybdate/tungstate ABC transporter (ModBC) from Methanosarcina acetivorans in a trans-inhibited state. The regulatory domains of the nucleotide-binding subunits proved to be in close contact, providing two oxyanion binding pockets at the shared interface. By specifically binding to these pockets, molybdate or tungstate prevent adenosine triphosphatase activity and lock the transporter in an inward-facing conformation, with the catalytic motifs of the nucleotide-binding domains separated. This allosteric effect prevents the transporter from switching between the inward-facing and the outward-facing states, thus interfering with the alternating access and release mechanism.

The cystic fibrosis transmembrane conductance regulator (CFTR; 3.A.1.202.1) is an ATP-dependent chloride channel. Jordan et al., 2008 compared CFTR protein sequences to those of ABCC4 proteins (the closest mammalian paralogs) to identify the evolutionary transition from transporter to channel activity. R352 in the sixth transmembrane helix interacts with D993 in TM9 to stabilize the open-channel state; D993 is absolutely conserved between CFTRs and ABCC4s. Thus CFTR channel activity evolved, at least in part, by converting the conformational changes associated with binding and hydrolysis of ATP, as are found in true ABC transporters, into an open permeation pathway by means of intraprotein interactions that stabilize the open state.  In general, plant ABC transport systems are more numerous than those in animals.  The maize systems have been categorized and their expression profiles have been determined (Pang et al. 2013).

The LolCDE complex of Escherichia coli (TC# 3.A.1.125.1) initiates the lipoprotein sorting to the outer membrane by catalysing their release from the inner membrane. LolC and/or LolE, membrane subunits, recognize lipoproteins anchored to the outer surface of the inner membrane, while LolD hydrolyses ATP on its inner surface. The ligand-bound LolCDE has been purified from the inner membrane in the absence of ATP (Ito et al., 2006). Liganded LolCDE represents an intermediate of the release reaction and exhibits higher affinity for ATP than the unliganded form. ATP binding to LolD weakens the interaction between LolCDE and lipoproteins and causes their dissociation in a detergent solution, while lipoprotein release from membranes requires ATP hydrolysis. A single molecule of lipoprotein is found to bind per molecule of the LolCDE complex.

The three structurally dissimilar constituents of the ABC uptake porters have generally arisen from a common ancestral porter system with minimal shuffling of constituents between/domain constituents is almost always the same. However the rates of sequence divergences differ drastically with the extracytoplasmic solute-binding receptors diverging most rapidly, the integral-membrane, channel-forming constituents diverging at an intermediate rate, and the cytoplasmic ATP-hydrolyzing constituents diverging most slowly. Thus, all ATP-hydrolyzing constituents are demonstrably homologous, but this is not true for the integral membrane constituents or the receptors. Nevertheless, clustering patterns are generally the same for all three types of proteins, and 3-dimensional structural data suggest that, in spite of their extensive sequence divergence, the extracytoplasmic solute-binding receptors are homologous to each other.

Unlike most of the known ABC transporters, ABCC1 (TC #3.A.1.208.8) has an additional membrane-spanning domain (MSD) at its amino terminus with a domain arrangement of MSD0-MSD1-NBD1-MSD2-NBD2. The additional MSD0 domain consists of five putative transmembrane segments with a predicted extracellular amino terminus. It has a U-shaped folding with the bottom of the U-structure facing cytoplasm and both ends in extracellular space. This U-shaped amino terminus probably functions as a gate to regulate the drug transport activity of human ABCC1 (Chen et al., 2006).

Polar lipid trafficking is essential in eukaryotic cells as membranes of lipid assembly are often distinct from final destination membranes. A striking example is the biogenesis of the photosynthetic membranes (thylakoids) in plastids of plants. Lipid biosynthetic enzymes at the endoplasmic reticulum and the inner and outer plastid envelope membranes are involved. This compartmentalization requires extensive lipid trafficking. Mutants of Arabidopsis disrupt the incorporation of endoplasmic reticulum-derived lipid precursors into thylakoid lipids. Two proteins affected in two of these mutants, trigalactosyldiacylglycerol 1 (TGD1) and TGD2, encode the permease and substrate binding component, respectively, of a proposed lipid translocator at the inner chloroplast envelope membrane. A third protein, TGD3, a small ABC-type ATPase, energizer transport. As in the tgd1 and tgd2 mutants, triacylglycerols and trigalactolipids accumulate in a tgd3 mutant. The TGD3 protein shows basal ATPase activity and is localized inside the chloroplast beyond the inner chloroplast envelope membrane. Proteins orthologous to TGD1, -2, and -3 are predicted to be present in Gram-negative bacteria, and the respective genes are organized in operons suggesting a common biochemical role for the gene products. The Tgd1,2,3 system (TC#3.A.1.27.2) probably transfers ER-derived lipids to the thylakoid membrane (Lu et al., 2007). It is one of the few known eukaryotic uptake systems.

 

Rodionov et al., 2009 identified 21 families of these substrate capture proteins, each with a different specificity predicted by genome context analyses. Roughly half of the substrate capture proteins (335 cases) examined by Rodionov et al., 2009 have a dedicated energizing module, but in 459 cases distributed among almost 100 gram-positive bacteria, different and unrelated substrate capture proteins share the same energy-coupling module. The shared use of energy-coupling modules was experimentally confirmed for folate, thiamine, and riboflavin transporters. Rodionov et al., 2009 proposed the name energy-coupling factor transporters for the new class of putative ABC membrane transporters. These membrane proteins are homologues to ABC-2 exporters. When evidence is minimal for association with an ABC-type ATP-hydrolyzing subunit, these porters are placed in category 2.A (secondary carriers; e.g., 2.A.88).

Canonical ABC importers play important roles in cell integrity, environmental stresses, cell-to-cell communication, cell differentiation and pathogenicity. An ABC sub-superfamily of micronutrient importers, the 'energy-coupling factor' (ECF) transporters, use ABC ATPases. Fundamental differences between tranditional ABC and ECF porters include the modular architecture and the independence of ECF systems of extracytoplasmic solute-binding proteins. Eitinger et al. (2011) review the roles of both types of transporters in diverse physiological processes including pathogenesis. They also point out the differences and similarities in modular assembly and their traits.

The uptake porters of the ABC superfamily and of the vitamin/small molecule transporters described by Rodionov et al., 2009 are homologous to the porters in the VUT family (2.A.88). In fact, studies indicated that all uptake porters of the ABC superfamily are of the ABC2 type (Zheng et al. 2013). When evidence suggests that homologous membrane transport proteins of the ABC2 type couple transport to ATP hydrolysis using a homologue of the ABC-type ATPases, we list these proteins in the ABC superfamily. If there is no such evidence, (e.g., experimental evidence and the occurrence of the gene for the membrane transporter protein is in an operon that lacks the ATPase and auxillary subunit) then the porter is placed into family 2.A.88.

Ter Beek et al. (2011) have determined the subunit stoichiometry and functional unit of the energy coupling factor (ECF)-type of ABC transporters (Rodionov et al., 2009). ECF transporters consist of a conserved energizing module (two peripheral ATPases and the integral membrane protein EcfT) and an integral membrane protein responsible for substrate specificity (S-component). S-components for different substrates  may associate with the same energizing module. The energizing module from Lactococcus lactis has been shown to form stable complexes with each of the eight predicted S-components found in this organism. Using light scattering, EcfT, the two ATPases (EcfA and EcfA'), and the S-component were found to be present in a stoichiometric 1:1:1:1 ratio. The complexes were reconstituted in proteoliposomes and shown to mediate ATP-dependent transport. ECF-type transporters are the smallest known ABC transporters.

Energy coupling factor (ECF) transporters are a subgroup of ATP-binding cassette (ABC) transporters involved in the uptake of vitamins and micronutrients in prokaryotes. In contrast to classical ABC importers, ECF transporters do not make use of water-soluble substrate binding proteins or domains but instead employ integral membrane proteins for substrate binding (S-components or EcfS). S-components form active translocation complexes with the ECF module, an assembly of two nucleotide-binding domains (NBDs, or EcfA) and a second transmembrane 'energy transducer' protein, EcfT. In many cases, the ECF module can interact with several different S-components that bind diverse substrates. The modular organization with exchangeable S-components on a single ECF module allows the transport of chemically different substrates via a common route. The determination of the crystal structures of the S-components that recognize thiamin and riboflavin provided clues about the mechanism of S-component exchange. Erkens et al. (2012) described current views of the transport mechanism by ECF transporters.

Some ABC exporters act on protein substrates. Export depends on the ABC transporter, a periplasmic 'adapter', the membrane fusion proteins (MFPs; 8.A.1) and an outer membrane factor (OMF; 1.B.17). Assembly of the tripartite complex can be transient and induced upon binding of the substrate to the ABC protein. Masi & Wandersman (2010) showed that in addition to the C-terminal targeting sequence, many additional signals throughout the substrate protein facilitate secretion. Interaction of the C-terminal 'targeting' signal activates the ATPase activity, causing disassembly of the complex. Thus, the proposed 'targeting' motif may signal dissociation rather than targeting (Masi & Wandersman et al., 2010). Dassa and Bouige (2001) have devised a phylogenetic/functional classification system for ABC transporters that overlaps the TC system. In their system, several of the TC families are included in single families. These reveal the closer phylogenetic relationship of TC families as follows:

Jones & George (2012) reported molecular dynamics simulations of the ATP/apo and ATP/ADP states of the bacterial ABC exporter Sav1866 (TC#3.A.1.106.2). Conformers of the active site have a canonical geometry for an in-line nucleophilic attack on the ATP γ-phosphate. The conserved glutamate immediately downstream of the Walker B motif is the catalytic base, forming a dyad with the H-loop histidine, while the Q-loop glutamine has an organising role. Each D-loop provides a coordinating residue of the attacking water, and comparison with the simulation of the ATP/ADP state suggested that via their flexibility, the D-loops modulate formation of the hydrolysis-competent state. A global switch involving a coupling helix delineates the signal transmission route by which allosteric control of ATP hydrolysis in ABC transporters is mediated. 

Binding of ATP to the nucleotide binding domains (NBDs) of ABC proteins drives the dimerization of NBDs, which, in turn, causes large conformational changes within the transmembrane domains.  NBD dimerization proceeds with a large gain of water entropy when ATP molecules bind to the NBDs. The energetic gain arising from direct NBD-NBD interactions is canceled by the dehydration penalty and the configurational-entropy loss. ATP hydrolysis induces a loss of the shape complementarity between the NBDs, which leads to the dissociation of the dimer, due to a decrease in the water-entropy gain and an increase in the configurational-entropy loss (Hayashi et al. 2014).

ABC proteins play critical roles in maintaining lipid and sterol homeostasis in higher eukaryotes. In human, several subfamily-A and -G members function as cholesterol transporters across the cellular membranes. Deficiencies of these ABC proteins can cause dyslipidemia that is associated with health conditions such as atherosclerosis, diabetes, fatty liver disease, and neurodegeneration (Xavier et al. 2018). The physiological roles of ABC cholesterol transporters have been implicated in mediating cholesterol efflux for reverse cholesterol transport and in maintaining membrane integrity for cell survival.  The membrane constituents of ABC transporters may play key roles in determining the transport substrates and the translocation mechanisms via the transmembrane domains. High resolution structures of human sterol transporter ABCG5/G8 and its functional homologs have shed light on the structural features of ABC transporters. Xavier et al. 2018 outlined what is known about ABCG cholesterol transporters, addressed key structural features in the putative sterol translocation pathway on the transmembrane domains, and concluded by proposing a mechanistic model of ABC cholesterol transporters.

ABC peptide/protein exporters are usuallly believed to export their substrates directly from the cytoplasm to the extracellular medium without a periplasmic intermediate.  However, a subgroup of systems, linked with a bacterial transglutaminase-like cysteine proteinase (BTLCP) apparently uses a two-step secretion mechanism. BTLCP-linked T1SSs transport a class of repeats-in-toxin (RTX) adhesins that are critical for biofilm formation. The prototype of this RTX adhesin group, LapA of Pseudomonas fluorescens Pf0-1, uses a novel N-terminal retention module to anchor the adhesin at the cell surface as a secretion intermediate threaded through the outer membrane-localized TolC-like protein LapE. This secretion intermediate is posttranslationally cleaved by the BTLCP family LapG protein to release LapA from its cognate T1SS pore. Thus, the secretion of LapA and related RTX adhesins into the extracellular environment appears to be a T1SS-mediated two-step process that involves a periplasmic intermediate (Smith et al. 2018).

Dassa and Bouige (2001) suggest the protein and domain organization of each of the various family-type proteins (see Table 1).

Table 1
D&B Family TC Families
Uptake
MOI SulT, + PhoT + MolT + FeT + POPT + ThiT
OTCN QAT + NitT + TauT
ISVH VB12 + FeCT
Export
DPL Lipid E + Glucan E + Prot1E + Prot2E + Pep1E + Pep2E + Pep3E + DrugE2 + DrugE3 + MDR + CFTR + Ste + TAP + HMT + MPE
OAD CT1 + CT2
EPD EPP + PDR
DRA DrugE1 + CPR
DRI NatE
CLS CPSE + LPSE + TAE

The generalized transport reaction for ABC-type uptake systems is:

Solute (out) + ATP → Solute (in) + ADP + Pi.

The generalized transport reaction for ABC-type efflux systems is:

Substrate (in) + ATP → Substrate (out) + ADP + Pi.



This family belongs to the ABC1, ABC2, ABC3 Superfamilies.

 

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3.A.1.1 The Carbohydrate Uptake Transporter-1 (CUT1) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.1.1

Maltooligosaccharide porter. The 3-D structure has been reported by Oldham et al. (2007). An altering access mechanism has been suggested for the maltose transporter resulting from rigid-body rotations (Khare et al., 2009). Bordignon et al. (2010) and Schneider et al. (2012) have reviewed the extensive knowledge available on MalEFGK2, its mode of action and its regulatory interactions.  The transporter sequesters the MalT transcriptional activator at the cytoplasmic surface of the membrane in the absence of the transport substrate (Richet et al. 2012).  The crystal structures of the transporter complex MBP-MalFGK2 bound with large malto-oligosaccharide in two different conformational states have also been determined. In the pretranslocation structure, Oldham et al. 2013 found that the transmembrane subunit MalG forms two hydrogen bonds with malto-oligosaccharide at the reducing end. In the outward-facing conformation, the transmrembrane subunit MalF binds three glucosyl units from the nonreducing end. These structural features explain why large modified malto-oligosaccharides are not transported by MalFGK2 despite their high binding affinity to MBP. In the transport cycle, substrate is channeled from MBP into the transmembrane pathway with a polarity such that both MBP and MalFGK2 contribute to the overall substrate selectivity of the system (Oldham et al. 2013).  Stabilization of the semi-open MalK2 conformation by maltose-bound MBP is key to the coupling of maltose transport to ATP hydrolysis in vivo, because it facilitates the progression of the MalK dimer from the open to the semi-open conformation, from which it can proceed to hydrolyze ATP (Alvarez et al. 2015). Both the binding of MalE to the periplasmic side of the transmembrane complex and binding of ATP to MalK2 are necessary to facilitate the conformational change from the inward-facing state to the occluded state, in which MalK2 is completely dimerized (Hsu et al. 2017). An integrated transport mechanism of the maltose ABC importer has been proposed (Mächtel et al. 2019).

Proteobacteria

MalEFGK of E. coli
MalE (receptor [R])
MalF (membrane [M])
MalG (membrane [M])
MalK (cytoplasmic [C])

 
3.A.1.1.10

Alginate (MW 27,000 Da) (and Alginate oligosaccharides) uptake porter. Sphingomonas species A1 is a 'pit-forming' bacterium that directly incorporates alginate into its cytoplasm through a pit-dependent transport system, termed a 'superchannel' (Murata et al., 2008). The pit is a novel organ acquired through the fluidity and reconstitution of cell surface molecules, and through cooperation with the transport machinery in the cells. It confers upon bacterial cells a more efficient way to secure and assimilate macromolecules (Murata et al., 2008).  The substrate-transport characteristics and quaternary structure of AlgM1M2SS with AlgQ1 have been determined (Maruyama et al. 2015). The addition of poly- or oligoalginate enhanced the ATPase activity of reconstituted AlgM1M2SS coupled with one of the periplasmic solute-binding proteins, AlgQ1 or AlgQ2. External fluorescence-labeled oligoalginates were specifically imported into AlgM1M2SS-containing proteoliposomes in the presence of AlgQ2, ATP, and Mg2+. The crystal structure of AlgQ2-bound AlgM1M2SS adopts an inward-facing conformation. The interaction between AlgQ2 and AlgM1M2SS induces the formation of an alginate-binding tunnel-like structure accessible to solvent. The translocation route inside the transmembrane domains contains charged residues suitable for the import of acidic saccharides (Maruyama et al. 2015).

Proteobacteria

AlgSM1M2Q1Q2 of Sphingomonas sp.A1
AlgS (C)
AlgM1 (M)
AlgM2 (M)
AlgQ1 (R)
AlgQ2 (R)

 
3.A.1.1.11

Saturated and unsaturated oligogalacturonide transporter, TogMNAB (transports di- to tetrasaccharide pectin degradation products which consist of D-galacuronate, sometimes with 4-deoxy-L-threo-5-hexosulose uronate at the reducing end of the oligosaccharide) (Hugouvieux-Cotte-Pattat et al. 2001). Regulated by pectin utilization regulator KdgR (Rodionov et al. 2004)

Proteobacteria

Oligogalacturonide transporter TogMNAB of Erwinia chrysanthemi
TogM (M)
TogN (M)
TogA (C)
TogB (R)

 
3.A.1.1.12Palatinose (isomaltulose; 6-O-α-D-glucopyranosyl-D-fructose) uptake porterProteobacteriaPalEFGK of Erwinia rhapontici
PalE (R)
PalF (M)
PalG (M)
PalK (C)
 
3.A.1.1.13Glucose, mannose, galactose porterCrenarchaeotaGlcSTUV of Sulfolobus solfataricus
GlcS (R)
GlcT (M)
GlcU (M)
GlcV (C)
 
3.A.1.1.14Arabinose, fructose, xylose porterCrenarchaeotaAraSTUV of Sulfolobus solfataricus
AraS (R)
AraT (M)
AraU (M)
AraV (C)
 
3.A.1.1.15Trehalose porterCrenarchaeotaTreSTUV of Sulfolobus solfataricus
TreS (R)
TreT (M)
TreU (M)
TreV (C)
 
3.A.1.1.16Maltooligosaccharide porter (Maltose is not a substrate, but maltotriose is.)EuryarchaeotaPF1933, 1936, 1937, 1938 of Pyrococcus furiosus
PF1938 (R)
PF1937 (M)
PF1936 (M)
PF1933 (C)
 
3.A.1.1.17Trehalose/maltose/sucrose porter (trehalose inducible)ProteobacteriaThuEFGK of Sinorhizobium meliloti
ThuE (R)
ThuF (M)
ThuG (M)
ThuK (C)
 
3.A.1.1.18N-Acetylglucosamine/N,N'-diacetyl chitobiose porter (NgcK (C) not identified)ActinobacteriaNgcEFG of Streptomyces olivaceoviridis
NgcE (R)
NgcF (M)
NgcG (M)
 
3.A.1.1.19Platinose (isomaltulose) (6-O-α-D-glucopyranosyl-D-fructofuranose) porterProteobacteriaPalEFGK of Agrobacterium tumefaciens
PalE (R)
PalF (M)
PalG (M)
PalK (C)
 
3.A.1.1.2

The galactooligosaccharide (transports the di, tri and tetrasaccharides) uptake porter GanOPQ (GanSPQ; MalEFG) functioning with the energizing ATPase MsmX (see 3.A.1.1.26).  These oligosaccharides are derived from galactans and arabinogalactans, compenents of pectins in plant cell walls (Watzlawick et al. 2016).

Bacteria

GanOPG of Bacillus subtilis
YufK, GanO or GanS (R) (O07009)
YufL or GanP (M) (O32261)
YufM or GanQ (M) (O07011)

MsmX (C) (see 3.A.1.1.26)

 
3.A.1.1.20The fructooligosaccharide porter, MsmEFGK (Barrangou et al., 2003) BacteriaMsmEFGK of Lactobacillus acidophilus
MsmE (R) AAO21856
MsmF (M) AAO21857
MsmG (M) AAO21858
MsmK (C) AAO21860
 
3.A.1.1.21The xylobiose porter; BxlEFG(K) (Tsujibo et al., 2004)BacteriaBxlEFGK of Streptomyces thermoviolaceus
BxlE (R) CAB88161
BxlF (M) CAB88162
BxlG (M) CAB88163
BxlK (C) Unknown
 
3.A.1.1.22

The maltose, maltotriose, mannotetraose (MalE1)/maltose, maltotriose, trehalose (MalE2) porter (Nanavati et al., 2005). For MalG1 (823aas) and MalG2 (833aas), the C-terminal transmembrane domain with 6 putative TMSs is preceded by a single N-terminal TMS and a large (600 residue) hydrophilic region showing sequence similarity to MLP1 and 2 (9.A.14; e-12 & e-7) as well as other proteins.

Thermotogae

MalE1E2FGK of Thermotoga maritima
MalE1 (R) (binds maltose, maltotriose and mannotetraose) (AAD36279)
MalE2 (R) (binds maltose, maltotriose and trehalose) (AAD36901)
MalF1 (M) (AAD36278)
MalG1 (M) (AAD36277)
[MalG2 (M) (AAD36899]
MalK (C) (AAD36351)

 
3.A.1.1.23

The cellobiose/cellotriose (and possibly higher cellooligosaccharides), CebEFGMsiK [MsiK functions to energize several ABC transporters including those for maltose/maltotriose and trehalose] (Schlösser et al., 1997, Schlösser et al., 1999)

Bacteria

CebEFGMsiK of Streptomyces reticuli
CebE (R) (CAB46342)
CebF (M) (CAB46343)
CebG (M) (CAB46344)
MsiK (CAA70125)

 
3.A.1.1.24The glucose/mannose porter TTC0326-8 plus MalK1 (ABC protein, shared with 3.A.1.1.25) (Chevance et al., 2006).Bacteria

TTC0326-8 MalK1 of Thermus thermophilus
TTC0326 (M) - Q72KX4
TTC0327 (M) - Q72KX3
TTC0328 (R) - Q72KX2
MalK1 or TTC0211 (C) - Q72L52

 
3.A.1.1.25The trehalose/maltose/sucrose/palatinose porter (TTC1627-9) plus MalK1 (ABC protein, shared with 3.A.1.1.24) (Chevance et al., 2006).BacteriaTTC1627-9 + MalK1 of Thermus thermophilus
TTC1627 (R) (Q72H68)
TTC1628 (M) (Q72H67)
TTC1629 (M) (Q72H66)
MalK1 (TTC0211) (C) (Q72L52)
 
3.A.1.1.26

The maltose porter, MdxEFG and MsmX (Ferreira and Sá-Nogueira, 2010)

Bacteria

The maltose porter of Bacillus subtilis, MalEFG/MsmX.
MalE (R) - O06989
MalF (M) - O06990
MalG (M) - O06991
MsmX (C) - P94360

 
3.A.1.1.27

Maltose/Maltotriose/maltodextrin (up to 7 glucose units) transporters MalXFGK (MsmK (3.A.1.1.28) can probably substitute for MalK; Webb et al., 2008).

Bacteria

MalXFGK of Streptococcus mutans:
MalX (R) (Q8DT28)
MalF (M) (Q8DT27)
MalG (M) (Q8DT26)
MalK (C) (Q8DT25)

 
3.A.1.1.28

The raffinose/stachyose transporter, MsmEFGK (MalK (3.A.1.1.27) can probably substitute for MsmK; Webb et al., 2008).

Bacteria

MsmEFGK of Streptococcus mutans:
MsmE (R) (Q00749)
MsmF (M) (Q00750)
MsmG (M) (Q00751)
MsmK (C) (Q00752)

 
3.A.1.1.29Aldouronate transporter, LplA,B,C (Chow et al., 2007)BacteriaLplABC of Paenibacillus sp. JDR-2:
LplA (R)(A9QDR6)
LplB (M)(A9QDR7)
YtcP (M)(A9QDR8)
LplC - not identified
 
3.A.1.1.3

Glycerol-phosphate porter. Transports both glycerol-3-P and glycerol-3-P diesters including glycerophosphocholine but not glycerol-2-P (Yang et al. 2009; Wuttge et al. 2012).  UgpB (the receptor) binds glycerol 3-P with high affinity, but not glycerol 2-P (Wuttge et al. 2012).

Proteobacteria

UgpABCE of E. coli
UgpB (R)
UgpA (M)
UgpE (M)
UgpC (C)

 
3.A.1.1.30

Glucose porter, GtsABCD (del Castillo et al., 2008).  The orthologue of GtsA (receptor) in P. aeruginosa (64% identical to the P. putida GtsA has been biochemically characterized (Stinson et al. 1977) and corresponds to the sequence with UniProt acc# Q9HZ48 (Friedhelm Pfeiffer, personal communication).

Bacteria

The glucose porter of Pseudomonas putida, GtsABCD:
GtsA (R) (Q88P38)
GtsB (M) (Q88P37)
GtsC (M) (Q88P36)
GtsD (C) (Q88P35)

 
3.A.1.1.31

The trehalose-recycling ABC transporter, LpqY-SugA-SugB-SugC (essential for virulence) (Kalscheuer et al., 2010).

Bacteria

LpqY-SugA-SugB-SugC of Mycobacterium tuberculosis
LpqY (R) (Q7D8J9)
SugA (M) (O50452)
SugB (M) (O50453)
SugC (C) (O50454)

 

 
3.A.1.1.32The glucosylglycerol uptake transporter (functions in osmoprotection and also transports sucrose and trehalose (Mikkat and Hagemann, 2000) (most similar to 3.A.1.1.8).BacteriaGgtABCD of Synechocystis sp. strain PCC6803
GgtA (C) (Q55035)
GgtB (R) (Q55471)
GtC (M) (Q55472)
GgTD (M) (Q55473)
 
3.A.1.1.33

The N,N'-diacetylchitobiose uptake transporter, DasABC/MsiK (MsiK energizes several ABC transporters (see 3.A.1.1.23)) (Saito et al., 2008).

Bacteria

DasABC MsiK of Streptomyces coelicolor
DasA (R) (Q8KN19)
DasB (M) (Q8KN18)
DasC (M) (Q8KN17)
MsiK (C) (Q9L0Q1)

 
3.A.1.1.34

The arabinosaccharide transporter AraNPQMsmX. Transports α-1,5-arabinooligosaccharides, at least up to four L-arabinosyl units; the key transporter for α-1,5-arabinotriose and α-1,5-arabinotetraose, but not for α-1,5-arabinobiose which is transported by AraE. MsmX is also used by the MdxEFG-MsmX system (3.A.1.1.36) (Ferreira and Sá-Nogueira, 2010). Involved in the uptake of pectin oligosaccharides with either MsmX or YurJ as the ATPase (Ferreira et al. 2017).

Bacteria

AraNPQ-MsmX of Bacillus subtilis 
AraN (R) (P94528) 
AraP (M) (P94529)
AraQ (M) (P94530)
MsmX (C) (P94360) 

 
3.A.1.1.35

Glycerol uptake porter, GlpSTPQV (Ding et al., 2012).

  α-proteobacteria

GlpSTPQV of Rhizobium leguminosarum 
GlpS (C) (G3LHY8)
GlpT (C) (G3LHY9)
GlpP (M) (G3LHZ0)
GlpQ (M) (G3LHZ1)
GlpV (R) (G3LHZ3) 

 
3.A.1.1.36

Putative transport system

Actinobacteria



Q93J94 (R)
Q93J93 (M)
Q93J92 (M)
Q9L0Q1 (C?)

 
3.A.1.1.37

Predicted arabinoside porter. Regulated by arabinose-responsive regulator AraR (Rodionova et al. 2012).

Thermotogae

AraEFG of Thermotoga maritima
AraE (R) (TM0277) -
AraF (M) (TM0278) Q9WYB4
AraG (M) (TM0279) Q9WYB5

 
3.A.1.1.38

Inositol phosphate porter (Rodionova et al. 2013). Binds inositol phosphate with low Kd and inositol with a lower affinity.

Thermotogae

InoEFGK of Thermotoga maritima
InoE (R) TM0418 (Q9WYP9)
InoF (M) TM0419 (Q9WYQ0)
InoG (M) TM0420 (Q9WYQ1)
InoK (C) TM0421 (Q9WYQ2)

 
3.A.1.1.39

Alpha-1,4-digalacturonate porter (Nanavati et al., 2006). Regulated by pectin utilization regulon UxaR (Rodionova et al. 2012).

Thermotogae

AguEFG of Thermotoga maritima
AguE (R) (TM0432) (Q9WYR3)
AguF (M) (TM0431) (Q9WYR2)
AguG (M) (TM0430) (Q9WYR1)

 
3.A.1.1.4Lactose porterProteobacteriaLacEFGK of Agrobacterium radiobacter
LacE (R)
LacF (M)
LacG (M)
LacK (C)
 
3.A.1.1.40

Predicted chitobiose porter. Regulated by chitobiose-responsive regulator ChiR (Kazanov et al., 2012).

Thermotogae

ChiEFG of Thermotoga maritima
ChiE (R) (TM0810) (Q9WZR7)
ChiF (M) (TM0811) (Q9WZR8)
ChiG (C) (TM0812) (Q9WZR9)

 
3.A.1.1.41

Trehalose porter. Also binds sucrose (Boucher and Noll, 2011). Induced by glucose and trehalose. Directly regulated by trehalose-responsive regulator TreR (Kazanov et al., 2012).

Thermotogae

TreG (M) (ThemaDRAFT_1378) G4FGN6

TreF (M) (ThemaDRAFT_1379) G4FGN7

TreE (R) (ThemaDRAFT_1380) G4FGN8

 
3.A.1.1.42

α-glucoside uptake permease, Agl3E/Agl3F/Agl3G. Plays a role in normal morphogenesis and antibiotic production. Strongly induced by trehalose and melibiose, and weakly induced by lactose and glycerol but not glucose (Hillerich and Westpheling 2006).The operon is controlled by a GntR homologue, Agl3R, and downstream of the gntR gene is a gene encoding an extracellular carbohydrase.

Actinobacteria

Agl2E/3F/3G of Streptomyces coelicolor
Agl3E (R); 425aas (Q9FBS5)
Agl3F (M) 6TMSs; 310aas (Q9FBS6)
Agl3G (M) 7TMSs; 303aas (Q9FBS7)
(ABC protein (C) not identified) 

 
3.A.1.1.43

Agl3E, Agl3F and Agl3G ABC porter. Induced by trehalose and melibiose using a GntR-like transcription factor (Hillerich and Westpheling 2006).  The ATPase subunit, Agl3K, may be the MsiK (Sco4240; see 3.A.1.1.33) protein (Saito et al. 2008).

Actinobacteria

Agl3EFG (Sco7167-5) of Streptomyces coelicolor.
Agl3E (R)
Agl3F (M)
Agl3G (M)
Agl3K (unknown)  

 
3.A.1.1.44

MalEFG (K unknown), involved in maltose and maltodextrin uptake (van Wezel et al. 1997).  The MalK protein may be the MsiK (Sco4240; Q9L0Q1; see 3.A.1.1.33) protein.

Actinobacteria

MalEFG (Sco2231-29) of Streptomyces coelicolor.
MalE (R)
MalF (M)
MalG (M)
 

 
3.A.1.1.45

Maltose transporter, MusEFGKI.  All five genes have been reported to be essential for uptake activity (Henrich et al. 2013).  The MusI gene product is of 215 aas with 5 TMSs and comprises the founding member of a distinct family of poorly characterized protein in TC family 9.B.28. 

Actinobacteria

MusEFGKI of Corynebacterium glutamicum

 
3.A.1.1.46

Probable glucoside uptake porter, YcjNOPV.  Encoded in an operon or gene cluster with a glucosyl hydrolase and two oxidoreductases (Moussatova et al. 2008).

Proteobacteria

YcjNOPV of E. coli
YcjN (R) (430 aas)
YcjO (M) (293 aas)
YcjP (M) (280 aas)
YcjV (C) (360 aas)

 
3.A.1.1.47

ABC-type fucose uptake porter FucABCD.  The ATPase subunit, FucD, has not been identified (Manzoor I., Shafeeq S., Afzal M. and Kuipers OP, JMMB, in press, 2015).

Firmicutes

FucABCD of Streptococcus pneumoniae
FucA, (R)
FucB, (M)
FucC, (M)

 
3.A.1.1.48

The lacto-N-biose I (LNB; Gal β-1,3-GlcNAc)/galacto-N-biose (GNB; Gal β-1,3-GalNAc) transporter.  The solute-binding protein crystallizes only in the presence of LNB or GNB, and it was therefore named GNB/LNB-binding protein (GL-BP) (Wada et al. 2007; Suzuki et al. 2008; Asakuma et al. 2011). Isothermal titration calorimetry measurements revealed that GL-BP specifically binds LNB and GNB with K(d) values of 0.087 and 0.010 μM, respectively, and the binding process is enthalpy-driven. The crystal structures of GL-BP complexed with LNB, GNB, and lacto-N-tetraose (Galbeta1-3GlcNAcbeta1-3Galbeta1-4Glc) were determined.  The MalF and MalG membrahe proteins are encoded adjacent to the gene for GL-BP, but the ATPase was not identified.

Actinobacteria

The LNB/GNB uptake transporter of Bifidobacterium longum
MalE homologue
MalF homologue
MalG homologue
MalK homologue, not identified.

 
3.A.1.1.49

The polyol (mannitol, glucitol (sorbitol), arabitol (arabinitol; lyxitol)) uptake porter, MtlEFGK (Brünker et al. 1998).

MtlEFGK of Pseudomonas fluorescens
MtlE, R, 436 aas
MtlF, M, 296 aas
MtlG, M, 276 aas
MtlK, C, 367 aas

 
3.A.1.1.5Hexitol (glucitol; mannitol) porterProteobacteriaSmoEFGK of Rhodobacter sphaeroides
SmoE (R)
SmoF (M)
SmoG (M)
SmoK (C)
 
3.A.1.1.50

Probable glycerophosphocholine (GPC) uptake porter (Chandravanshi et al. 2016). The system may include a receptor and three membrane proteins (of 378 aas and 6 TMSs, 299 aas and 7 TMSs, and 113 aas and 3 TMSs (?). The ATPase has not been identified.

GPC uptake porter of Thermus thermophilus

 
3.A.1.1.51

Maltose - maltoheptose transporter, MalEFGK .  MalEF is a R-M fusion protein with the MalE domain N-terminal and the MalF domain C-terminal. The protein, of 733 aas, has 8 TMSs, one N-terminal to MalE (a signal sequence for export of the MalE domain to the periplasm), an extra TMS at the N-terminus to bring the N-terminus to the periplasmic side of the inner membrane, and then the usual 6 TMSs observed for most ABC membrane proteins.  MalG (M, 272 aas, 6 TMSs) and MalK (C, 374 aas) are of normal size and composition. While MalE of E. coli was able to additionally increase ATPase activity of MalFGK2Bb in vitro, the isolated MalE domain of B. bacteriovorus failed to stimulate the E. coli system (Licht et al. 2018).

MalEF/MalG/MalK of Bdellovibrio bacteriovorus
MalEF, R-M, 733 aas, 8 TMSs
MalG, M, 272 aas, 6 TMSs
MalK, C, 374 aas

 
3.A.1.1.52

Sugar (sucrose, maltose, glucose, fructose, esculin (coumarin β-glucoside)) uptake system possibly consisting of 5 or 6 proteins (see below) (Nieves-Morión and Flores 2017). These proteins are all implicated in sugar uptake, but they may include components of multiple transporters. The system may also regulate formation of septal nanopores (Flores et al. 2018).

Sugar uptake porter of Nostoc (Anabaena) strain PCC7120
GlsR, MalE-like, All1916, 418 aas and 1 N-terminal TMS (R) (Q8YVQ8)
GlsQ, MalF-like, Alr2532, 301 aas and 6 TMSs (M) (Q8YU29)
GlsP, MalG-like, All0261, 276 aas and 6 TMSs (M) (Q8Z042)
GlsC, MalK-like, Alr4781, 432 aas and 0 TMSs (C) (Q8YMZ3)
GlsD, MalK-like, All1823, 366 aas and 0 TMSs (C) (Q8YVZ3)

 
3.A.1.1.53

Oligosaccharide transporter RafEFGK. RafE, the binding protein, has be extensively characterized.  It binds α-(1,6)-linked glucosides and galactosides of varying size, linkage, and monosaccharide composition with preference for the trisaccharides raffinose and panose. This preference is reflected in the α-(1,6)-galactoside uptake profile of the bacterium. Structures of RafE (BlG16BP) in complex with raffinose and panose revealed the basis for the ligand binding plasticity, which recognizes the non-reducing α-(1,6)-diglycosidic linkages in its ligands (Ejby et al. 2016). RafK has not be identified experimentally, but it may be NCIB protein acc# WP_022543180.1, ATP binding protein, annotated as UgpC, and this protein has been enterred into TCDB as RafK. Sugar binding substrates of RafE include: raffinose (highest affinity), panose, melibiose, stachyose, verbascose, isomaltose, isomaltotriose, isomaltotetraose, isomaltopentaose, isomaltohexaose, and isomaltoheptaose (Ejby et al. 2016).

RafEFGK of Bifidobacterium animalis
RafE, (R) D3R799; 439 aas and 1 N-terminal TMS
RafF, (M) D3R798;  330 aas and 6 TMSs
RafG, (M) D3R797; 301 aas and 6 TM
RafK (C) WP_022543180.1, 377 aas and 0 TMSs.

 
3.A.1.1.54

Putative ABC sugar uptake porter with 4 constituents which unlike other members of this subfamily, has two large membrane proteins of 16 - 18 TMSs.

ABC porter of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)
OLS24721 R, 427 aas
OLS20027, M, 641 aas and 16 putative TMSs
OLS20028, M, 779 aas and 18 putative TMSs
OLS20029, C, 379 aa

 
3.A.1.1.55

Four comoponent ABC uptake porter, possibly transporting mannosyl glycerate.  The four components of this system and a potential mannosyl glycerate hydrolase are encoded within a single operon.

Putative mannosy glycerate transporter
R, 428 aas and 1 N-terminla TMS, D7BAR7
M, 281 aas and 6 TMSs, D7BAR6
M, 266 aas and 6 TMSs, D7BAR5
C, ATPase, cytoplasmic, D7BAR4

 
3.A.1.1.56

Uptake transport system for L-arabinose and D-xylose, XacGHIJK (Johnsen et al. 2019). The system has a receptor, two 6 TMS membrane proteins and two ATPases.  xacGHIJK is upregulated by growth in the presence of either D-xylose or L-arabinose, mediated by the transcriptional regulator, XacR, the general regulator of xac catabolic genes (Johnsen et al. 2019).

XacGHIJK of Halofax volcanii

 
3.A.1.1.6Cyclodextrin porterProteobacteriaCymDEFG of Klebsiella oxytoca
CymE (R)
CymF (M)
CymG (M)
CymD (C)
 
3.A.1.1.7Maltose/trehalose porterEuryarchaeotaMalEFGK of Thermococcus litoralis
MalE (R)
MalF (M)
MalG (M)
MalK (C) (not sequenced)
 
3.A.1.1.8Sucrose/maltose/trehalose porter (sucrose-inducible)ProteobacteriaAglEFGK of Sinorhizobium meliloti
AglE (R)
AglF (M)
AglG (M)
AglK (C)
 
3.A.1.1.9

The oligosaccharide (glucuronate-linked to a xylo-oligosaccharide) ABC uptake porter, GuoEFGK in AguEFGK. GuoE binds with high affinity a four sugar aldotetrouronic
acid [2-O-α-(4-O-methyl-α-D-glucuronosyl)-xylotriose] (Shulami et al., 1999; S.Shulami, personal communication)

Bacteria

GuoEFGK of Geobacillus stearothermophilus
AguE or GuoE (R) (C9RT46)
AguF or GuoF (M) (Q09LY7)
AguG or GuoG (M) (Q09LY6)
AguK or GuoK (C) (not identified)

 


3.A.1.10 The Ferric Iron Uptake Transporter (FeT) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.10.1Ferric iron (Fe3+) porterProteobacteriaSfuABC of Serratia marcescens
SfuA (R)
SfuB (M)
SfuC (C)
 
3.A.1.10.2Ferric iron (Fe3+) porterCyanobacteriaFut A1A2BC of SynechocystisPCC6803
FutA1 (R)
FutA2 (R)
FutB (M)
FutC (C)
 
3.A.1.10.3

Ferric iron (Fe3+) porter (selective for trivalent cations, Fe3+, Ga3+ and Al3+) (Anderson et al., 2004)

Proteobacteria

FbpABC (HitABC) of Haemophilus influenzae
FbpA (R) (AAC21773)
FbpB (M) (AAC21774)
FbpC (C) (AAC21775)

 
3.A.1.10.4

The Fe-hydroxamate-type siderophore uptake porter (transports Fe+3 bound to ferrioxamine, ferrichrome or pyoverdine siderophores) (Vajrala et al., 2010).

Bacteria

NitABC of Nitrosomonas europaea
NitA (R) (Q82VN7)
NitB (M) (Q82VN6)
NitC (C) (Q82VN5)

 
3.A.1.10.5

Siderophore-independent iron uptake system, AfuABC (Saken et al. 2000).

Proteobacteria

AfuABC of Yersinia enterocolitica
AfuA (R)
AfuB (M)
AfuC (C)

 
3.A.1.10.6

Fe3+ uptake porter consisting of 3 subunits, R, 330 aas, M, 516 aas and 12 TMSs, and C, 350 aas (Mandal et al. 2019).

Fe3+ uptake porter of Thermus thermophilus with 3 subunits.

 


3.A.1.101 The Capsular Polysaccharide Exporter (CPSE) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.101.1Capsular polysaccharide exporterGram-negative bacteriaKpsMT of E. coli KpsM
KpsM (M) - (P24584)
KpsT (C) - (P24586)
 
3.A.1.101.2Vi polysaccharide exporter, VexBC (Hashimoto et al, 1993).Gram-negative bacteriaVexBC of Salmonella typhi
VexB (M) - (P43109)
VexC (C) - (P43110)
 
3.A.1.101.3

Capsular polysialate exporter, CtrC/D (functions with 1.B.18.2.3 (OMA) and 1.B.4.2.1 (MPA2)) (Larue et al., 2011).

Bacteria

CtrABCD of Neisseria meningitidis
CtrC (M) (B3FHE1)
CtrD (C) (B3FHE0) 

 


3.A.1.102 The Lipooligosaccharide Exporter (LOSE) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.102.1Lipooligosaccharide exporter (nodulation proteins, NodIJ)Gram-negative bacteriaNodIJ of Rhizobium galegae
NodJ (M)
NodI (C)
 


3.A.1.103 The Lipopolysaccharide Exporter (LPSE) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.103.1Lipopolysaccharide exporterGram-negative bacteriaRfbAB of Klebsiella pneumoniae
RfbA (M)
RfbB (C)
 
3.A.1.103.2

Heteropolysaccharide O-antigen exporter, Wzm/Wzt (Feng et al., 2004). The C-terminal cytoplasmic domain of Wzt (an IgG-like β-sandwich) determines the specificity of the transporter for either O8 or O9a O-PS (Cuthbertson et al., 2007). The transporter structure reveals a continuous transmembrane channel in a nucleotide-free state (Caffalette et al. 2019). Upon ATP binding, large structural changes within the nucleotide-binding and transmembrane regions push conserved hydrophobic residues at the substrate entry site towards the periplasm and provide a model for polysaccharide translocation. With ATP bound, the transporter forms a large transmembrane channel with openings toward the membrane and periplasm. The channel's periplasmic exit is sealed by detergent molecules that block solvent permeation. Molecular dynamics simulation data suggest that, in a biological membrane, lipid molecules occupy this periplasmic exit and prevent water flux in the transporter's resting state (Caffalette et al. 2019).

Gram-negative bacteria

Wzm/Wzt of E. coli
Wzm (M) (AAS99164)
Wzt (C) (AAS99165)

 
3.A.1.103.3

ABC transporter required for O-antigen biosynthesis and multicellular development, RfbAB (Guo et al. 1996). Functions with the RfbC glycosyl transferase (TC#4.D.1.3.4). 

Proteobacteria

RfbAB of Myxococcus xanthus 
RfbA (M) 260aas (Q50862)
RfbB (C) 437aas (Q50863) 

 
3.A.1.103.4

RfbAB lipopolysaccharide exporter (Guo et al. 1996).

Proteobacteria

RfbAB of Myxococcus xanthus.
RfbA (MXAN_4623) (M)
RfbB (MXAN_4622) (C) 

 
3.A.1.103.5

ABC transporter mediating ethanol tolerance, Slr0977 (M)/Slr0982 (C) (Zhang et al. 2015).  Present in a gene cluster with (lipo)polysaccharide biosynthetic enzymes, so could be a cell surface carbohydrate export system.

Cyanobacteria

Ethanol tolerance transporter of Synechocystis sp. (strain PCC 6803 / Kazusa)

 
3.A.1.103.6

Two component lipopolysaccharide exporter, Wzm/Wzt.  Wzm is the membrane component (265 aas with 6 TMSs) which forms a ring-like large ion conductance channel. The ATPase, Wzt, functions both as the energizer and regulator (Mohammad et al. 2016).

Wzm/Wzt of Pseudomonas aeruginosa

 
3.A.1.103.7

ABC-type polysaccharide/polyol phosphate export systems, permease componentof 262 aas and 6 or 7 TM

Transporter of Acidovorax sp. MR-S7

 
3.A.1.103.8

ABC transporter of 258 aas and 6 TMSs.

ABC transporter of Moranbacteria bacterium

 
3.A.1.103.9

ABC O-antigen lipopolysaccharide/polysaccharide export transporter, Wzm/Wzt of 253 aas and 6 TMSs (Wzm; also called AbcT3) and 396 aas and 0 TMSs (Wzt). The crystal structure is available (PDB 6AN7) (Bi et al. 2018) for the Wzm-Wzt homologue from Aquifex aeolicus in an open conformation. The transporter forms a transmembrane channel that is sufficiently wide to accommodate a linear polysaccharide. Its nucleotide-binding domain and a periplasmic extension form 'gate helices' at the cytosolic and periplasmic membrane interfaces that probably serve as substrate entry and exit points (Bi et al. 2018).

Wzm/Wzt of Aquifex aeolicus

 


3.A.1.104 The Teichoic Acid Exporter (TAE) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.104.1

Teichoic acid exporter, TagGH.  Appears to be present in a large complex with the teichoic acid precursor synthetic enzymes (Formstone et al. 2008).  The substrate may be the diphospholipid-linked disaccharide portion of the teichoic acid precursor (Schirner et al. 2011).  3-d structural studies have been reported (Ko et al. 2016). TagG and TagH are localized on the cytoplasmic membrane in a patch, and the TMS of TagH is important for normal transport activity (Yamada et al. 2018).

Gram-positive bacteria

TagGH of Bacillus subtilis
TagG (M)
TagH (C)

 
3.A.1.104.2

The teichoic acid precursor exporter, TarGH. May be specific for the diphospholipid linked disaccharide portion of the teichoic acid precursor (Schirner et al. 2011). TarG is the target of a small antimicrobial inhibitor of S. aureus growth (Swoboda et al. 2009). TarGH is a WTA transporter and has been purified and reconstituted in proteoliposomes (Matano et al. 2017). They showed that a new compound series inhibits TarH-catalyzed ATP hydrolysis even though the binding site maps to TarG, near the opposite side of the membrane. These are the first ABC transporter inhibitors to block ATPase activity by binding to the transmembrane domain.

Firmicutes

TarGH of Staphylococcus aureus 
TarG (M) (D1GQ18)
TarH (C) (D1GQ17) 

 


3.A.1.105 The Drug Exporter-1 (DrugE1) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.105.1

Daunorubicin, doxorubicin etc. (multidrug resistance) exporter, DrrAB.  DrrB binds drugs with variable affinities and contains multiple drug binding sites. The two asymmetric nucleotide binding sites in DrrA have strikingly different binding affinities. Long-range conformational changes occur between DrrA and DrrB. The transduction pathway from the nucleotide-binding DrrA subunit to the substrate binding DrrB subunit includes the Q-loop and CREEM motifs in DrrA and the EAA-like motif in DrrB (Rahman and Kaur 2018).

Gram-positive bacteria

DrrAB of Streptomyces peucetius
DrrA (C), 330 aas
DrrB (M), 283 aas and 6 TM

 
3.A.1.105.10

AbcG homologue, ABCH1 of 705 aas and 6 TMSs in a C-M arrangement.  May be involved in steroid or drug efflux (Popovic et al. 2010).  Of the vertbrates, it may be restricted to fish. 

Animals

AbcH1 (C-M) of Danio rerio

 
3.A.1.105.11

ABC-2 transporter probably specific for a lantibiotic.  The genes for this system are adjacent to an S2P-M50 peptidase (G0Q3D2), probably involved in pro-lantibiotic processing, as well as a lantibiotic biosynthetic enzyme (G0Q3D1) and a lantibiotic dehydratase (G0Q3D0). 

Actinobacteria

ABC-2/ATPase of Streptomyces griseus
ABC-2 (M) (G0Q3D4)
ATPase (C) (G0Q3D3)

 
3.A.1.105.12

ABC-2 transporter with ABC ATPase

Archaea

ABC transporter
ABC2 (M) (F8D412)
ABC ATPase (C) (F8D413) 

 
3.A.1.105.13

SclAB (Sco4359-60) (Gominet et al. 2011).

Actinobacteria

SclAB of Streptomyces coelicolor.
SclA (C)
SclB (M)

 
3.A.1.105.14

RagAB, involved in both aerial hyphae formation and sporulation (San Paolo et al. 2006).

Actinobacteria

RagAB of Streptomyces coelicolor.
RagA: Sco4075 (C)
RagB: Sco4074 (M) 

 
3.A.1.105.15

Putative drug exporter, YbhFGRS (Moussatova et al. 2008).

Proteobacteria

YbhFGRS of E. coli
YbhF, (C) (578 aas)
YbhG, (MFP) (332 aas)
YbhR, (M) (368 aas)
YbhS, (M) ((377 aas)

 

 
3.A.1.105.16

Putative ABC export system (MDR?), RbbA/YhhJ/YhiI (All three genes are in a single operon; this system may comprise a single ABC exporter with MFP; substrate unknown (Moussatova et al. 2008 and unpublished observations).

Proteobacteria


RbbA/YhhJ/YhiI of E. coli
RbbA (C-M; 911 aas; C8TJS4)
YhhJ (M; 374 aas; P0AGH1)
YhiI (MFP; 355 aas; P37626)

 
3.A.1.105.17

The putative polyketide drug exporter, YadGH.  May also transport phospholipids, participating in phospholipid trafficking together with the Mla complex. It interacts with MlaABCDEF (TC# 3.A.1.27.3) to preserve outer membrane asymmetry (Malinverni and Silhavy 2009; Babu et al. 2018).

Proteobacteria

YadGH of E. coli
YadG (C; 308 aas)
YadH (M, 256 aas)

 
3.A.1.105.19

Poorly characterized ABC exporter involved in bacterial competitiveness and bioflim morphology, YfiLMN (Stubbendieck and Straight 2017).

YfiLMN of Bacillus subtilis
YfiL (C) 311 aas, 0 TMSs
YfiM (M) 296 aas, 6 TMSs
YfiN (N) 385 aas, 6 TMSs

 
3.A.1.105.2Oleandomycin (drug resistance) exporterGram-positive bacteriaOleC4-OleC5 of Streptomyces antibioticus
OleC4 (C)
OleC5 (M)
 
3.A.1.105.20

Putative 5 component ABC exporter with two membrane constituents, two cytoplasmic ATPases, and one membrane fusion protein (truncated at the N-terminus, probably because of an incorrect initiation codon assignment).

5-component ABC exporter of Bdellovibrio bacteriovorus
Q6MLX4 (M)
Q6MLX5 (M)
Q6MLX6 (C)
Q6MLX7 (C)
Q6MLX8 (MFP)

 
3.A.1.105.21

Uncharacterized ABC transporter with two components, a transmembrane protein with 6 TMSs and an ATPase. The substrate in unknown.

ABC system of Candidatus Saccharibacteria bacterium

 
3.A.1.105.22

Uncharacterized protein pair of a presumed ABC transporter. One is of 280 aas and 7 putative TMSs; the other is of 275 aas and 6 putative TMSs. The genes encoding these two proteins map adjacent to each other.  The ATPase has not been identified.

UP of Candidatus Eisenbacteria bacterium RBG_16_71_46 (subsurface metagenome)

 
3.A.1.105.23

Putative ABC exporter with two consitutents, M is of 256 aas and 6 TMSs; C is of 317 aas.  The genes encoding these two proteins are adjacent to each other.

ABC exporter of Armatimonadetes bacterium (groundwater metagenome)

 
3.A.1.105.24

Putative ABC exporter with two membrane constituents encoded by adjacent genes.  The ATPase does not map adjacent to these genes and has not been identified.

Putative ABC exporter of Methanomassiliicoccus sp.

 
3.A.1.105.25

ATP-binding cassette transporter subfamily Gof 687 aas and 7 TMSs in a 1 + 6 TMS arrangement. 13 ABCG genes were identified in N. lugens, and expression levels of these ABCG transporter genes after treatment with thiamethoxam, abamectin, and cyantraniliprole has been examined.  Some increase in amounts while others do not (Yang et al. 2019).

ABCG of Nilaparvata lugens (Brown plant leafhopper)

 
3.A.1.105.3The 4A-4E-O-dideacetyl-chromomycin A3 (biosynthetic precursor of chromomycin) exporter (may also export chromomycin and mithramycin (Menendez et al., 2007).Gram-positive Bacteria CmrAB of Streptomyces greseus
CmrA(C) (Q70J75)
CmrB(M) (Q70J76)
 
3.A.1.105.4

The pyoluteorin (a chlorinated polyketide) efflux pump, PltHIJKN (Brodhagen et al. 2005; Huang et al. 2006).

γ-Proteobacteria

PltHIJKN of Pseudomonas sp. M18:
PltH (336aas; MFP) - (Q4VWD0)
PltI (589aas; C-C) - (Q4VWC9)
PltJ (377aas; M; COG0842; similar to 9.B.74.2 (ABC-2)) - (Q4VWC8)
PltK (372aas; M; The C-terminal hydrophobic half has 5TMSs and is most similar to PltJ, and then to 9.B.74.2, but it is also homologous to 3.A.1.105.2 and 3.A.1.102.1) - (Q4VWC7)
PltN (480aas; OMF) - (Q4VWC6)

 
3.A.1.105.5

AbcG homologue

Animals

AbcG homologue of Drosophia melanogaster

 
3.A.1.105.6

The ABC-2-like transporter

Bacteria

ABC-2-like transporter of Dehalococcoides ethenogenes
ABC2 protein (M) (Q3Z8A7)
ATPase (C) (Q3Z8A8)

 
3.A.1.105.7

Putative ABC2 tranport system, SagGHI; may export streptolysin S.

Firmicutes

Putative Streptolysin ABC2 tranport system, SagGHI.
SagG (C) (Q9A0K0)
SagH (M) (Q9A0J9)
SagI (M) (Q9A0J8)

 
3.A.1.105.8

ABC-2 transporter.  The two genes encoding this system are adjacent to one encoding an squalene-hopene cyclase that coverts squalene to hopene.  The substrate could therefore be hopene or a hydrocarbon triterpene derivative of it (Racolta et al. 2012).

Planctomycetes

ABC2 membrane protein (Q7UE57) and ATPase (Q7UE58) of Rhodopirellula baltica

 
3.A.1.105.9

ABC2 membrane proteins (J7ZHK9 and J8A8S6) with ATPase (J8ABC0) transporter

Firmicutes

ABC2 transporter of Bacillus cereus

 


3.A.1.106 The Lipid Exporter (LipidE) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.106.1

Phospholipid, LPS, lipid A and drug exporter, MsbA, which flips the substrate from the inner leaflet of the cytoplasmic membrane to the outer leaflet (Eckford and Sharom, 2010). MsbA also confers drug resistance to azidopine, daunomycin, vinblastine, Hoechst 33342 and ethidium (Reuter et al., 2003). Four x-ray structures, trapped in different conformations, two with and two without nucleotide, have been solved (Ward et al., 2007). They suggest an alternating accessibility mode of transport with major conformational changes.  The mechanism and conformational transitions have been discussed (Moradi and Tajkhorshid 2013).  MsbA is energized both by ATP hydrolysis and the H+ electrochemical gradient (Singh et al. 2016). Mi et al. 2017 used single-particle cryo-electron microscopy to elucidate the structures of lipid-nanodisc-embedded MsbA in three functional states. The 4.2 Å-resolution structure of the transmembrane domains of nucleotide-free MsbA revealed that LPS binds deeply inside MsbA at the height of the periplasmic leaflet. Two sub-nanometre-resolution structures of MsbA with ADP-vanadate and ADP revealed a closed and an inward-facing conformation, respectively. A  2.9 A resolution structure of MsbA in complex with G907, a selective small-molecule antagonist with bactericidal activity, revealed an unanticipated mechanism of ABC transporter inhibition. G907 traps MsbA in an inward-facing, lipopolysaccharide-bound conformation by wedging into an architecturally conserved transmembrane pocket. A second allosteric mechanism of antagonism occurs through structural and functional uncoupling of the nucleotide-binding domains (Ho et al. 2018). Coupled ATPase-adenylate kinase activity in ABC transporters including MsbA has been demonstrated (Kaur et al. 2016).

Gram-negative bacteria

MsbA (M-C) of E. coli

 
3.A.1.106.10

Involved in the export of a molecule required for the autochemotactic process. AbcA integrated permease/ATPase (M-C) protein, MXAN_1286 (Ward et al. 1998). 

Proteobacteria

MXAN_1286 (M-C) of Myxococcus xanthus.

 
3.A.1.106.11

HlyA/MsbA family transporter of 595 aas.  The gene for this protein is adjacent to and probably in the same operon as that encoding 3.A.1.106.12.  They both have 6 TMSs, so they may together comprise a single heterodimeric system. 

Cyanobacteria

ABC exporter of Gloeobacter violaceus

 
3.A.1.106.12

HlyA/MsbA family transporter of 577 aas.  The gene encoding this protein is adjacent to and in the same operon with that encoding 3.A.1.106.11.  They both have 6 TMSs, so they may together comprise a single heterodimeric system. 

Cyanobacteria

ABC exporter of Gloeobacter violaceus

 
3.A.1.106.13

Multidrug resistance-like ABC exporter, MdlAB; exports peptides of 6 - 21 aas (Moussatova et al. 2008).

Proteobacteria

MdlAB of E. coli
MdlA (M-C; 590 aas)
MdlB (M-C; 593 aas)

 
3.A.1.106.14

Lipid A exporter homologue of 593 aas and 6 TMSs (N-terminal with a C-terminal ATPase domain.  Essential for acid, salt and thermal tolerance (Matsuhashi et al. 2015).

Exporter of Synechocystis sp. PCC6803

 
3.A.1.106.15

Lipid flippase, PglK or WlaB, of 564 aas and 6 N-terminal TMSs with a C-terminal ATPase domain.  Mediates the ATP-dependent translocation of an undecaprenylpyrophosphate-linked heptasaccharide intermediate across the cell membrane, an essential step during the N-linked protein glycosylation pathway. Transport across the membrane is effected via ATP-driven conformation changes. Most likely, only the polar and charged part of the glycolipid enter the substrate-binding cavity, and the lipid tail remains exposed to the membrane lipids during the transmembrane flipping process (Alaimo et al. 2006; Kelly et al. 2006; Perez et al. 2015).

PglK (M-C) of Campylobacter jejuni

 
3.A.1.106.16

Probable integral membrane protein NMA1777 with 6 TMSs in a 2 + 2 + 2 arrangement, ; function and ATPase unknown.

UP of Klebsiella pneumoniae

 
3.A.1.106.17

ABC1 transporter

transporter of Acidobacterium capsulatum

 
3.A.1.106.18

Peptide and multidrug resistance porter of the ABC superfamily, TmrAB. TmrA (Q72J05; 600 aas with 6 N-terminal TMSs) and TmrB (Q72J04; 578 aas with 6 N-terminal TMSs) comprise this heterodimeric transporter, both proteins of the M-C structure.  The system has been found to export the dye, hoechst 33342, and to be inhibited by verapamil (Zutz et al. 2011). The subnanometre-resolution structure of detergent-solubilized TmrAB in a nucleotide-free, inward-facing conformation by single-particle electron cryomicroscopy has been solved (Kim et al. 2015). A cavity in the transmembrane domain is accessible laterally from the cytoplasmic side of the membrane as well as from the cytoplasm, indicating that the transporter lies in an inward-facing open conformation. The two nucleotide-binding domains remain in contact via their carboxy-terminal helices. Comparison between this structure and those of other ABC transporters suggests a possible trajectory of conformational changes that involves a sliding and rotating motion between the two nucleotide-binding domains during the transition from the inward-facing to outward-facing conformations (Kim et al. 2015). A subset of annular lipids is normally invariant in composition, with negatively charged lipids binding tightly to TmrAB, suggesting that this exporter may be involved in glycolipid translocation (Bechara et al. 2015). Coupled ATPase-adenylate kinase activity in ABC transporters including TmrAB has been demonstrated (Kaur et al. 2016). A 2.7-Å X-ray structure of TmrAB has been determined. It not only shares structural homology with the antigen translocation complex TAP, but is also able to restore antigen processing in human TAP-deficient cells. TmrAB exhibits a broad peptide specificity and can concentrate substrates several thousandfold, using only one single active ATP-binding site. It adopts an asymmetric inward-facing state, and the C-terminal helices, arranged in a zipper-like fashion, play a role in guiding the conformational changes associated with substrate transport (Nöll et al. 2017). Conformational coupling and trans-inhibition have been characterized (Barth et al. 2018).

TmrAB of Thermus thermophilus

 
3.A.1.106.19

ABC exporter.  It has been suggested that it might be a glycolate exporter (Braakman et al. 2017). However it's closest hit in TCDB (31% identity in the transmembrane domain) has TC# 3.A.1.106.18, which is probably a peptide/multidrug (and possibly glycolipid) exporter with broad substrate specificity. 

ABC exporter of Prochlorococcus marinus

 
3.A.1.106.2

The homodimeric Sav1866 multidrug exporter (transports doxorubicin, verapamil, ethidium, tetraphenylphosphonium, vinblastine and the fluorescent dye, Hoechst 33342; 3-D structure known at 3 Å resolution; Dawson and Locher, 2006; Velamakanni et al., 2008) The empty site opens by rotation of the nucleotide-binding domain whereas the ATP-bound site remains occluded (Jones and George, 2011). Conformational changes induced by ATP-binding and hydrolysis have been proposed (Becker et al. 2010; Oliveira et al., 2011). The alternating access mechanism and the flippase activity of this ABC exporter has been shown to be lipid-dependent (Immadisetty et al. 2019).

Gram-positive Bacteria

Sav1866 of Staphylococcus aureus (M-C) 2HYDA/2HYDB (578 aas)

 
3.A.1.106.20

MsbA of 582 aas and 6 TMSs in an M-C arrangement.  The X-ray structure at 2.8 Å resolution in an inward-facing conformation after cocrystallization with lipid A and using a stabilizing facial amphiphile has been reported (Padayatti et al. 2019). The structure displays a large amplitude opening in the transmembrane portal, which is likely to be required for lipid A to pass from its site of synthesis into the protein-enclosed transport pathway. Putative lipid A density is observed further inside the transmembrane cavity, consistent with a trap and flip model. Additional electron density attributed to lipid A is observed near an outer surface cleft at the periplasmic ends of the transmembrane helices (Padayatti et al. 2019). This protein is 96% identical to the E. coli ortholog, TC# 3.A.1.106.1.

MsbA of Salmonella enterica

 
3.A.1.106.3

The dimeric multidrug resistance exporter, ABC1/2 (exports the peptide antimicrobials, nisin and polymyxin; (Margolles et al., 2006) (both ABC1 and ABC2 also show striking similarity to family 3.A.1.117).

Gram-positive Bacteria

ABC1/2 of Brevibacterium longum:
ABC-1 (M-C) (ZP_00121338)
ABC-2 (M-C) (ZP_00121339)

 
3.A.1.106.4The duplicated ABC transporter, CgR_1214 (1247 aas; MC(poorly conserved) MC(well conserved))BacteriaCgR_1214 of Corynebacterium glutamicum (MCMC) (A4QD95)
 
3.A.1.106.5The heterodimeric multidrug efflux pump, SmdAB (exports norfloxacin, tetracycline, 4',6-diamidino-2-phenylindole (DAPI), and Hoechst 33342) (Matsuo et al., 2008).BacteriaSmdAB of Serratia marcescens:
SmdA (M-C) (A7VN01)
SmdB (M-C) (A7VN02)
 
3.A.1.106.6Multidrug efflux pump, Rv0194 (exports & causes resistance to ampicillin, streptomycin and chloramphenicol by 32- to 64-fold and to vancomycin and tetracycline by 4- to 8-fold (Danilchanka et al., 2008)).BacteriaRv0194 of Mycobacterium tuberculosis (MCMC) (O53645)
 
3.A.1.106.7

The Salmochelin/Enterobactin secretory exporter, IroC (Crouch et al., 2008; Müller et al. 2009).

Bacteria

IroC of Salmonella enterica (MCMC) (Q8RMB7)

 
3.A.1.106.8

The heterodimeric BmrC/BmrD (YheHI) MDR transporter.  Transports a wide range of structurally unrelated drugs including doxorubicin, mitoxantrone, ethidium, and hoechst 33342 (Torres et al., 2009). It activates the sensor kinase, KinA, during sporulation initiation (Fukushima et al. 2006). Large scale purification has been achieved (Galián et al. 2011).  It has been reconstituted in giant unilamellar vesicles (Dezi et al. 2013).  It exhibits an asymmetric configuration of catalytically inequivalent nucleotide binding sites. The two-state transition of the TMS domains, from an inward- to an outward-facing conformation, may be driven exclusively by ATP hydrolysis (Mishra et al. 2014).

Bacteria

BmrC/BmrD (YheHI) of Bacillus subtilis
YheH (M-C) (O07549)
YheI (M-C) (O07550)

 
3.A.1.106.9

SoxR regulon single protein ABC exporter, Sco7008, containing an N-terminal membrane domain and a C-terminal ATPase domain (Shin et al. 2011). SoxR responds to extracellular redox-active compounds.  Thus, it is induced in stationary phase during the production of the benzochromanequinone blue-pigmented antibiotic, actinorhodin (Naseer et al. 2014). Possibly an actinorhodin exporter.

Actinobacteria

Sco7008 (M-C) of Streptomyces coelicolor.

 


3.A.1.107 The Putative Heme Exporter (HemeE) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.107.1Putative heme exporter, CcmABC=CycVWZ (Note: CcmC may function independently of CcmAB) (Feissner et al., 2006; Christensen et al., 2007)Gram-negative bacteriaCycVWZ of Bradyrhizobium japonicum
CycV (C)
CycW (M)
CycZ (M)
 
3.A.1.107.2The mitochondrial ABC transporter involved in cytochrome c maturation, CcmA/CcmB. (Note: CcmA is nuclearly encoded while CcmB is mitochondrially encoded) (Rayapuram et al., 2007) Plant Mitochondria

CcmA/CcmB of Arabidopsis thaliana
CcmA (C) (Q9C8T1)
CcmB (M) (P93280)

 
3.A.1.107.3

CcmABCD exporter; CcmD (69aas, 1TMS) is required for the release of CcmE (which binds heme in the periplasm) from CcmABC. CcmC (9.B.14.2.3) is required for the transfer of heme to CcmE in the periplasm (Richard-Fogal et al., 2008) In the presence of heme, CcmC and CcmE form a stable complex (Richard-Fogal & Kranz, 2010) as do CcmE and CcmF (San Francisco and Kranz 2014).

Proteobacteria

CcmABCD of E. coli
CcmA (C) (Q8XE58)
CcmB (M; 7 TMSs) (P0ABM0)
CcmC (M; 6 TMSs) (P0ABM1)
CcmD (M; 1 TMS) (P0ABM7)

 
3.A.1.107.4

Cytochrome c maturation system (heme exporter?), CcmA/B

γ-Proteobacteria

CcmAB of Pseudomonas virdiflava
CcmA (C) (K6BJ24)
CcmB (M) (K6BIH6)

 


3.A.1.108 The β-Glucan Exporter (GlucanE) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.108.1β-Glucan exporterGram-negative bacteriaNdvA (M-C) of Rhizobium meliloti
 


3.A.1.109 The Protein-1 Exporter (Prot1E) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.109.1

α-Hemolysin exporter. HlyB has an (inactive?) N-terminal C39 peptidase-like domain (Lecher et al., 2011).  It is essential for secretion and interacts with the unfolded HlyA, thereby protecting it from cytoplasmic degradation (Lecher et al. 2012).

Gram-negative bacteria

HlyB (M-C) of E. coli

 
3.A.1.109.2

Cyclolysin exporter, CyaB (Glaser et al., 1988) (Possesses an N-terminal lysosomal sorting signal within the amino-terminal transmembrane domain; Kamakura et al., 2008).

Gram-negative bacteria

CyaB (M-C) of Bordetella pertussis

 
3.A.1.109.3LapA adhesin protein exporter, LapB (Hinsa et al., 2003)BacteriaLapB of Pseudomonas putida
LapB (MC) (AAN65800)
 
3.A.1.109.4

The biofilm inducible ABC drug (tobramycin, gentamycin, and ciprofloxacin) resistance pump, PA1875-PA1877 (Zhang and Mah, 2008).  It is specifically induced and is most active when  growing in a biofilm.

Proteobacteria

PA1875-PA1877 of Pseudomonas aeruginosa
PA1875 (OMF; 425 aas) (Q9I2M2)
PA1876 (ABC; M-C; 723 aas) (Q9I2M1)
PA1877 (MFP; 395 aas) (Q9I2M0)

 
3.A.1.109.5

Probable giant non-fimbrial adhesin, SiiE, exporter, SiiFDC.  SiiF interacts with SiiAB (TC# 1.A.30.4.1) which probably forms a proton channel homologous to that of MotAB (TC# 1.A.30.1.1) and facilitates energization of SiiE export using the pmf (Wille et al. 2013).

Proteobacteria

SiiFDC of Salmonella enterica
SiiF (M-C; 688 aas; E1WEV2)
SiiD (MFP; 425 aas; E1WEV0)
SiiC (OMF; 439 aas; E1WEU9)

 
3.A.1.109.6

Probable 2646 aa extracellular adhesin (acc# C6BWI7) ABC exporter of 715 aas.  Functions as a type I protein secretion system together with an MFP and an OMF which all are encoded within a single operon together with the adhesin and SiiAB homologues as for TC# 3.A.1.109.5.

Proteobacteria

ABC/MFP/OMF type I protein secretion system of Desulfovibrio salexigens
ABC protein (M-C; 715 aas; C6BWI0)
MFP protein (430 aas; C6BWj0)
OMF protein (513 aas; C6BWI6)

 
3.A.1.109.8

Leukotoxin export protein of 707 aas, LtxB (has a fused M-C structure with 6 TMSs) (Guthmiller et al. 1995). Functions with the MFP, LtxD (TC# 8.A.1.3.4) and the TolC-like protein, TdeA (TC# 1.B.17.3.11).

Leukotoxin exporter of Aggregatibacter (Actinobacillus; Haemophilus) actinomycetemcomitans

 


3.A.1.11 The Polyamine/Opine/Phosphonate Uptake Transporter (POPT) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.11.1

Polyamine (putrescine/spermidine) uptake porter.  Plays a role in biofilm formation (Zhang et al. 2013).  Spermidine-preferring (Igarashi and Kashiwagi 1996).

Proteobacteria

PotABCD of E. coli
PotA (C)
PotB (M)
PotC (M)
PotD (R)

 
3.A.1.11.10

The 3-component polyamine uptake transporter, PotABD. Transports homospermidine and possibly other polyamines. Inactivation of the potADB gene cluster (potADB) disrupted diazotrophic growth, clearly suggesting the importance of polyamine homeostasis in Anabaena. (Burnat et al. 2018). 

PotABD of Anabaena variabilis

 
3.A.1.11.2

Putrescine porter (Igarashi and Kashiwagi 1996).

Proteobacteria

PotGHIF of E. coli
PotG (C)
PotH (M)
PotI (M)
PotF (R)

 
3.A.1.11.3Mannopine porterProteobacteriaMotABCD of Agrobacterium tumefaciens plasmid pTi15955
MotA (R)
MotB (C)
MotC (M)
MotD (M)
 
3.A.1.11.4Chrysopine porterProteobacteriaChtGHIJK of Agrobacterium tumefaciens
ChtG (C)
ChtH (R)
ChtI (R)
ChtJ (M)
ChtK (M)
 
3.A.1.11.52-aminoethyl phosphonate porterProteobacteriaPhnSTUV of Salmonella typhimurium
PhnS (R)
PhnT (C)
PhnU (M)
PhnV (M)
 
3.A.1.11.6The γ-aminobutyrate (GABA) uptake system, GtsABCD (White et al., 2009).

Bacteria

GtsABCD of Rhizobium leguminosarum
GtsA (R) (Q1M7Q4)
GtsB (M) (Q1M7Q3)
GtsC (M) (Q1M7Q2)
GtsD (C) (Q1M7Q1)

 
3.A.1.11.7

The spermidine/putrescine uptake porter, PotABCD (Shah et al. 2008; Shah et al. 2006; Ware et al. 2006).

Firmictues

PotABCD of Streptococcus pneumoniae
PotA (C) 385 aas
PotB (M) 275 aas (also called PotH)
PotC (M) 257 aas
PotD (R) 356 aas

 
3.A.1.11.8

The spermine/spermidine uptake porter, PotABCD.

Firmicutes

PotABCD of Staphylococcus aureus
PotA (C)
PotB (M)
PotC (M)
PotD (R)

 

 
3.A.1.11.9

Putative polyamine (spermidine/putrescine) uptake porter, YdcSTUV (Moussatova et al. 2008). May also be involved in the uptake of double stranded DNA (Sun 2018).

Proteobacteria

YdcSTUV of E. coli
YdcS (R; 381 aas)
YdcT (C; 337 aas)
YdcU (M; 313 aas)
YdcV (M; 264 aas)

 


3.A.1.110 The Protein-2 Exporter (Prot2E) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.110.10The AlgE-type Mannuronan C-5-Epimerase exporter, EexD (PrtD) (Gimmestad et al., 2006).Bacteria

EexD of Azotobacter vinelandii (C1DS84)

 
3.A.1.110.11

Secretion system for metalloprotease, PrtA, PrtDEF (Akatsuka et al. 1997). (PrtF=1.B.17.1.2)

Gram-negative bacteria

PrtDEF of Erwinia chysanthemi 
PrtD (M-C) (P23596)
PrtE (MFP) (P23597) 

 
3.A.1.110.12

Thermostable lipase, TliA (Q9ZG91; 476 aas with a C-terminal region that shows similarity to members of the RTX toxin family (1.C.11)) exporter, TliDEF.  The wild type transporter has a temperature sensitive defect which can be corrected by a single mutation in TliD (Eom et al. 2016).

TliDEF of Pseudomonas fluorescens
TliD, 578 aas (M-C) and 6 N-terminal TMSs
TliE, 433 aas (MFP)
TliF, 481 aas (OMF)

 
3.A.1.110.13

Protein export system, PrtD of 564 aas and 6 TMSs. The 3.15 Å structure has been solved (Morgan et al. 2017).  The structure suggests a substrate entry window just above the transporter's nucleotide binding domains. Highly kinked transmembrane helices, which frame a narrow channel, not observed in canonical peptide transporters, are likely involved in substrate translocation. The PrtD structure supports a polypeptide transport mechanism distinct from alternating access (Morgan et al. 2017).

PrtD of Aquifex aeolicus

 
3.A.1.110.3The multiple protein exporter, PrsD/PrsE (exports EPS glycanases, PlyA and PlyB, as well as Rhizobium adhering proteins) (Russo et al., 2006). 12 substrates have been identified; PrsDE provide the major route of protein export in R. leguminosarum (Krehenbrink and Downie, 2008).Gram-negative bacteriaPrsD/PrsE of Rhizobium leguminosarum
PrsD(M-C) (O05693)
PrsE(MFP) (O05694)
 
3.A.1.110.4Alkaline protease exporterGram-negative bacteriaAprD (M-C) of Pseudomonas aeruginosa
 
3.A.1.110.5S-layer protein exporterGram-negative bacteriaRsaD (M-C) of Caulobacter crescentus
 
3.A.1.110.6

Exporter for lipase LipA, protease PrtA and S-layer protein SlaA, LipBCD (Akatsuka et al. 1997).   LipABC is also called PrtDEF.

Gram-negative bacteria

LipBCD of Serratia marcescens
LipB (M-C) (Q54456)
LipC (MFP) (Q54457)
LipD (OMF) (O87950)

 
3.A.1.110.7

Exporter for heme-binding protein, HasA and metaloprotease, PrtA.  Functions as a complex spanning the two membranes of the cell envelope: HasDEF (HasD = ABC protein; HasE = the MFP; HasF = the OMF (see 2.A.6.2.31 for HasF) (Akatsuka et al. 1997).

Gram-negative bacteria

HasDEF of Serratia marcescens
HasD (M-C) (Q53368)
HasE (MFP) (Q57387)
HasF (OMF) (Q54452) 

 

 
3.A.1.110.8Surface layer protein exporterGram-negative bacteriaSapD (M-C) of Campylobacter fetus
 
3.A.1.110.9Exporter of HasA lipase, and alkaline proteaseGram-negative bacteriaHasD (M-C) of Pseudomonas fluorescens
 


3.A.1.111 The Peptide-1 Exporter (Pep1E) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.111.1Hemolysin/bacteriocin (cytolysin) exporter with associated proteolytic activityGram-positive bacteriaCylT (M-C) (CylB) of Enterococcus faecalis
 
3.A.1.111.2Subtilin (toxic peptide) exporterGram-positive bacteriaSpaB (M-C) of Bacillus subtilis
 
3.A.1.111.3Nisin exporterGram-positive bacteriaNisT (M-C) of Lactococcus lactis
 
3.A.1.111.4Bacteriocin immunity protein, SmbG (198 aas; 6TMSs in a 2+2+2 arrangement. (Exports bacteriocins and causes resistance to antibiotics such as tetracycline, penicillin and triclosan). Upregulated by exposure to antibiotics (Matsumoto-Nakano and Kuramitsu, 2006)Gram-positive bacteriaSmbG (M-C) of Streptococcus mutans (Q5TLL2)
 
3.A.1.111.5The lacticin Q exporter, LcnDR3 (Yoneyama et al., 2009).

Gram-positive bacteria

LcnDR3 (M-C) of Lactococcus lactis (P37608)

 
3.A.1.111.6

Salivericin 9 exporter, SivT (692 aas; 6 TMSs) (Wescombe et al., 2011)

Firmicutes

SivT of Strepococcus salivarius (F8LI02)

 
3.A.1.111.7

Nukacin ISK-1 bacteriocin exporter, NukT of 694 aas and 6 TMSs.  The protease domain is N-terminal, the membrane domain is central, and the ATPase domain in C-terminal. NukT and its peptidase-inactive mutant have been expressed, purified, and reconstituted into liposomes for analysis of their peptidase and ATPase activities. The ATPase activity of the NBD (C) region is required for the cysteine-type peptidase activity, and leader peptide cleavage enhances the ATPase activity (Zheng et al. 2017).

NukT of Staphylococcus warneri (P-M-C)

 
3.A.1.111.8

Uncharacterized ABC export system of 608 aas and 6 N-terminal TMSs in a 2 + 2 + 2 TMS arrangement followed by the ATPase domain (M-C).  It is adjacent to a 10  protein where the TMSs are in a 5 + 5 TMS arrangement.  Possibly this latter protein is a chaparone protein for proper insertion and folding of the transporter (see TC# 9.B.29.2.17 whick seems to be a chaparone protein for insertion and folding of ABC transporter with TC# 3.A.1.122.2. 

ABC exporter of Lachnospiraceae bacterium

 


3.A.1.112 The Peptide-2 Exporter (Pep2E) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.112.1

Competence factor (CSF; a heptadecapeptide) exporter of 717 aas.  The transporter is fused to an N-terminal peptidase  domain and functions with an MFP  accessory protein, ComB (TC# 8.A.1.4.2) (Ishii et al. 2006). 

Gram-positive bacteria

ComA (peptidase-M-C) of Streptococcus pneumoniae (functions with MFP accessory protein, ComB)

 
3.A.1.112.10

Bacteriocin exporter of 721 aas and 7 TMSs. Residues 10 - 134: peptidase with N-terminal TMS; residues 167 - 446: TM domain; residues 480 - 715: ATPase.

Peptide exporter of Bacteroides salanitronis

 
3.A.1.112.11

Enterocin CRL35 exporter, MunB, of 674 aas and 6 TMSs in an M-C domain arrangement.  The specific receptor for Enterocin CRL35 (MunA; TC# 1.C.24.1.15) acts as a docking molecule, not a structural part of the pore, but the bacteriocin must be anchored to the membrane (Ríos Colombo et al. 2019).

Enterocin CRL35 exporter of Enterococcus mundtii

 
3.A.1.112.12

Colicin V exporter. The ATPase is a GTPase (Zhong and Tai 1998; ).

Enteric bacteria

CvaB (M-C) of E. coli

 
3.A.1.112.13

Microcin E492 exporter, MceFGH (MceF has 5 - 7 TMSs and is most likely a CAAX amino terminal protease that might function in the processing of microcin E492; MceG has a short hydrophilic N-terminus, a centra 6 TMS ABC domain, and a C-terminal ABC ATPase domain; MceH has 1 N-terminal TMS) (Bieler et al., 2006; Lagos et al., 1999)

Proteobacteria

MceGH of Klebsiella pneumoniae
MceG (C-M-C) (Q93GK5)
MceH (MFP) (Q93GK4)

 
3.A.1.112.2Pediocin PA-1 exporterGram-positive bacteriaPedD (M-C) of Pediococcus acidilactici
 
3.A.1.112.3

Bacteriocin (lactococcin) exporter. 

Gram-positive bacteria

LcnC (M-C) of Lactococcus lactis (functions with putative MFP accessory protein LcnD)

 
3.A.1.112.4Sublancin exporter, SunTGram-positive bacteriaSunT (M-C) of Bacillus subtilis
 
3.A.1.112.5

Exporter of the BlpC peptide pheromone (B5E242) and several bacteriocins, BlpAB (Kochan and Dawid 2013).

Firmicute

BlpAB of Streptococcus pneumoniae
BlpA (M-C) (B3E244)
BlpB (MFP) (B3E242)

 
3.A.1.112.6

Putative ABC transporter (6 TMSs)

Bacteria

ABC Transporter of Ureaplasma parvum (Q9PPY0)

 
3.A.1.112.8

Mesenterici Y105 (bacteriocin) ABC exporter and porcessing protease, MesD(E) of 722 aas and 6 TMSs (MesD) (Fremaux et al. 1995). MesDE can transport and catalyze maturation of the two pre-bacteriocins, mesentericin Y105 and B105 (Aucher et al. 2004).  Hydrophobic conserved amino acyl residues and the C-terminal GG doublet of the leader peptide of pre-mesentericin Y105 are critical for optimal secretion (Aucher et al. 2005).  MesE has TC# 8.A.1.4.1.

Firmicutes

MesDE of Leuconostoc mesenteroides

 
3.A.1.112.9

ABC bacteriocin exporter with two peptidase domains, Pcat1.  The pathway for peptide export consists of an large α-helical barrel for small folded peptides.  ATP binding alternates access to the transmembrane pathway and reglates protease activity (Lin et al. 2015).

Pcat1 of Ruminiclostridium thermocellus

 


3.A.1.113 The Peptide-3 Exporter (Pep3E) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.113.1Modified cyclic peptide (syringomycin) exporter, SyrD Gram-negative bacteriaSyrD (M-C) of Pseudomonas syringae
 
3.A.1.113.2Pyoverdin (siderophore) exporterGram-negative bacteriaPvdE (M-C) of Pseudomonas aeruginosa
 
3.A.1.113.3

The multidrug/microcin J25 (MccJ25; 21 aa cyclic peptide antibiotic; the precursor peptide is McjA) exporter, YojI (Delgado et al., 2005). TolC is also required for export; Vincent and Morero, 2009). This system exports many phytol derivatives (Upadhyay et al. 2014).  Also exports L-cysteine (Yamada et al., 2006).  This is one of two microcin J25 exporters, the other being McjD (TC# 3.A.1.118.1).

Gram-negative bacteria

YojI of E. coli (P33941)

 


3.A.1.114 The Probable Glycolipid Exporter (DevE) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.114.1

Glycolipid exporter (under nitrogen control in heterocysts), DevABC-HgdD (Moslavac et al., 2007). Heterocyst envelope glycolipids (HGLs) function as an O2 diffusion barrier, being deposited over the heterocyst outer membrane, surrounded by an outermost heterocyst polysaccharide envelope. DevBCA and TolC form an ATP-driven efflux pump required for the export of HGLs across the Gram-negative cell wall (Staron et al., 2011). DevB, the MFP, must be hexameric to create a functional export complex.  This system is under NtcA and nitrogen control and is required for heterocyst development (Fiedler et al. 2001).

Cyanobacteria

DevABC-HgdD of Anabaena variabilis (sp. strain PCC7120)
DevA (C)
DevB (MFP)
DevC (M)
HgdD (TolC like)

 


3.A.1.115 The Na+ Exporter (NatE) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.115.1

Na+ efflux pump NatAB

Gram-positive bacteria

NatAB of Bacillus subtilis
NatA (M)
NatB (C)

 
3.A.1.115.2

Putative Na extrusion pump, NatAB.  NatB has an N-terminal NatB domain (residues 1 - 375) as well as a C-terminal CAAX protease domain (9.B.2; residues 380 - 650).

Planctomycetes

NatAB of Rhodopirellula baltica

 
3.A.1.115.3

ABC transporter of unknown function

ABC transporter
AKM79972, (M)
AKM79973, (C)

 


3.A.1.116 The Microcin B17 Exporter (McbE) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.116.1Microcin B17 exporterEnteric bacteriaMcbEF of E. coli
McbE (M)
McbF (C)
 


3.A.1.117 The Drug Exporter-2 (DrugE2) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.117.1

The multidrug exporter, LmrA (can also substitute for MsbA [TC #3.A.1.106.1] to export lipid A; Reuter et al., 2003).  A structural model has been presented (Federici et al. 2007). Hoechst 33342 is a substrate (van den Berg and van Saparoea et al. 2005). Coupled ATPase-adenylate kinase activity in ABC transporters including LmrA has been demonstrated (Kaur et al. 2016).

Gram-positive bacteria

LmrA (M-C) of Lactococcus lactis

 
3.A.1.117.2

Hop resistance protein, HorA. Reconstitution in phosphatidyl ethanolamine bilayers resulted in normal activity, but reconstitution in phosphatidyl choline resulted in uncoupling of ATP hydrolysis from transport and a change in the orientations of the TMSs (Gustot et al. 2010).

Gram-positive bacteria

HorA (M-C) of Lactobacillus brevis

 
3.A.1.117.3

Multidrug resistance homodimeric efflux pump, BmrA (YvcC) of 589 aas (Dalmas et al. 2005).  The low resolution cryo-electron microscopy reconstitution suggests large conformational changes occur during it's catalytic cycle (Fribourg et al. 2014).

Firmictues

BmrA of Bacillus subtilis

 


3.A.1.118 The Microcin J25 Exporter (McjD) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.118.1

The cyclic peptide antibiotic, microcin J25 (MccJ25; the precursor peptide is JcjA) exporter, the self immunity protein, McjD. TolC is also required for export; Vincent and Morero, 2009.  The 3-d structure has been determined to 2.7Å resolution in an outward occluded state (Choudhury et al. 2014).  Binding and efflux as well as stimulation of the ATPase activity upon binding of MccJ25 have been demonstrated (Choudhury et al. 2014).  This is one of two MCCJ25 exporters, the other being YojI (TC# 3.A.1.113.3).  The large conformational changes in some crystal structures may not be necessary even for a large substrate like MccJ25 (Gu et al. 2015).

Gram-negative bacteria

McjD (M-C) of E. coli

 


3.A.1.119 The Drug/Siderophore Exporter-3 (DrugE3) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.119.15-Hydroxystreptomycin and other streptomycin-like aminoglycoside exporter, StrVWGram-positive bacteriaStrVW of Streptomyces glaucescens
StrV (M-C)
StrW (M-C)
 
3.A.1.119.2Tetracycline/oxytetracycline/oxacillin exporter, TetABGram-positive bacteriaTetAB (StrAB) of Corynebacterium striatum
TetA (M-C)
TetB (M-C)
 
3.A.1.119.3

Exochelin exporter, ExiT (Zhu et al. 1998).

Gram-positive bacteria

ExiT of Mycobacterium smegmatis
(MC-M-C)

 
3.A.1.119.4

Putative coelichelin (hydroxamate siderophore) exporter, Sco0493; the gene is in a gene cluster encoding the recognized coelichelin uptake system (TC# 3.A.1.14.12) as well as coelichelin biosynthetic enzymes (Barona-Gómez et al. 2006).  Sco0493 may function together with Sco0540 which is another putative ABC exporter of similar equence (see TC# 3.A.1.119.5).  However, alternatively, these two genes may encode two distinct transport systems.

Actinobacteria

Putative coelichelin exporter, Sco0493, of Streptomyces coelicolor (M-C)

 
3.A.1.119.5

Putative coelichelin (hydroxamate siderophore) exporter, Sco0493; the gene is in a gene cluster encoding the recognized coelichelin uptake system (TC# 3.A.1.14.12) as well as coelichelin biosynthetic enzymes (Barona-Gómez et al. 2006).  Sco0493  (see TC# 3.A.1.119.4) may function together with Sco0540, both of which are putative ABC exporters of similar sequence. Alternatively, these two genes may encode two distinct transport systems.

Actinobacteria

Sco0540 of Streptomyces coelicolor (M-C)

 


3.A.1.12 The Quaternary Amine Uptake Transporter (QAT) Family (Similar to 3.A.1.16 and 3.A.1.17)


Examples:

TC#NameOrganismal TypeExample
3.A.1.12.1

Glycine betaine/proline porter, ProU or ProVWX (also transports proline betaine, carnitine, dimethyl proline, homobetaine, γ-butyrobetaine and choline with low affinity).  Contributes to the regulation of cell volume is response to osmolarity.  A reconsituted system shows osmotic strength-gating (Gul and Poolman 2012).

Proteobacteria

ProVWX of E. coli
ProW (M)
ProX (R)
ProV (C)

 
3.A.1.12.10The OpuC transporter selective for glycine betaine > choline, acetylcholine, carnitine and proline betaine (contains tandem cystathionine-β-synthase (CBS) domains in the ABC component of OpuC that are required for osmoregulatory function (Chen and Beattie, 2007)). ProteobacteriaOpuCA, CB, CC of Pseudomonas syringae
OpuCC (R) (Q87WH3)
OpuCB (M) (Q87WH4)
OpuCA (C) (Q87WH5)
 
3.A.1.12.11The glycine betaine uptake porter, GbpABCD (Saum et al., 2009).

Archaea

GbpABCD of Methanosarcina mazei
GbpA (R) (Q8Q040)
GbpB (M) (Q8Q043)
GbpC (M) (Q9Q042)
GbpD (C) (Q8Q041)

 
3.A.1.12.12

The CbcWV/CbcX (choline)/CaiX (carnitine)/BetX (betaine) transporter with 3 binding receptors for distinct quaternary ammonium compounds. Only the ligand-bound receptor binds to the transporter with high affinity (Chen et al., 2010; Thomas et al., 2010).

Bacteria

CbcWV/CbcX/CaiX/BetX of Pseudomonas aeruginosa
CbcW (M) (Q9HTI7)
CbcV (C) (Q9HTI8)
CbcX (R) (Q9HTI6)
CaiX (R) (Q9HTH6)
BetX (R) (Q9HZ04)

 
3.A.1.12.13

High affinity (2mμM) choline uptake porter. The choline binding receptor exhibits a venus fly trap mechanism of substrate binding. (ChoX binds acetyl choline and betaine with low affinity (80μM and 470μM, respectively) (Aktas et al., 2011) (most similar to 3.A.1.12.7)

Bacteria

ChoVWX of Agrobacterium tumefaciens 
ChoX (R) (Q7CXG0)
ChoW (M) (Q7CXG1)
ChoV (C) (A9CI32)

 
3.A.1.12.14

OsmU (OsmVWXY) transporter for glycine betaine and choline-O-sulfate uptake. Induced by osmotic stress (0.3M NaCl) (Frossard et al., 2012). Also called OpuCA/CB1/CB2/CC.

Proteobacteria

OsmU or OsmVWXY of Salmonella enterica 
OsmV (STM1491) (C) (Q8ZPK4)
OsmW (STM1492) (M) (Q8ZPK3)
OsmX (STM1493) (R) (Q8ZPK2)
OsmY (STM1494) (M) (Q8ZPK1) 

 
3.A.1.12.15

Putative osmoprotectant (glycine/betaine/choline) uptake transporter, YehWXYZ.  Induced by osmotic stress and growth into the stationary phase; under RpoS (σS) control (Ibanez-Ruiz et al. 2000; Checroun and Gutierrez 2004).  YehZ is also called OsmF.

Proteobacteria

YehWXYZ of E. coli
YehW (M) 243 aas
YehX (C) 308 aas
YehY (M) 385 aas
YehZ or OsmF (R) 305 aas

 
3.A.1.12.2

Glycine betaine OpuAA/AB/AC porter (also transports dimethylsulfonioacetate and dimethylsulfoniopropionate).  The system has been reconstituted in nanodiscs and shows substrate-dependent ionic stringth-gated gating and energy coupling dependent on anionic lipids (Karasawa et al. 2013).

Firmicutes

OpuAA, AB, AC of Bacillus subtilis
OpuAA (C)
OpuAB (M)
OpuAC (R)

 
3.A.1.12.3Choline porterFirmicutesOpuBA, BB, BC, BD of Bacillus subtilis
OpuBA (C)
OpuBB (M)
OpuBC (R)
OpuBD (M)
 
3.A.1.12.4Uptake system for choline, L-carnitine, D-carnitine, glycine betaine, proline betaine, crotonobetaine, γ-butyrobetaine, dimethylsulfonioacetate, dimethylsulfoniopropionate, ectoine and choline-O-sulfateFirmicutesOpuCA, CB, CC, CD of Bacillus subtilis
OpuCA (C)
OpuCB (M)
OpuCC (R)
OpuCD (M)
 
3.A.1.12.5

Uptake system for glycine-betaine (high affinity) and proline (low affinity) (OpuAA-OpuABC) or BusAA-ABC of Lactococcus lactis). BusAA, the ATPase subunit, has a C-terminal tandem cystathionine β-synthase (CBS) domain which is the cytoplasmic K+ sensor for osmotic stress (osmotic strength)while the BusABC subunit has the membrane and receptor domains fused to each other (Biemans-Oldehinkel et al., 2006; Mahmood et al., 2006; Gul et al. 2012). An N-terminal amphipathic α-helix of OpuA is necessary for high activity but is not critical for biogenesis or the ionic regulation of transport (Gul et al., 2012).

Firmicutes

BusAA-AB of Lactococcus lactis
BusAA (C-CBS)
BusAB (M-R)

 
3.A.1.12.6Uptake system for hisitidine, proline, proline-betaine and glycine-betaineProteobacteriaHutXWV of Sinorhizobium meliloti
HutX (R)
HutW (M)
HutV (C)
 
3.A.1.12.7High affinity (3 μM) choline-specific uptake system (Dupont et al., 2004)ProteobacteriaChoXWV of Sinorhizobium meliloti
ChoX (R) (AAM00244)
ChoW (M) (AAM00245)
ChoV (C) (AAM00246)
 
3.A.1.12.8A proline/glycine betaine uptake system. Also reported to be a bile exclusion system that exports oxgall and other bile compounds, BilEA/EB or OpuBA/BB (required for normal virulence) (R.D. Sleator et al., 2005). BacteriaOpuBA/BB or BilEA/EB of Listeria monocytogenes
OpuBA (C) (Q93A35)
OpuBB (M-R) (Q93A34)
 
3.A.1.12.9The salt-induced glycine betaine OtaABC transporter (Schmidt et al., 2007)ArchaeaOtaABC of Methanosarcina mazei Go1
OtaA (C) Q8U4S5
OtaB (M) Q8U4S4
OtaC (R) Q8U4S3
 


3.A.1.120 The (Putative) Drug Resistance ATPase-1 (Drug RA1) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.120.1Macrolide ATPase (membrane constituent unknown) Gram-positive bacteriaSrmB (C-C) of Streptomyces ambofaciens
 
3.A.1.120.2Tylosin ATPase (membrane constituent unknown) Gram-positive bacteriaTlrC (C-C) of Streptomyces fradiae
 
3.A.1.120.3Oleandomycin resistance ATPase (membrane constituent unknown)Gram-positive bacteriaOleB (C-C) of Streptomyces antibioticus
 
3.A.1.120.4Carbomycin resistance ATPase (membrane constituent unknown)Gram-positive bacteriaCarbomycin, CarA (C-C), protein of Streptomyces thermotolerans
 
3.A.1.120.5The acetate resistance ABC acetate exporter (Nankano et al., 2006)Gram-negative bacteriaAatA (C-C) of Acetobacter aceti (BAE71146)
 
3.A.1.120.6

The Uup protein (required for bacterial competitiveness (Murat et al., 2008); 39% identical to 3.A.1.120.5).

Gram-negative bacteria

Uup of E. coli (P43672)

 
3.A.1.120.7

ABC transporter, SgvT2 (ATP-hydrolyzing subunit of 551 aas. Functions to export griseoviridin and viridogrisein (etamycin) (Xie et al. 2017). However, it may also function as an ATP-binding cassette domain of elongation factor 3, interacting with the ribosome which stimulates its ATPase activity (Sasikumar and Kinzy 2014).

SgvT2 of Streptomyces griseoviridis

 
3.A.1.120.8

 ABC protein of 558 aas and 0 TMSs, Rv2477c.  It is a translation factor that gates the progression of the 70S ribosomal initiation complex (IC, containing tRNA (fMet) in the P site) into the translation elongation cycle by using a mechanism sensitive to the ATP/ADP ratio. Binds to the 70S ribosome E site where it modulates the state of the translating ribosome during subunit translocation. It is an ABC-F subfamily protein, members of which are implicated in diverse cellular processes such as translation, antibiotic resistance, cell growth and nutrient sensing. Daniel et al. 2018 showed that Rv2477c displays strong ATPase activity (Vmax = 45 nmol/mg/min; Km = 90 muM) that is sensitive to orthovanadate. The ATPase activity was maximal in the presence of Mn2+ at pH 5.2. The protein hydrolyzed GTP, TTP and CTPas well as ATP but at lower rates. Glutamate to glutamine substitutions of amino acid residues 185 and 468 in the two Walker B motifs severely inhibited its ATPase activity. The antibiotics, tetracycline and erythromycin, which target protein translation, were able to inhibit the ATPase activity. Daniel et al. 2018 postulated that Rv2477c is involved in mycobacterial protein translation and in resistance to tetracyclines and macrolides.

v2477c of Mycobacterium tuberculosis

 


3.A.1.121 The (Putative) Drug Resistance ATPase-2 (Drug RA2) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.121.1Erythromycin ATPase (membrane constituent unknown) Gram-positive bacteriaMsrA (C-C) of Staphylococcus epidermidis
 
3.A.1.121.10

ABCF1 (out of 5 isoforms) of 595 aas and 0 TMSs. Functions as a ribosome regulator.

ABCF1 of Arabidopsis thaliana (Mouse-ear cress)

 
3.A.1.121.11

ATP-binding cassette sub-family F member 2, ABCF2 of 623 aas and 0 TMSs.  Its function is unknown, but it is probably not a transporter (Sakamoto et al. 2019).

ABCF2 of Homo sapiens

 
3.A.1.121.2Pristinamycin resistance protein, VgaGGram-positive bacteriaVgaB (C-C) of Staphylococcus aureus
 
3.A.1.121.3Antibiotic (virginiamycin and lincomycin) resistance protein, VmlRGram-positive bacteriaVmlR (C-C) of Bacillus subtilis (P39115)
 
3.A.1.121.5

ABC-type streptogammin A resistance exporter, VgaA of 522 aas and 0 TMSs (C-C arrangement).  Inhibited by pristinamycin IIA (Jacquet et al. 2008). A transport function is not known.

VgaA of Staphylococcus aureus

 
3.A.1.121.6

MsrD of 487 aas and 0 TMSs. Involved in macrolide resistance (Zhang et al. 2016). Two ATPase domains are present in tandem. A membrane constituent is not known. Iannelli et al. 2018 suggested that MefA (TC# 2.a.1.21.1) can function with MsrD, and therefore that this MFS exporter can function as an ABC drug exporter.  However, the data presented seem inconsistent with this suggestion. Nevertheless, the two genes encoding these two proteins are adjacent to each other, suggesting that they may somehow function together (Iannelli et al. 2018).

MsrD of Streptococcus pyogenes (C-C)

 
3.A.1.121.7

Putative ABC protein of 684 aas and 0 TMSs, ATCF1.  Found to be essential for bloodstream-form Trypanosoma brucei through a genome-wide RNAi screen (Schmidt et al. 2018).

ABCF1 of Trypanosoma brucei

 
3.A.1.121.8

ATP-binding cassette subfamily F member 1, ABCF1 or ABC50, of 845 aas and 0 TMSs. There is no transmembrane protein associated with ABCF1, and this protein does not function in transport.  It is required for efficient Cap- and IRES-mediated mRNA translational initiation, not in ribosome biogenesis (Paytubi et al. 2009).

ABCF1 of Homo sapiens

 
3.A.1.121.9

ABCF3 of 709 aas and 0 TMSs. It is not a transporter, but is a translational regulator that also promotes apoptosis (Hirose and Horvitz 2014). It has an antiviral effect against flaviviruses (Sakamoto et al. 2019).

ABCF3 of Homo sapiens

 


3.A.1.122 The Macrolide Exporter (MacB) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.122.1

Macrolide (14- and 15- but not 16-membered lactone macrolides including erythromycin) exporter, MacAB (formerly YbjYZ). Both MacA and MacB are required for activity (Tikhonova et al., 2007). MacAB functions with TolC to export multiple drugs and heat-stable enterotoxin II (enterotoxin STII) (Yamanaka et al., 2008). The crystal structure of MacA is available (Yum et al., 2009). MacB is a dimer whose ATPase activity and macrolide-binding capacity are regulated by the membrane fusion protein MacA (Lin et al., 2009). Xu et al. (2009) have reported the crystal structure of the periplasmic region of MacB which they claim resembles the periplasmic domain of RND-type transporters such as AcrB (TC# 2.A.6.2.2). Also exports L-cysteine (Yamada et al., 2006). The periplasmic membrane proximal domain of MacA acts as a switch in stimulation of ATP hydrolysis by the MacB transporter (Modali and Zgurskaya, 2011). Fitzpatrick et al. 2017 presented an electron cryo-microscopy structure of the tripartite assembly (MacAB-TolC) at near-atomic resolution. A hexamer of the periplasmic protein MacA bridges a TolC trimer in the outer membrane to a MacB dimer in the inner membrane, generating a quaternary structure with a central channel for substrate translocation. A gating ring found in MacA may act as a one-way valve in substrate transport. The MacB structure features an atypical transmembrane domain with a closely packed dimer interface and a periplasmic opening that is the likely portal for substrate entry from the periplasm, with subsequent displacement through an allosteric transport mechanism (Fitzpatrick et al. 2017). The structure of ATP-bound MacB has been solved, revealing precise molecular details of its mechanism (Crow et al. 2017). MacB has a fold that is different from other structurally characterized ABC transporters and uses a unique molecular mechanism termed mechanotransmission. Unlike other bacterial ABC transporters, MacB does not transport substrates across the inner membrane in which it is based, but instead couples cytoplasmic ATP hydrolysis with transmembrane conformational changes that are used to perform work in the extra-cytoplasmic space. In the MacAB-TolC tripartite pump, mechanotransmission drives efflux of antibiotics and export of a protein toxin from the periplasmic space via the TolC exit duct. Homologous tripartite systems from pathogenic bacteria similarly export protein-like signaling molecules, virulence factors and siderophores (Greene et al. 2018).

Gram-negative bacteria

MacAB of E. coli:
MacA(MFP) (P75830)
MacB(C-M) (P75831)

 
3.A.1.122.10

Duf214 (423aas) ABC3 membrane protein with ABC-type ATPase (232 aas).  Sandwiched inbetween the genes encoding these two proteins is a large protein of 869 aas with 2 TMSs, N- and C-terminal. Some homologues are annotated as "S-layer domain protein".  It may be an ABC auxiliary protein.  Most members occur in archaea, but distant homologues are also found in bacteria.

Archaea

Duf214/ABC system of Sulfurisphaera tokodaii (Sulfolobus tokodaii):
Duf214 protein (M) (Q973J4)
ATPase (C) (Q973J6)
Putative auxiliary protein (Q973J5)

 
3.A.1.122.11

The hemin resistance transporter, HrtAB. Expression is activated by hemin or hemoglobin via the ChrAS transmembrane sensor kinase/response regulator system (Bibb and Schmitt 2010).

Bacteria

HrtAB of Corynebacterium diphtheriae
HrtA (C) (H2GZC3)
HrtB (M) (H2GZC4) 

 
3.A.1.122.12

Arthrofactin efflux pump, ArfDE (Balibar et al. 2005).

γ-Proteobacteria

ArfDE of Pseudomonas sp. MIS38
ArfD (MFP) (Q84BQ3)
ArfE (ABC) (A0ZUB1)

 
3.A.1.122.13Putative ABC3-type antimicrobial peptide transporter, fused ATPase-porter protein, U-ABC3-1b (667aas; 4TMSs:1+3)BacteriaU-ABC3-1b of Lactobacillus brevis (CM) (Q03RZ6)
 
3.A.1.122.14

ABC transporter of unknown function, but aspects of its structure and mechanism of action are known (Yuan et al. 2001; Zoghbi and Altenberg 2013).  Nucleotide-binding domain dimerization occurs as a result of binding to the natural nucleotide triphosphates, ATP, GTP, CTP and UTP, as well as the analog ATP-gamma-S. All the natural nucleotide triphosphates are hydrolyzed at similar rates, whereas ATP-gamma-S is not hydrolyzed. The non-hydrolyzable ATP analog AMP-PNP, frequently assumed to produce the nucleotide-bound conformation, failed to elicit nucleotide-binding domain dimerization (Fendley et al. 2016).

Archaea

ABC transporter of Methanocaldococcus jannaschii (Methanococcus jannaschii)
Membrane protein, MJ0797 (M) (Q58207)
ATPase, MJ0796 (C) (Q58206)

 
3.A.1.122.15

Putative heavy metal ion exporter, YbbAB (Moussatova et al. 2008).

Proteobacteria

YbbAB of E. coli
YbbA (C; 228 aas)
YbbB (M; 804 aas)

 
3.A.1.122.16

Putative macrolide-specific efflux system, MacAB

MacAB of Bifidobacterium longum

 
3.A.1.122.17

LolC/E family lipoprotein releasing system, transmembrane protein of 639 aas and 4 TMSs

LolC/E family lipoprotein releasing system, transmembrane protein of Candidatus Saccharibacteria bacterium

 
3.A.1.122.18

MacAB-TolC MDR effllux porter. Exports macrolide antibiotics, virulence factors, peptides and cell envelope precursors. The 3-d crystal structure of MacB has been solved at 3.4 Å resolution (Okada et al. 2017). MacB forms a dimer in which each protomer contains a nucleotide-binding domain and four TMSs that protrude in the periplasm into a binding domain for interaction with the membrane fusion protein MacA. It has unique structural features (Okada et al. 2017).

MacAB of Acinetobacter baumannii
MacA, Q2FD52, 445 aas and 1 TMS
MacB, N9J6M5, 664 aas and 4 TMSs

 
3.A.1.122.19

ABC3-type efflux porter, YtrEF, encoded within an operon, ytrABCDEF, apparently encoding two ABC exporters, one, YtrBCD, with TC# 3.A.1.153.1, and the other, this one. The operon is induced in early stationary phase under the control of YtrA, a GntR-type HTH transcriptional regulator, probably a repressor (Yoshida et al. 2000). These authors suggest this operon may be involve in acetoin secretion and/or reutilization.

YtrEF of Bacillus subtilis
YtrE, C, 231 aas; O34392
YtrF, M, 436 aas; O35005

 
3.A.1.122.2

The SpdC antimicrobial peptide resistance efflux pump, YknXYZ (Butcher and Helmann, 2006).  YknW (TC# 9.B.29.2.17), a 5 TMS protein, interacts directly with YknXYZ and is essential for facilitation of its assembly, thus serving as an integral membrane chaparone  (Yamada et al., 2012). The MFP YknX requires the ATP-binding cassette (ABC) transporter YknYZ and the Yip1 family protein YknW to form a functional complex. YknX (MFP) is hexameric (Xu et al. 2017).

Bacteria

YknXYZ of Bacillus subtilis
YknX (MFP) (O31710)
YknY (C) (O31711)
YknZ (M) (O31712)

 
3.A.1.122.20

MacAB-MFP complex of 3 subunits involved in the resistance of antibiotics and antimicrobial peptides. Yang et al. 2018 reported the crystal structures of Spr0694-0695 (MacAB) at 3.3 Å and Spr0693 (MFP; TC# 8.A.1) at 3.0 Å resolution, revealing a MacAB-like efflux pump. The dimeric MacAB adopts a non-canonical fold, the transmembrane domain of which consists of a dimer with eight tightly packed TMSs (4 per subunit) with an extracellular domain between the first and second helices, whereas Spr0693 (the MFP) forms a nanotube channel docked onto the ABC transporter. Structural analyses, combined with ATPase activity and antimicrobial susceptibility assays, enabled the proposal of a putative substrate-entrance tunnel with lateral access controlled by a guard helix (Yang et al. 2018).

MacAB-MFP of Streptococcus pneumoniae
MacA, Spr0694, 233 aas (C)
MacB, Spr0695, 419 aas (M)
MFP, Spr0693, 399 aas, (MFP)

 
3.A.1.122.21

ABC transport system with a type 3 ABC membrane protein (386 aas and 4 TMSs; B8GHI1) and an ABC ATPase (234 aas; B8GHI2).  The encoding genes are adjacent to those encoding a putative transport system with TC# 9.B.29.2.7.

ABC transporter of Methanocorpusculum labreanum

 
3.A.1.122.22

Uncharacterized ABC exporter of two subunits, a 4 TMS membrane subunit of 177 aas, and an ATPase of 229 aas

UP ABC exporter
(M) 177 aas and 4 TMSs, KKK40843
(C)  229 aas and ) TMSs, KKK48044

 
3.A.1.122.23

Uncharacterized ABC exporter

Uncharacterized ABC exporter of Candidatus Thorarchaeota
(M) 173 aas and 4 TMSs, RDE13437
(C) 225 aas, RDE13438

 
3.A.1.122.24

Uncharacterized ABC exporter

ABC exporter of Candidatus Odinarchaeota
(M) 166 aas and 4 TMSs, OLS17116
(C)  232 aas, OLS17115

 
3.A.1.122.25

3-component ABC3-type transporter with two 4 TMS membrane proteins and one ATPase, all encoded within a single operon with the three genes next to each other.

ABC exporter of Corallococcus coralloides

 
3.A.1.122.26

Uncharacterized two comoponent ABC3-type efflux transporter of 805 aas and 8 TMSs in a 1 + 3 + 1 +3 TMS arrangement. The ATPase is a distinct protein of 250 aas.

Uncharacterized ATP-energized exporter of Candidatus Heimdallarchaeota
ABC3-type membrane protein of 805 aas and 8 TMSs (M)
ATPase of 250 aas (C).

 
3.A.1.122.27

Putative ABC3-type transporter with an ATPase and a possible auxiliary protein encoded by a gene sandwiched in between the membrane protein and the ATPase. Some homologues of the auxiliary protein are annotated as S-layer domain proteins. This system resembles 3.A.1.122.10 which also has such an auxiliary protein.

ABC3-type transporter
E6NBB1 (M), 413 aas with 4 TMSs in a 1 + 3 TMS arrangement
E6NBB0 (C), 236 aas
E6N374 (Putative auxiliary protein), 597 aas and 1 TMS at the C-terminus

 
3.A.1.122.28

ABC3 exporter including a membrane protein of 392 aas and 4 TMSs in a 1 + 3 TMS arrangement and a putative auxiliary transport protein of 944 aas and 1 C-terminal TMS. It is annotated as an S-layer domain protein. While these two recognized proteins are encoded by adjacent genes, an ATPase was not encoded nearby, and it has not been identified.

Putative incomplete ABC3 exporter of Ignicoccus hospitalis

 
3.A.1.122.29

ABC3-type exporter with 3 components, the permease of 457 aas with 4 TMSs, an ATPase of 236 aas, and a putative auxiliary protein of 805 aas and 2 TMSs, N-and C-terminal. The permease subunit is annotated as an ABC-type lipoprotein release transport system, and the auxiliary protein is a COG1361 protein.

ABC3 porter of Anaerobacterium chartisolvens

 
3.A.1.122.3The enterocin AS-48 exporter, As-48FGHGram-positive bacteriaAs-48FGH on plasmid pMBL of Enterococcus faecalis:
As-48F (MFP) (Q7AUQ4)
As-48H (M) (Q8RKC0)
As-48G (C) (Q8RKC1)
 
3.A.1.122.30

ABC3 exporter with three constituents, the 4 TMS membrane protein of 529 aas, the ATPase of 251 aas, and an auxiliary protein of 431 aas and 2 TMSs, N-terminal and C-terminal.

ABC3 exporter of Bifidobacterium longum subsp. infantis

 
3.A.1.122.31

Uncharacterized ABC porter with a single membrane protein of 224 aas and 4 TMSs, plus two ATPases, of 237 and 243 aas, respectively.

ABC porter of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)
Porter, M, OLS20810
ATPase, C, OLS20809
ATPase, C, OLS20808

 
3.A.1.122.32

Putative 3-component ABC exporter with two uncharacterized homologous membrane proteins of 930 aas and 1090 aas, both with 10 TMSs in a 1 + (3 +2 +1) +3 TMS arrangement, plus an ATPase.

Actinobacteria

Uncharacterized  ABC exporter of Cellulomonas flavigena

 
3.A.1.122.33

Putative 3 component ABC transporter with two membrane proteins of 907 and 1113 aas plus an ATPase of 319 aas.  Both membrane proteins have 10 TMSs in a 1 + (3 + 2 + 1) + 3 TMS arrangement.

ABC exporter of Streptomyces coelicolor

 
3.A.1.122.34

Uncharacterized putative ABC exporter of 4 components, all encoded by adjacent genes: one membrane protein, two ATPases and one membrane fusion protein (MFP).

ABC exporter of Paenibacillus mucilaginosus

 
3.A.1.122.4Probable Heme exporter, HrtAB (Stauff et al., 2008)BacteriaHrtAB of Staphylococcus aureus:
HrtA (C) (Q7A3X3)
HrtB (M) (Q7A7X2)
 
3.A.1.122.5ABC transporter of unknown function (DUF214 protein) (4TMSs)/ABC protein [Msed1528/Msed1530] ArchaeaMsed1528/Msed1530 of Metallosphaera sedula (M) (A4YGY2)
 
3.A.1.122.6ABC transporter of unknown function (DUF214 protein) (4TMSs)/ABC protein [MA2839/MA2840]ArchaeaMA2839/MA2840 of Methanosarcina acetivorans
MA2839 (M) (Q8TM31)
MA2840 (C) (Q8TM30)
 
3.A.1.122.7ABC transporter of unknown function (Duf214 protein (409aas; 4TMSs:1+3)/ABC protein)ArchaeaDuf214 protein/ ABC protein of Methanococcus voltae:
Duf214 protein (M) (A8TDX0)
ABC protein (C) (A8TDW7)
 
3.A.1.122.8Putative ABC3 permease, PC1,2,3.BacteriaPC1,2,3 of Treponema denticola:
PC1 (C) - Q73MJ2
PC2 (M) - Q73MJ3
PC3 (M) - Q73MJ4
 
3.A.1.122.9Duf214 protein (405aas)/ ABC proteinArchaeaDuf214/ABC system of Caldivirga maquilingensis:
Duf214 protein (M) (A8M8Z1)
 


3.A.1.123 The Peptide-4 Exporter (Pep4E) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.123.1

Pep5 lantibiotic exporter, PepT

Gram-positive bacteria

PepT (M-C) of Staphylococcus epidermidis

 
3.A.1.123.2Aureocin A70 multipeptide bacteriocin (AurA, AurB, AurC, AurD) exporter, AurTGram-positive bacteriaAurT (M-C) of Staphylococcus aureus
 
3.A.1.123.3The one component lantibiotic exporter, GdmT (Sibbald et al., 2006) Gram-positive bacteriumGdmT (M-C) of Staphylococcus gallinarum (A3QNP2)
 


3.A.1.124 The 3-component Peptide-5 Exporter (Pep5E) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.124.1

The 3-component nisin immunity exporter, NisFEG. Contains an essential E-loop (Okuda et al., 2010).

Gram-positive bacteria

NisFEG of Lactococcus lactis
NisF (C)
NisE (M)
NisG (M)

 
3.A.1.124.2The 3-component subtilin immunity exporter, SpaEFGGram-positive bacteriaSpaEFG of Bacillus subtilis
SpaE (M)
SpaF (C)
SpaG (M)
 
3.A.1.124.3The lantibiotic Nukacin ISK-1 (TC# 1.C.21.1.5)/NukH (BAD01013; 92aas) exporter, NukEFG (Okuda et al., 2008)Gram-positive bacteriaNukEFG of Staphylococcus warneri
NukE (M) (Q75V14)
NukF (C) (Q75V15)
NukG (M) (Q75V13)
 
3.A.1.124.4The macedocin exporter, McdEFG (Papadelli et al., 2007) Gram-positive bacteriaMcdEFG of Streptococcus macedonicus
McdE (M; 254 aas) (A6MER6)
McdG (M; 245 aas) (A6MER7)
McdF (C; 304 aas) (A6MER5)
 
3.A.1.124.5The salivaricin exporter, SboEFG (Hyink et al., 2007)Gram-positive bacteriaSboEFG of Streptococcus salivarius
SboE (M; 249 aas) (Q09IH9)
SboF (C; 303 aas) (Q09II0)
SboG (M; 242 aas) (Q09IH8)
 
3.A.1.124.6

CprABC antimicrobial peptide resistance ABC exporter.  Exports both mammalian and bacterial toxic peptides (McBride and Sonenshein 2011).

Firmicutes

CprABC of Clostridium difficile
CprA (C, 235 aas)
CprB (M, 238 aas, 6 TMSs)
CprC (M, 252 aas, 6 TMSs)

 


3.A.1.125 The Lipoprotein Translocase (LPT) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.125.1

Lipoprotein translocation system (translocates lipoproteins from the inner membrane to periplasmic chaperone, LolA, which transfers the lipoproteins to an outer membrane receptor, LolB, which anchors the lipoprotein to the outer membrane of the Gram-negative bacterial cell envelope) (see 1.B.46; Narita et al., 2003; Ito et al., 2006; Watanabe et al., 2007). The structure of ligand-bound LolCDE has been solved (Ito et al., 2006). LolC and LolE each have 4 TMSs (1+3). Unlike most ATP binding cassette transporters mediating the transmembrane flux of substrates, the LolCDE complex catalyzes the extrusion of lipoproteins anchored to the outer leaflet of the inner membrane. The LolCDE complex is unusual in that it can be purified as a liganded form, which is an intermediate of the lipoprotein release reaction (Taniguchi and Tokuda, 2008). LolCDE has been reconstituted from separated subunits (Kanamaru et al., 2007).  LolE binds the outer membrane lipoprotein, PAL (Mizutani et al. 2013).

Gram-negative bacteria

LolCDE of E. coli
LolC (M)
LolD (C)
LolE (M)

 
3.A.1.125.2Putative lipoprotein LolCDE homologue LolCE (10TMSs:1+6+3)/LolDBacteriaLolCE/LolD of Mycobacterium tuberculosis
LolCE (M) (Q7D911)
LolD (C) (O53899)
 
3.A.1.125.3Duf214 protein (843aas; 10TMSs:1+6+3)BacteriaDuf214 protein/ ABC protein of Frankia sp. CcI3:
Duf214 protein (M) - Q2J9P4
[LolD/FtsE/SalX]-type ABC protein (C) - Q2J9P5
 
3.A.1.125.5

Uncharacterized ABC transporter with two consituents, a 4 TMS (in a 1 + 3 TMS arrangement) membrane (M) protein and an ATPase (C). 

Uncharacterized ABC transporter of Opitutus terrae
M: B1ZMT9
C: B1ZMU0

 
3.A.1.125.6

Putative ABC transporter, LolCDE, with three components, similar to (but substantially different from) LolC, LolD and LolE of E. coli. The three genes encoding these proteins are adjectent to each other on the bacteria chromosome, but there is no direct experimental evidence that they function together as lipoprotein exporters.

LolCDE of Candidatus Heimdallarchaeota archaeon LC_3
LolC, 690 aas and 4 TMSs in a 1 + 3 TMS arrangement (MC)
LolD, 236 aas with 2 or 3 TMSs followed by a hydrophilic C-terminal domain (MC)
LolE, 1106 aas and 12 TMSs in a 1 + 3 + 4 +1 + 3 TMS arrangement (MM)

 


3.A.1.126 The β-Exotoxin I Exporter (βETE) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.126.1Exporter of β-exotoxin I, BerABBacteriaβ-exotoxin exporter, BerAB, of Bacillus thuringiensis
BerA (C)
BerB (M)
 
3.A.1.126.2

Putative ABC transporter with a 6 TMS membrane protein and an ATPase of the ABC-type encoded by the adjacent gene.

Bacteria

Putative ABC transporter of Arthrobacter (Paenarthrobacter) aurescens (A1R938)

 
3.A.1.126.3

Putative exporter of polyketide antibiotic-like protein (~12 TMSs) with an ABC ATPase encoded by the adjacent gene.

Actinobacteria

Putative exporter of Amycolicicoccus (Hoyosella) subflavus (F6EHL8)

 
3.A.1.126.4

6TMS putative ABC transporter protein with an ABC-type ATPase encoded by the adjacent gene.  This memebrane protein also maps adjacent to protein fragments that show similarity to ABC transport proteins as well as a protease (9.B.218.1.4; D4TYE3).

Bacteria

Putative ABC transporter system of Actinomyces odontolyticus (D4TYE0)

 


3.A.1.127 The AmfS Peptide Exporter (AmfS-E) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.127.1Exporter of AmfS extracellular peptidic morphogen (Chater and Horinouchi, 2003; Ueda et al., 2002)BacteriaAmfS exporter, AmfAB of Streptomyces griseus
AmfA (MC) (BAA33537)
AmfB (MC) (BBA33538)
 


3.A.1.128 The SkfA Peptide Exporter (SkfA-E) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.128.1

Exporter of SkfA processed peptide (spO31422), SkfEF (González-Pastor et al., 2003)

Bacteria

SkfEF (YbdAB) of Bacillus subtilis
SkfE (C) O31427
SkfF (M-M) O31438

 
3.A.1.128.10

Apparent two component ABC transporter, probably an exporter of the sporulation killing factor, SkfB. The membrane component has 12 TMSs, and therefore is probably either due to an intragenic duplication of the usual 6 TMS domain protein or a fusion of two such proteins that are more usual for this subfamily of ABC exporters.  This system acts in conjunction with a CAAX protease (EMI14127; TC# 9.B.2.13.1) that presumably processes SkfB to the mature form. The two genes of this ABC system are preceded by a gene coding for a 174 aa proteins possibly involved in SkfB synthesis and/or export.

ABC SkfB exporter of Bacillus stratosphericus

 
3.A.1.128.11

ABC exporter, possibly for the sporulation killer factor SkfB.

ABC exporter of Parageobacillus thermoglucosidasius

 
3.A.1.128.2Putative ABC exporter, Teth 514-0346 & 0347

Bacteria

Teth 514-0346 & 0347 of Thermoanaerobacter sp. x514:
Teth514-0346 (C) (B0K2P2)
Teth514-0347 (M-M) (B0K2P3)

 
3.A.1.128.3Putative ABC exporter, CLK2533/CLK2534

Bacteria

CLK2533/CLK2534 of Clostridium botulinum
CLK2533 (M-M) (B1L0U0)
CLK2534 (C) (B1L0U1)

 
3.A.1.128.4Putative ABC exporter Tiet1371/1372

Bacteria

Tiet1371/72 of Thermotoga lettingae
Tiet1371 (M-M) (A8F6Z4)
Tiet1372 (C) (A8F6Z5)

 
3.A.1.128.5

Putative ABC transporter.  The genes encoding this system map adjacent to a beta-lactamase (A9BGZ6) gene and one encoding a C4 anaerobic dicarboxylate carrier (A9BGZ7).

Thermatogae

Putative ABC transporter of Petrotoga mobilis

 
3.A.1.128.6

Putative ABC exporter

Euryarchaea

ABC exporter of Pyrococcus horikoshii
Membrane protein (M) (O58947)
ATPase (C) O58948)

 
3.A.1.128.7

Uncharacterized ABC permease, TA0065/TA0066

Euryarchaea

UP of Thermoplasma acidophilum
TA0065 (M-M; permease; 515 aas, 12 TMSs)
TA0066 (C; ATPase)

 
3.A.1.128.8

ABC transporter encoded by two adjacent genes, a membrane protein and an ABC ATPase.

ABC transporter
(M) KXH73395
(C)  KXH73394

 
3.A.1.128.9

Three component ABC transport system of unknown function.

ABC porter of Paenibacillus larvae subsp. pulvifaciens

 


3.A.1.129 The CydDC Cysteine Exporter (CydDC-E) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.129.1

Thiol (Cysteine/Glutathione) exporter, CydDC; CydC is also called MdrH (periplasmic cysteine is required for cytochrome bd assembly) (Cruz-Ramos et al., 2004).  The purified asymmetric heterodimer exhibits low ATPase activity which is activated by both thiols and heme (e.g., heme b) compounds, suggesting that heme binds to and activates thiol transport (Yamashita et al. 2014).  Bacterial redox homoeostasis during nitrosative stress is influenced by CydDC.  Periplasmic low molecular weight thiols restore haem incorporation into a cytochrome complex (Holyoake et al. 2016).

Bacteria

CydDC of E. coli
CydD (M-C) (P29018)
CydC (M-C) (P23886)

 


3.A.1.13 The Vitamin B12 Uptake Transporter (B12T) Family (Similar to 3.A.1.14)


Examples:

TC#NameOrganismal TypeExample
3.A.1.13.1

Vitamin B12 porter. The 3-D structure of BtuCDF has been solved to 2.6 Å (Hvorup et al., 2007). The conformational transition pathways of BtuCD has been revealed by targeted molecular dynamics simulations (Weng et al., 2012). Asymmetric states of BtuCD are not discriminated by its cognate substrate binding protein BtuF (Korkhov et al., 2012).  ATP hydrolysis occurs at the nucleotide-binding domain (NBD) dimer interface, whereas substrate translocation takes place at the translocation pathway between the TM subunits, which is more than 30 angstroms away from the NBD dimer interface.  Hydrolysis of ATP appears to facilitate substrate translocation by opening the cytoplasmic end of translocation pathway (Pan et al. 2016). The molecular mechanism of ATP hydrolysis by BtuCD-F may proceeds in a stepwise manner (Prieß et al. 2018). First, nucleophilic attack of an activated lytic water molecule at the ATP gamma-phosphate yields ADP + HPO42-. A conserved glutamate located close to the gamma-phosphate transiently accepts a proton acting as a catalytic base. In the second step, the proton transfers back from the catalytic base to the gamma-phosphate, yielding ADP + H2PO4-. These two reaction steps are followed by rearrangements of the hydrogen bond network and the coordination of the Mg2+ ion. The overall free energy change of the reaction is close to zero, suggesting that ATP binding is essential for tight dimerization of the nucleotide-binding domains and the transition of the transmembrane domains from inward- to outward-facing. ATP hydrolysis resets the conformational cycle (Prieß et al. 2018).

Proteobacteria

BtuCDF of E. coli
BtuC (M)
BtuD (C)
BtuF (R)

 
3.A.1.13.2

Putative cobalamin (vitamin B12) uptake porter, BtuFCD (Rodionova et al. 2015).

BtuFCD of Chloroflexus aurantiacus
BtuF (R; 1 TMS)
BtuC (M; 9 TMSs)
BtuD (C; 0 TMSs)

 


3.A.1.130 The Multidrug/Hemolysin Exporter (MHE) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.130.1The multidrug/hemolysin exporter, CylA/B (note: CylK (AAF01071) may influence its activity)(Gottschalk et al., 2006)BacteriaCylA/B of Streptococcus agalactiae
CylA (C) (Q9X432)
CylB (M) (Q9X433)
 
3.A.1.130.2

ABC export system, possibly an MDR pump, consisting of two proteins, and membrane protein of 293 aas and 6 TMSs, and an ATPase of 301 aas.

ABC exporter of Acidipropionibacterium virtanenii

 
3.A.1.130.3

ABC exporter with two constituents, a membrane protein of 263 aas and 6 TMSs, and an ATPase of 310 aas.

ABC exporter of Lactobacillus hokkaidonensis

 


3.A.1.131 The Bacitracin Resistance (Bcr) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.131.1

The 2 or 3 component bacitracin-resistance efflex pump, BcrAB or BcrABC (Podlesek et al., 1995; Bernard et al., 2003) (BcrA is most similar to SpaF (3.A.1.124.2), but BcrB (5-6 TMSs) is only distantly related to other ABC2-type membrane proteins (Wang et al., 2009). BcrC is not sufficiently similar to detect similarity in BLAST searches. BcrC (5TMSs) belongs to the PAP2 phosphatase superfamily and may not be a contituent of the BcrAB transporter. Transcription is regulated by BcrR, a one-component transmembrane signal transduction system (Darnell et al. 2019).

Bacteria

BcrABC of Bacillus licheniformis
BcrA (C) - (P42332)
BcrB (M) - (P42333)

 
3.A.1.131.2

Lantibiotic immunity system, LanEF. Contains an essential E-loop, a variant of the Q-loop, well conserved in nucleotide binding domains of lantibiotic exporters (Okuda et al., 2010).

Gram-positive bacteria

LanEF of Bacillus licheniformis
LanE (M) (Q65DD3)
LanF (C) (Q65DD1)

 
3.A.1.131.3

Transporter homologue, Tiet1372

Bacteria

Tiet1372 of Thermotoga lettingae (A8F6Z5)

 


3.A.1.132 The Gliding Motility ABC Transporter (Gld) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.132.1

The GldAFG putative ABC transporter required for ratchet-type gliding motility; may function in secretion of a macromolecule such as an exopolysaccharide. (Agarwal et al., 1997; Hunnicutt et al., 2002; McBride and Zhu 2013). Soluble GldG homologues (no TMSs) are found in eukaryotes (e.g. intraflagellar protein transporter, IPT52 of Chlamydomonas reinhardtii; XP_001692161)

Bacteria

GldAFG of Flavobacterium johnsoniae:
GldA (C; 298 aas) - (O30489)
GldF (M; 241 aas; 6TMSs (2+2+2) - (Q93LN1)
GldG (M-periplasm; putative auxillary subunit with 2TMSs at the N and C-termini; 561 aas)- (Q93LN0).

 
3.A.1.132.10

Putative ABC exporter of unknown function, Gll1303/Gll1302, with two probable subunits of 477 and 494 aas with 6 TMSs each at their N-termini (M) and ATPase domains (C) in the C-termini.

Cyanobacteria

Gll1303/Gll1304 putative ABC exporter of Gloeobacter violaceus
Gll1303, (M)
Gll1302, (M)

 
3.A.1.132.11

Putative ABC exporter with two membrane proteins of 478 and 417 aas and 6 TMSs respectively, and one ATPase.  The encoding genes are adjacent to a TonB-dependent OMR with possible specificity for a siderophore.  Thus, this ABC exporter could transport a siderophore.

Proteobacteria

Uncharacterized ABC exporter of Saccharophagus degradans
Sde_3610 (C), 249 aas (Q21EL4)
Sde_3609 (M), 478 aas and 6 TMSs (Q21EL5)
Sde_3608 (M), 417 aas and 6 TMSs (Q21EL6)

 
3.A.1.132.12

ABC exporter necessary for social motility, pilus assembly and pilus subunit (PilA) export, PilGHI. Mutants show elevated sporulation rates and abnormal development (Wu et al. 1998).

Proteobacteria

PilHI of Myxococcus xanthus
PilH (C) ABC protein (O30385)
PilT (M) 6 TMS membrane protein of 255aas (O30386) 

 
3.A.1.132.2The NosDFY Copper ABC transporter (Chan et al., 1997)BacteriaNosDFY of Sinorhizobium meliloti
NosD (R; periplasmic copper binding receptor)(Q52899)
NosF (C; like GldA) (Q52900)
NosY (M; like GldF) (O07330)
 
3.A.1.132.3

The uncharacterized ABC transporter with GldF-GldG homologues fused.  The adjacent gene encodes the ATPase, GldA, and the next gene encodes an auxiliary protein of the MPA1-C family (TC# 8.A.3).

Bacteria

GldAFG homologues of Magnetococcus sp. MC-1
GldFG (M-Aux; 964 aas) (A0L4K8)
GldA (C; 399 aas) (A0L4L0)

 
3.A.1.132.4The uncharacterized ABC transporter with GldF-GldG homologues fusedBacteriaGldAFG homologues of Hahella chejuensis
GldF-G (M-Aux; 978 aas) (Q2SDB0)
GldA (C; 315 aas) (Q2SDB1)
 
3.A.1.132.5

Putative ABC2 transporter: Membrane protein of 274aas and 6 TMSs; Cytoplasmic ATPase of 302aas.

Proteobacteria

Putative ABC2 transporter of Shewanella pealeana
(M) (A8GZV3)
(C) (A8GZV2) 

 
3.A.1.132.6

Putative ABC2 transporter: Membrane protein of 274aas and 6 TMSs; Cytoplasmic ATPase of 302aas.

Firmicutes

Putative ABC-2 transporter of Streptococcus pyogenes 
(M) (Q99ZC7)
(C) (Q99ZC8) 

 
3.A.1.132.7

Putative ABC membrane protein with 12 TMSs. (ATPase subunit unknown, and not encoded by an adjacent gene).

Planctomycetes

ABC membrane protein of Rhodopirellula baltica

 
3.A.1.132.8

ABC transporter, annotated as involved in multi copper protein maturation

Archaea

ABC exporter of Methanocella conradii
permease (M) (H8I780)
ATPase (C) (H8I779)

 
3.A.1.132.9

Putative ABC exporter, Odosp_3144/Odosp_3145. Odosp_3144 is a 6 TMS ABC2 membrane protein (N-terminal 250 aas) fused to an auxiliary protein with one N- and one C-terminal TMS, homologous to GldG of Cytophaga johnsonae (3.A.1.132.1).

Bacteroidetes

Putative ABC transporter of Odoribacter splanchnicus 
Odosp_3144 (M) (761 aas; 7 TMSs) (F9Z892)
Odosp_3145 (C) (306 aas) (F9Z893) 

 


3.A.1.133 The Peptide-6 Exporter (Pep6E) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.133.1The modified YydF* peptide exporter, YydIJ (Butcher et al., 2007)BacteriaYydIJ of Bacillus subtilis:
YydI (C) (Q45593)
YydJ (M) (Q45592)
 
3.A.1.133.2A 6TMS homologue of YydJ (ORF1) of 280aasBacteriaORF1 of Flavobacteria bacterium BBFL7 (Q26C21)
 


3.A.1.134 The Peptide-7 Exporter (Pep7E) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.134.1The lantibiotic, salivericin A exporter, SalXYGram-positive bacteriaSalXY of Streptococcus salivarius
SalX (C)
SalY (M)
 
3.A.1.134.10

Peptide exporter, YsaB (667 aas and 10 TMSs)/YsaC (257 aas).  Probably exports lantibiotic antibiotics (Draper et al. 2015).

Firmicutes

YsaBC of Lactococcus lactis
YsaB (M)
YsaC (C)

 
3.A.1.134.11

Lantibiotic detoxification ABC transporter, VraD (252 aas)/VraE (626 aas; 10 TMSs)/VraH ( (Draper et al. 2015).  Upregulated in response to exposure to beta-defensin 3 (Sass et al. 2008).  Exports antimicrobial peptides such as nisin, bacitracin, daptomycin and gallidermin. Expression of vraH in the absence of vraDE is sufficient to mediate low-level resistance, but VraDEH is required to  confer high-level resistance against daptomycin and gallidermin. (Popella et al. 2016).

Firmicutes

VraDE of Staphylococcus aureus

VraD (Q9RL74)
VraE (Q9KWJ6)
VraH (T1YED1)

 
3.A.1.134.12

ABC multidrug resistance efflux pump, AnrAB.  Exports nisin, gallidermin, bacitracin and β-lactam antibiotics  (Collins et al. 2010).

Firmicutes

AnrAB of Listeria monocytogenes
AnrA (C)
AnrB (M; 642 aas and 10 TMSs)

 
3.A.1.134.13

Putative ABC exporter with three constituent proteins, two membrane proteins with a probable 10 TMS topology in a 1 (N-terminal) + 6 (middle) + 3 (C-terminal) TMS arrangement, and one ATPase

ABC transporteer of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)

 
3.A.1.134.14

Putative ABC3-type porter with a membrane protein and an ATPase encoded by adjacent genes, but next to the genes that encoded by the systems in TCDB under TC#s 3.A.1.207.7 and 8.

ABC3-type porter of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)

 
3.A.1.134.2The bacitracin-resistance (putative bacitracin exporter), MbrAB. Participate with BreSR to control its own gene expression (Bernard et al., 2007).Gram-positive bacteriaMbrAB of Streptococcus mutans
MbrA (C)
MbrB (M)
 
3.A.1.134.3

The putative bacitracin exporter, BceAB (BarAB; YtsCD) (Bernard et al., 2003; Ohki et al., 2003).  Functions in both signaling to the two component system, BceRS, and in export of the antimicrobial peptide (Dintner et al. 2014).  BceB interacts directly with BceS, and BceB binds bacitracin (Dintner et al. 2014).  Specific regions and residues are invollved in signalling or transport (Kallenberg et al. 2013).  More recent studies suggest taht BceAB may cause bacitracin resistance by transferring undecaprenyl pyrophosphate from the exteral to the internal leaflet of the inner membrane where it can't bind bacitracin and other lantibiotics that use Lipid II as a receptor (Draper et al. 2015).

Firmicutes

BceAB (YtsCD) of Bacillus subtilis
BceA (C) CAB15016
BceB (M) CAB15015

 
3.A.1.134.4

The bacitracin/vancoresmycin (a tetramic acid antibiotic) resistance exporter (Becker et al. 2009) (most like 3.A.1.134.2)

Firmicutes

SPR0812/SPR0813 of Streptococcus pnenmoiae
SPR0812 (C) (Q8DQ77)
SPR0813 (M) (Q8DQ76)

 
3.A.1.134.5

The MDR exporter, YvcRS. Possibly linked to regulation by a sensor kinase/response regulator system (YvcQP) (Joseph et al., 2002; Bernard et al., 2007).

Bacteria

YvcRS of Bacillus subtilis
YvcR (C) (O06980)
YvcR (M) (O06981)

 
3.A.1.134.6

The cationic peptide/MDR exporter, YxdLM. Possibly linked to a sensor kinase/reponse regulator system (YxdJK) (Joseph et al., 2002; Bernard et al., 2007).

Bacteria

YxdLM of Bacillus subtilis
YxdL (C) (P42423)
YxdM (M) (P42424)

 
3.A.1.134.7

The VraFG ABC transporter interacts with GraXSR [GraX, Q7A2W7; GraS, A6QEW9; GraR, A6QEW8] to form a five-component system required for cationic antimicrobial peptide sensing and resistance (Falord et al., 2012).  VraX has been termed a two component system connector and may not be a component of the transporter.

Bacteria

VraFG/GraXSR of Staphylococcus aureus 
VraF (A6QEX0)
VraG (A6QEX1)
VraX (Q7A2W7)

 
3.A.1.134.8

Antimicrobial peptide exporter, ABC12 or YvoST (Revilla-Guarinos et al. 2013).

Firmicutes

YvoST of Lactobacillus casei

 
3.A.1.134.9

Two component toxic peptide exporter with a membrane subunit of 663 aas and 10 TMSs and an ATPase of 256 aas, ABC09 (Revilla-Guarinos et al. 2013).

Firmicutes

ABC09 of Lactobacillus casei

 


3.A.1.135 The Drug Exporter-4 (DrugE4) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.135.1

The heterodimeric multidrug exporter, YdaG/YbdA  (Both proteins are ABC half transporters; only the heterodimer is active; ethidium, daunomycin and BCECF-AM are substrates; Lubelski et al., 2004) These proteins have been renamed LmrC and LmrD (Lubelski et al., 2006)

Gram-positive bacteriaYdaG/YdbA of Lactococcus lactis YdaG (M-C) (AAK04408)
YdbA (M-C) (AAK04409)
 
3.A.1.135.10

Uncharacterized two component ABC transporter, both of M-C domain order with 6 N-terminal TMSs. The genes encoding these two proteins are adjacent to  a putative ABC transporter of TC# 9.B.29.2.13.

UPs of Caldicellulosiruptor saccharolyticus

 
3.A.1.135.11

ABC transporter with two components, each with 6 N-terminal TMSs + a C-terminal ATPase

ABC exporter of Methanobrevibacter sp.

 
3.A.1.135.12

Two component ABC exporter, both subunits with 611 and 600 aas with 6 N-terminal TMSs in a 2 + 2 + 2 arrangement.  The C-terminal domain is the ATPase

ABC exporter of Lokiarchaota

 
3.A.1.135.13

Two component netropsin resistance ABC netropsin exporter, NetP1/NetP2 (Stumpp et al. 2005).

Netropsin resistance efflux porter of Streptomyces netropsis (Streptoverticillium netropsis)
NetP1 of 618 aas and 6 TMSs (M-C) (Q66LJ1)
NetP2 of 635 aas and 6 TMSs (M-C) (Q66LJ0)

 
3.A.1.135.2The heterodimeric putative multidrug exporter, RscA/RscB; probably orthologous to YdaG/YbdA (TC #3.A.1.117.4) [Transcription is activated by stress conditions (heat, acid) and repressed by a 2-component system, CovRS (Dalton et al., 2006)]Gram-positive bacteriaRscAB of Streptococcus pyogenes RscA (M-C) (568 aas) (Q9A1K5)
RscB (M-C) (594 aas) (Q9A1K4)
 
3.A.1.135.3

Narrow spectrum fluoroquinolone (ciprofloxacin and norfloxacin) efflux pump, SatAB (Escudero et al. 2011).

Firmicutes

SatAB of Streptococcus suis
SatA, 568 aas (M-C) (G9CHY8)
SatB, 594 aas, (M-C) (G9CHY9)

 
3.A.1.135.4

Multidrug resistance ABC exporter, PatAB (PatA, 564 aas; PatB, 588 aas) (Bidossi et al. 2012).

Firmicutes

PatAB of Streptococcus pneumoniae
PatA (M-C)
PatB (M-C)

 
3.A.1.135.5

The hetrodimeric ABC transporter, TM287/TM288.  The 2.9-Å crystal structure has been solved in the inward-facing state. The two nucleotide binding domains (NBDs) remain in contact through an interface involving conserved motifs that connect the two ATP hydrolysis sites.  AMP-PNP binds to a degenerate catalytic site which deviates from the consensus sequence in the same positions as the eukaryotic homologs, CFTR (TC# 3.A.1.202.1) and TAP1-TAP2 (TC# 3.A.1.209.1) (Hohl et al. 2012).  The structural basis for allosteric crosstalk (positive cooperativity) between the two ATP binding sites has been studied (Hohl et al. 2014).  The two NBDs exhibit unexpected differences and flexibility (Bukowska et al. 2015). It exports daunomycin and the nonfluorescent 2,7-bis(carboxyethyl)-5(6)-carboxyfluorescein-acetoxymethylester (BCECF-AM) (Hohl et al. 2012). Timachi et al. 2017 observed hydrolysis-independent closure of the NBD dimer, further stabilized as the consensus site nucleotide is committed to hydrolysis.

Thermatogae

TM287/TM288 of Thermatoga maritima

 
3.A.1.135.6

Two component multidrug efflux pump with the 6 TMS membrane domain preceding the ATPase domain in both proteins.  Confers resistance to erythromycin and tetracycline and catalyzes export of Hoechst 33342 (Moodley et al. 2014).  Expression is induced by the presence of erythromycin.

Actinobacteria

MDR pump of Bifidobacterium longum

 
3.A.1.135.7

Multidrug exporter, EfrAB.  Confers resistance to many structurally unrelated antimicrobial agents, such as norfloxacin, ciprofloxacin, doxycycline, acriflavine, 4,6-diamidino-2-phenylindole, tetraphenylphosphonium chloride, daunorubicin, and doxorubicin (Lee et al. 2003).  Induced by half minimal inhibitory concentrations (MIC) of gentamicin, streptomycin and chloramphenicol which are also exporter (Lavilla Lerma et al. 2014).  In some strains, this system may not be the primary drug exporter (Hürlimann et al. 2016).

EfrAB of Enterococcus faecalis
EfrA (MC), 567 aas and 6 TMSs
EfrB (MC), 589 aas and 6 TMSs

 
3.A.1.135.8

Multidrug efflux pump, EfrCD.  Exports daunorubicin, doxorubicin, ethidium and Hoechst 33342.  Mediates efflux of fluorescent substrates and confers resistance towards multiple dyes and drugs including fluoroquinolones (Hürlimann et al. 2016).

EfrCD of Enterococcus faecalis
EfrC, MC, 571 aas and 6 TMSs
EfrD, MC, 589 aas and 6 TMSs

 
3.A.1.135.9

Multidrug exporter, EfrEF.  Mediates efflux of fluorescent substrates and confers resistance towards multiple dyes and drugs including fluoroquinolones (Hürlimann et al. 2016).

EfrEF of Enterococcus faecalis
EfrE, MC, 575 aas and 6 TMSs
EfrF, MC, 592 aas and 6 TMSs

 


3.A.1.136 The Uncharacterized ABC-3-type (U-ABC3-1) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.136.1Putative ABC3 permease complex U-ABC3-1a (403aas; 4TMSs:1+3)BacteriaU-ABC3-1a of Treponema denticola (M) (Q73MJ0)
 
3.A.1.136.2

ABC-type antimicrobial peptide transporter of 421 aas and 4 TMSs

ABC transporter of Bdellovibrio bacteriovorus

 


3.A.1.137 The Uncharacterized ABC-3-type (U-ABC3-2) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.137.1Putative ABC-3-type permease complex, ABC3-2aArchaeaABC3-2a of Pyrobaculum calidifontis:
ABC3-2a (M) (A3MWP2)
ABC3-2a (C) (A3MWP1)
 
3.A.1.137.2

ABC-type antimicrobial peptide transporter of 786 aas and 8 TMSs

ABC transporter of Bdellovibrio bacteriovorus

 


3.A.1.138 The Unknown ABC-2-type (ABC2-1) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.138.1Unknown ABC-2 transporter complex-1, U-ABC2-TC-1ArchaeaU-ABC2-TC-1 of Picrophilus torridus:
U-ABC2-TC-1a (M) (Q6KYW9)
U-ABC2-TC-1a (C) (Q6KYW8)
 


3.A.1.139 The UDP-Glucose/Iron Exporter (U-GlcE) Family (UPF0014 Family)


Examples:

TC#NameOrganismal TypeExample
3.A.1.139.1

UDP-glucose exporter, STAR1/STAR2 (sensitive to aluminum rhizotoxicity) (Probable Type I topology) (Huang et al. 2009).

Plants

STAR1/STAR2 of Oryza sativa
STAR1 (C) (Q5Z8H2)
STAR2 (M) (Q5W7C1)

 
3.A.1.139.2

The FetA (YbbL)/FetB (YbbM) iron exporter (SwissProt family UDF0014; 6 or 7 putative TMSs).  Expression enhances resistance to oxidative stress (Nicolaou et al. 2013).

Bacteria

FetA/B of E. coli
FetA (C) (P77279)
FetB (M) (P77307)

 
3.A.1.139.3

The uncharacterized ABC exporter, U-ABC-M/C

Bacteria

U-ABCC/U-ABC-M of Spirochaeta africana
U-ABC-C (C) (H9UM45)
U-ABC-M (M) (H9UM46)

 
3.A.1.139.4

Plasma membrane ABC exporter, sensitive to aluminum rhizotoxicity 1/2, STAR1/STAR2 (Larsen et al., 2005). Induced in response to aluminum exposure. 

Plants

STAR1/2 of Arabidopsis thaliana 
STAR1 (C) (Q9C9W0)
STAR2 (M) (Q9ZUT3) 

 


3.A.1.14 The Iron Chelate Uptake Transporter (FeCT) Family (Similar to 3.A.1.13 and 3.A.1.15)


Examples:

TC#NameOrganismal TypeExample
3.A.1.14.1Iron (Fe3+) or ferric-dicitrate porter (Braun and Herrmann, 2007)ProteobacteriaFecBCDE of E. coli
FecB (R)
FecC (M)
FecD (M)
FecE (C)
 
3.A.1.14.10

The heme porter, Shp/SiaABC (HtsABC). Shp is a cell surface heme binding protein that transfers the heme directly to HstA (Nygaard et al., 2006). The crystal structure of the heme binding domain of Shp has been solved (Aranda et al., 2007). HtsABC is required for the uptake of staphyloferrin A (Beasley et al. 2009). The Shp cell surface heme receptor feeds iron-heme to the transporter in preparation for uptake (Sun et al. 2010; Ouattara et al., 2010). 

Bacteria

Shp/HtsABC of Streptococcus pyogenes
Shp (R1) (291 aas; Q1J548)
HtsA (R2) (294 aas; Q99YA2)
HtsB (M) (340 aas; Q99YA3)
HtsC (C) (278 aas; Q99YA4)

 
3.A.1.14.11

The molybdate/tungstate ABC transporter, MolABC.  For MolC; HI1470(C)/MolB; HI1471(M), the 3D structure is known at 2.4 Å resolution; Pinkett et al., 2007).  MolA binds to MolBC with low affinity (50 - 100μM), forming a transient complex that is stabilitzed by ligand binding (Vigonsky et al. 2013).

Proteobacteria

MolABC of Haemophilus influenzae
MolC; HI1470 (C) (Q57399)
MolB; HI1471 (M; 10 TMSs; type II fold) (Q57130)
MolA; HI1472 (R) (E3GUW2)

 
3.A.1.14.12

Desferrioxamine B uptake porter, DesABC (Barona-Gomez et al., 2006)

Bacteria

DesABC of Streptomyces coelicolor
DesA (R) (1 TMS) (Sco7499; Q9L178)
DesB (M-M) (18 TMSs; 9 9 TMSs) (Sco7498; Q9L179)
DesC (C) (0 TMSs) (Sco7400; Q9L177)

 
3.A.1.14.13

Ferric iron-coelichelin uptake porter, CchCDEF (Barona-Gomez et al., 2006).

Actinobacteria

CchCDEF of Streptomyces coelicolor
CchC (M) (Sco0497) (Q9RK09)
CchD (M) (Sco0496) (Q9RK10)
CchE (C) (Sco0495) (Q9RK11)
CchF (R) (Sco0494) (Q9RK12)

 
3.A.1.14.14

The Fe3+ /Fe3+ferrichrome/Fe3+heme uptake porter; SiuABDG (FTSABCD) (Montañez et al., 2005; Hanks et al. 2005; Li et al. 2013).  A similar system has been characterized in S. iniae (Wang et al. 2013).

Bacteria

SiuABDG (FtsABCD) of Streptococcus pyogenes
SiuA; FtsA (C) (Q9A197)
SiuD; FtsB (R) (Q9A199)
SiuB; FtsC (M) (Q9A198)
SiuG; FtsD (M) (Q06A41) 

 
3.A.1.14.15

Uptake transporter for the catecholic trilactone (2, 3-dihydroxybenzoate-glycine-threonine)3 siderophore bacillibactin (for ferric iron scavenging), FeuABC (Gaballa and Helmann, 2007; Miethke et al., 2006).

Bacteria

FeuABC of Bacillus subtilis
FeuA (R) (P40409)
FeuB (M) (P40410)
FeuC (M) (P40411)

 
3.A.1.14.16

The heme-specific uptake porter, HemTUV (Létoffé et al., 2008).

Bacteria

HemTUV of Serratia proteamaculans
HemT (R) - (A8GDS8)
HemU (M) - (A8GDS7)
HemV (C) - (A8GDS6)

 
3.A.1.14.17Heme acquisition ABC uptake transporter, IsdDEF (Liu et al., 2008)FirmicutesIsdDEF of Staphylococcus aureus
IsdD (?) (358aas, 2TMSs) (Q5HGV2)
IsdE (R) (295aas, 1TMS) (Q7A652)
IsdF (M) (273aas; 8TMSs) (Q7A651)
 
3.A.1.14.18

The heme uptake porter, ShuTUV (Burkhard and Wilks, 2008). Transports a single heme per reaction cycle (Mattle et al., 2010). (3-d structure of ShuT is known (2RG7).

Bacteria

ShuTUV of Shigella dysenteriae
ShuT(R) (Q32AX9)
ShuU(M) (Q32AY2)
ShuV(C) (Q32AY3)

 
3.A.1.14.19Heme uptake porter, HugBCD (Villarreal et al., 2008); also called HmuTUV.

Bacteria

HugBCD of Plesiomonas shigelloides
HugB (R) (Q93SS3)
HugC (M) (Q93SS2)
HugD (C) (Q93SS1)

 
3.A.1.14.2

Iron (Fe3+)-enterobactin porter

Proteobacteria

FepBCDG of E. coli
FepB (R) (C8U2V6)
FepC (C) (P23878)
FepD (M) (P23876)
FepG (M) (P23877)

 
3.A.1.14.20

Heme-iron (hemin) utilization transporter BhuTUV ( Brickman et al., 2006; Vanderpool and Armstrong, 2004).  The crystal structures of BhuUV with or without the periplasmic haem-binding protein BhuT have been solved (Naoe et al. 2016). The TMSs show an inward-facing conformation, in which the cytoplasmic gate of the haem translocation pathway is completely open. Since this conformation is found in both the haem- and nucleotide-free form, the structure of BhuUV-T provides the post-translocation state and the missing piece in the transport cycle of type II importers.

Gram-negative bacteria

BhuTUV of Bordetella pertussis
BhuT (R) (Q7VSQ6)
BhuU (M) (Q7W024)
BhuV (C) (Q7W025)

 
3.A.1.14.21

The heme uptake porter, PhuTUV (transports one heme per reaction cycle) (Mattle et al., 2010).

Proteobacteria

PhuTUV of Pseudomonas aeruginosa
PhuT (R) (Q9HV90)
PhuU (M) (O68878)
PhuV (C) (O68877)

 
3.A.1.14.22

The putative ferric iron-desferrioxamine E uptake porter, DesEFGH.  The DesE binding receptor has been characterized (Barona-Gómez et al. 2006).  The remaining three (desFGH) genes cluster together without a gene encoding a receptor (R).  They are believed to function with DesE based on sequence similarity and phylogenetic analyses (Getsin et al., 2013).

Actinobacteria

DesEFGH of Streptomyces coelicolor
DesE (Sco2780) (R) (349 aas; 1 TMS) (Q9L074)
DesF (Sco1785) (C) (301 aas; 0 TMSs) (Q9S215)
DesG (Sco1786) (M) (375 aas; 9 TMSs) (Q9S214)
DesH (Sco1787) (M) (345 aas; 9 TMSs) (Q9S213)

 
3.A.1.14.23

Two components of a vitamin B12 (cobalamin) uptake porter, BtuCD.  BtuAB must exist but have not been identified (Deutschbauer et al. 2011). 

BtuCD of Shewanella oneidensistu
BtuC (M) of 380 aas
BtuD (C) of 314 aas

 
3.A.1.14.24

FecB1CDE iron siderophore uptake transporter. Transports iron chelated dihydroxamate xenosiderophores, either ferric schizokinen (FeSK) or a ferric siderophore of the filamentous cyanobacterium Anabaena variabilis ATCC 29413 (a schizokinen derivative, SAV), as the sole source of iron in a TonB-dependent manner (Obando S et al. 2018). The gene schT encodes the TonB-dependent outer membrane transporter (TC# 1.B.14.9.6).

FecB1CDE of Synechocystis sp. PCC 6803
FecB1 (R), 315 aas, P72593
FecC (M), 343 aas, 9 TMSs
FecD (M), 349 aas, 9 TMSs
FecE (C), 268 aa

 
3.A.1.14.25

Heme uptake porter with three subunits (Mandal et al. 2019).

Heme porter of Thermus thermophilus

 
3.A.1.14.26

Cyanocobalamin uptake porter with 3 components, R, M and C (Mandal et al. 2019).

Cyanocobalamin porter of Thermus thermophilus

 
3.A.1.14.27

Heme transporter with three components, HmuU (M), HmuV (C) and HmuT (R).  Chemo-mechanical coupling in the transport cycle has been proposed with outward open, inward open and occluded states (Tamura et al. 2019).

HmuUVT of Burkholderia cenocepacia (Burkholderia cepaci)
HmuU, B4EKB4 (M)
HmuV, B4EKB5 (C)
HmuT, B4EKB3 (R)

 
3.A.1.14.3Iron (Fe3+)-hydroxamate (ferrichrome, coprogen, aerobactin, ferrioxamine B, schizakinen, rhodotorulic acid) porter, albomycin porterProteobacteriaFhuBCD of E. coli
FhuB (M-M; 20 TMSs; 10+10)
FhuC (C)
FhuD (R)
 
3.A.1.14.4Iron-chrysobactine porterProteobacteriaCbrABCD of Erwinia chrysanthemi
CbrA (R)
CbrB (M)
CbrC (M)
CbrD (C)
 
3.A.1.14.5

Heme (hemin) uptake porter. The receptor, HmuT, binds two parallel stacked heme molecules, and two are transported per reaction cycle (Mattle et al., 2010).

Proteobacteria

HmuTUV of Yersinia pestis
HmuT (R) (Q56991)
HmuU (M) (Q56992)
HmuV (C) (Q56993)

 
3.A.1.14.6The iron-vibriobactin/enterobactin uptake porterProteobacteriaViuPDGC of Vibrio cholerae
ViuP (R)
ViuD (M)
ViuG (M)
ViuC (C)
 
3.A.1.14.7

Iron (Fe3+)-hydroxamate porter (transports Fe3+-ferrichrome and Fe3+-ferrioxamine B with FhuD1, and these compounds plus aerobactin and coprogen with FhuD2).  FhuB may function with FhuG (A6QEV8) together with FhuD2 to form a ferrichrome transporter where FhuB and FhuG have conserved arginine residues (R71 and R61, respectively) that form essential salt bridges with FhuD2 (Vinés et al. 2013).

Firmicutes

FhuBCD1D2 of Staphylococcus aureus
FhuB (M)
FhuC (C)
FhuD1 (R)
FhuD2 (R)

 
3.A.1.14.8The iron-vibrioferrin uptake porter (Tanabe et al., 2003) ProteobacteriaPvuBCDE of Vibrio parahaemolyticus
PvuB (R) (BAC16540)
PvuC (M) (BAC16541)
PvuD (M) (BAC16542)
PvuE (C) (BAC16543)
 
3.A.1.14.9The Corrinoid porter, BtuCDE (Woodson et al., 2005)ArchaeaBtuCDE of Halobacterium sp. strain NRC-1
BtuC (M) (AAG19698)
BtuD (C) (NP_444218)
BtuE (R) (AAG19697)
 


3.A.1.140 The FtsX/FtsE Septation (FtsX/FtsE) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.140.1

The FtsX/FtsE ABC transporter (Arends et al., 2009) (FtsX is of the type III topology). FtsEX directly recruits EnvC to the septum via an interaction between EnvC and a periplasmic loop of FtsX. FtsEX variants predicted to be ATPase defective still recruit EnvC to the septum but fail to promote cell separation. Amidase activation via EnvC in the periplasm is regulated by conformational changes in the FtsEX complex mediated by ATP hydrolysis in the cytoplasm. Since FtsE has been reported to interact with FtsZ, amidase activity may be coupled with the contraction of the FtsZ cytoskeletal ring (Yang et al., 2011).

Bacteria

FtsX/FtsE of E. coli
FtsX (M) (P0AC31)
FtsE (C) (P0A9R7)

 
3.A.1.140.2

The cell division ABC system, FtsX/FtsE

FstE/X of Caldanaerobacter subterraneus subsp. tengcongensis (Thermoanaerobacter tengcongensis)

 
3.A.1.140.3

Cell division ABC system, FtsXE.

FtsXE of Nostoc punctiforme
FtsX (M), 300 aas, 4 TMSs
FtsE (C), 248 aas

 
3.A.1.140.4

Cell division ABC system, FtsXE of 300 aas and 4 TMSs, and 229 aas and 0 TMSs, respectively.

FtsXE of Actinokineospora spheciospongiae
FtsX, (M), 300 aas and 4 TMSs
FtsE, (C), 229 aas and 0 TMSs

 
3.A.1.140.5

Cell division ABC system, FtsXE.

FtsXE of Candidatus Nitrosopumilus salaria
FtsX, (M), 301 aas, 4 TMSs
FtsE, (C), 222 aas, 0 TMSs

 
3.A.1.140.6

Cell division system, FtsXE.  The FtsEX:PcsB complex forms a molecular machine that carries out peptidoglycan (PG) hydrolysis during normal cell division. FtsEX transduces signals from the cell division apparatus to stimulate PG hydrolysis by PcsB, an amidase, which interacts with extracellular domains of FtsX (Bajaj et al. 2016).

FtsXE of Streptococcus pneumoniae
FtsX, (M), 308 aas and 4 TMSs
FtsE, (C), 226 aas and 0 TMSs

 


3.A.1.141 The Ethyl Viologen Exporter (EVE) Family (DUF990 Family)


Examples:

TC#NameOrganismal TypeExample
3.A.1.141.1

The ethyl (methyl; benzyl) viologen export pump, EvrABC (EvrB and EvrC of 6 TMSs are members of the large DUF990 superfamily (Prosecka et al., 2009); They appear to be of the ABC-2 topological type).

Bacteria

EvrABC of Synechocystis sp. PCC6803
P73329 slr1910, ABC protein (EvrA)
P74256 slr1174, membrane protein (EvrB)
P74757 slr0610, membrane protein (EvrC)

 
3.A.1.141.2

ABC transporter of unknown specificity, AbcABC

Bacteria

AbcABC of Thermoanaerobacter tengcongensis
AbcA (M) (Q8R6Q6)
AbcB (M) (Q8R6Q5)
AbcC (C) (Q8R6Q4)

 


3.A.1.142 The Glycolipid Flippase (G.L.Flippase) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.142.1

Glycolipid translocase (flippase) Spr1816/Spr1817 (R.Hakenbeck, personal communication)

Firmicutes

Glycolipid flippase, Spr1816/Spr1817, of Streptococcus pneumoniae
Spr1816 (M) (Q8DNC0)
Spr1817 (C) (Q8DNB9)

 
3.A.1.142.2

ABC exporter, YvfS/YvfR of 284 and 287 aas, respectively

YvfSR of Bdellovibrio bacteriovorus
YvfS (M)
YvfR (C)

 


3.A.1.143 The Exoprotein Secretion System (EcsAB(C))


Examples:

TC#NameOrganismal TypeExample
3.A.1.143.1

The exoprotein (including α-amylase) secretion system, EcsAB(C) (Leskelä et al., 1999). Also may play roles in sporulation, competence (Leskelä et al., 1996) and transformation using purified DNA (Takeno et al., 2011). An involvement of EcsC in transport is not established, but it is homologous to the C-terminus of the P-type ATPase, 3.A.3.31.2.

Bacteria

EcsAB(C) of Bacillus subtilis 
EcsA (C) (P55339)
EcsB (M) (P55340)
EcsC (M) (P55341) 

 
3.A.1.143.2

YthQ (386aas; 8-9 TMSs)/YthP (ATPase; 0 TMSs)

Bacteria

YthPQ (EscAB) of Bacillus amyloliquefaciens
EscA (YthP) (G0IP52)
EscB (YthQ) (G0IP51)

 


3.A.1.144 Functionally Uncharacterized ABC2-1 (ABC2-1) Family

 


Examples:

TC#NameOrganismal TypeExample
3.A.1.144.1

Functionally uncharacterized ABC2 transporter #1.  This system is encoded by two genes that overlap and are therefore probably translationally coupled; they are in the same operon with the genes for 2.A.1.144.2.

Archaea

ABC2 transporter #1 of Methanocella arvoryzae 
ABC2-1 (M) (Q0W8T3)
ABC2-1 (C) (Q0W8T4) 

 
3.A.1.144.2

Functionally uncharacterized ABC2 transporter #2.  This system is encoded by two genes that overlap and are therefore probably translationally coupled; they are in the same operon with the genes for 2.A.1.144.1.

Archaea

ABC2 transporter #2 of Methanocella arvoryzae
ABC2-2 (M) (Q0W8T6)
ABC2-2 (C) (Q0W8T7) 

 
3.A.1.144.3

Functionally uncharacterized ABC2 transporter #3.

%u03B4-Proteobacteria

ABC2 transporter of Myxococcus xanthus
ABC2-3 (M) (Q1D0V0)
ABC2-3 (C) (Q1D0V1) 

 
3.A.1.144.4

Functionally uncharacterized ABC2 transporter #4 of 751 aas with 18 putative TMSs.  The first 6 TMSs are duplicated to give the N-terminal 12 TMSs.  The last 6 TMSs are non-homologous and are of the DUF95 family (TC #9.B.98) which may consist of ABC exporter auxiliary subunits/domains.

Chloroflexi

ABC2 transporter of Oscillochloris trichoides 
ABC2 (M) (E1IBA3)
ABC2 (C) (E1IBA4) 

 


3.A.1.145 Peptidase Fused Functionally Uncharacterized ABC2-2 (ABC2-2) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.145.1

ABC2 transporter domain fused to an aminopeptidase N domain (Peptidase M1 family) of 1200 aas with 13 putative N-terminal TMSs.

δ-proteobacteria

ABC2 protein of Myxococcus xanthus

 
3.A.1.145.2

Putative ABC2 permease of 529 aas and 12 TMSs, Glr0437.

Cyanobacteria

Glr0437 of Gloeobacter violaceus

 
3.A.1.145.3

ABC2 fusion protein of 1194 aas and 13 putative TMSs.  Annotated as ABC transporter involved in multi-copper enzyme maturation; permease component.

Bacteroidetes

ABC2 protein of Cecembia lonarensis

 
3.A.1.145.4

Putative ABC2 protein of 537 aas and 14 putative TMSs

Archaea

ABC2 permease of Methanocella paludicola

 
3.A.1.145.5

Uncharacterized ABC membrane transport protein of 222 aas and 6 TMSs.

UP of Candidatus Wolfebacteria bacterium

 


3.A.1.146 The actinorhodin (ACT) and undecylprodigiosin (RED) exporter (ARE) family


Examples:

TC#NameOrganismal TypeExample
3.A.1.146.1

The probable actinorhodin (ACT) and undecylprodigiosin (RED) exporter (Lee et al. 2012), AreABCD (Sco3956-9).

Actinobacteria

 

AreABCD (Sco3956-9) of Streptomyces coelicolor
AreA (C) (Sco3956)
AreB (M) (Sco3957)
AreC (C) (Sco3958)
AreD (M) (Sco3959)

 
3.A.1.146.2

Putative ABC exporter, Isop2111-Isop2114

Planctomycetes

Isop2111-Isop2114 of Isophaera pallida
Isop2111 (C) (332 aas) (E8R490)
Isop2112 (M) (359 aas; 6 TMSs) (E8R491)
Isop2113 (C) (340 aas) (E8R492)
Isop2114 (M) (298 aas; 7 TMSs) (E8R493) 

 
3.A.1.146.3

Putative four component ABC exporter with two membrane proteins and two ABC ATPases.

Putative ABC porter of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)

 


3.A.1.147 Functionally Uncharacterized ABC2-3 (ABC2-3) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.147.1

Putative two component ABC exporter with a membrane protein of 573 aas and 12 TMSs and an ATPase encoded adjacent to the membrane protein and also adjacent to a gene encoding an adenine glycosylase, probably within a single operon.

Gemmatimonadetes

ABC exporter of Gemmatimonas aurantiaca
Membrane protein (M) (C1A6K7)
ATPase (C) (C1A6K8)

 
3.A.1.147.10

Uncharacterized protein of 627 aas and 12 TMSs

Firmicutes

UP of Desulfosporosinus meridiei

 
3.A.1.147.2

Putative 2-component sporulation-related ABC exporter.  The genes encoding this system are adjacent to a spore germination receptor (TC# 2.A.3.9.5) and a putative signalling molecule transporter (2.A.86.1.11).

Firmicutes

Putative 3-component ABC exporter of Paenibacillus mucilaginosus
Protein of 572 aas and 12 putative TMSs (M) (F8FLY8)
ATPase protein of 243 aas (C) (F8FLY7)

 
3.A.1.147.3

Putative two component ABC exporter with the membrane protein having 623 aas and 12 TMSs.

Planctomycetes

ABC exporter of Isosphaera pallida
Membrane protein (M) (E8R692)
ATPase (C) (E8R694)

 
3.A.1.147.4

Putative two component ABC exporter with a membrane protein of 537 aas and 12 TMSs.

Firmicutes

ABC exporter of Ruminococcus torques
Membrane protein (M) (D4M3V3)
ATPase (C) (D4M3V2)

 
3.A.1.147.5

Putative 2 component ABC exporter with a membrane protein of 569 aas and 12 TMSs.

Firmicutes

Putative exporter of Natranaerobius thermophilus
Membrane protein (M) (B2A6N2)
ATPase (C) (B2A6N1)

 
3.A.1.147.6

Putative two component ABC exporter

Firmicutes

Putative ABC exporter of Clostridium difficile
Membrane protein (M) (C9XJW9)
ATPase (C) (C9XJX0)

 
3.A.1.147.7

Putative ABC transporter with a membrane protein of 582 aas and 11 TMSs.

Firmicutes

ABC transporter of Thermaerobacter marianensis
Membrane protein (M) (E6SIR8)
ATPase (C) (E6SIR7)

 
3.A.1.147.8

Putative ABC exporter with a membrane protein of 544 aas and 12 TMSs

Firmicutes

ABC exporter of Streptococcus pneumoniae
Membrane protein (M) (B8ZKM8)
ATPase (C) (B8ZKM9)

 
3.A.1.147.9

Putative ABC exporter

Euryarchaea

ABC exporter of Methanocella conradii
Membrane protein (M) (H8I7G4)
ATPase (C) (H8I7G5)

 


3.A.1.148 Functionally Uncharacterized ABC2-4 (ABC2-4) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.148.1

ABC lantibiotic NAI-107 immunity exporter, MlbYZ (Pozzi et al. 2015).

Actinobacteria

MlbYZ of Microbispora sp. ATCC PTA-5024
MlbY (258 aas, 6 TMSs; M)
MlbZ (300 aas; C)

 
3.A.1.148.2

ABC transport system, PspY (264 aas)/PspZ (301 aas)

Actinobacteria

PspYZ of Planomonospora alba
PspY (M; 264 aas)
PspZ (C; 301 aas)

 
3.A.1.148.3

Uncharacterized ABC transporter

Chloroflexi

Uncharacterized ABC transporter of Ktedonobacter racemifer

 
3.A.1.148.4

Uncharacterized ABC transporter, AbcYZ [Y (D2BBE4) = M with 6 TMSs; Z (D2BBE3)= C.]

Actinobacteria

AbcYZ of Streptosporangium roseum

 


3.A.1.149 Functionally Uncharacterized ABC2-5 (ABC2-5) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.149.1

ABC immunity system, TrnFG, protecting the bacteria from the bacteriocin, thuricin CD. TrnF is of 213 aas and 6 TMSs while TrnG is of 285 aas and 0 TMSs.  A 79 aa protein, TrnI with 2 TMSs, also provides immunity against thuricin CD, but the mechanism is unknown (Mathur et al. 2014). These proteins incoded in the thuricin operon.

TrnFG of Bacillus thuringiensis

 
3.A.1.149.2

Uncharacterized two component ABC-2 transporter.

UP of Clostridium intestinale
U2PSG5, M, 216 aas, 6 TMSs in a 2 + 4 arrangement
U2NJR5, C, ATPase of 290 aas

 
3.A.1.149.3

Putative 2 component ABC exporter.

Putative ABC exporter
S7U3S6, M, 215 aas, 6 TMSs in a 2 + 4 arrangement
S7U8X0, C, 285 aas, ATPase, ABC-2

 


3.A.1.15 The Manganese/Zinc/Iron Chelate Uptake Transporter (MZT) Family (Similar to 3.A.1.12, 3.A.1.14 and 3.A.1.16)


Examples:

TC#NameOrganismal TypeExample
3.A.1.15.1Manganese (Mn2+) porterCyanobacteriaMntABC of Synechocystis 6803
MntA (C)
MntB (M)
MntC (R)
 
3.A.1.15.10The Mn2+/Zn2+ transporter MntABC (KB of Mn2+ and Zn2+ is 0.1μM which bind with equal affinity to the same site (Lim et al., 2008)BacteriaMntABC of Neisseria meningitidis:
MntA (C) (A1IQK5)
MntB (M) (A1IQK4)
MntC (R) (Q5FA63)
 
3.A.1.15.11

The zinc uptake porter, YcdHI-YceA; AdcA/AdcC/AdcB (Gaballa et al., 2002).

Firmicutes

YcdHI-YceA of Bacillus subtilis
AdcA (YcdH) (R) (O34966)
AdcC (YcdI) (C) (O34946)
AdcB (YceA) (M) (O34610)

 
3.A.1.15.12

Metal ion (probably iron) uptake permease , YtgABC-RD. The third gene in the ytg operon is fused, the N-terminal membrane domain being fused to the C-terminal transcriptional regulator homologous to the diphtheria toxin repressor, DtxR. These two domains may be proteolitically processed yielding the two active proteins (Thompson et al. 2012). 

Chlamydiae

YtgABC-RD of Chlamydia trachomatis 
YtgA (R) (O9S529)
YtgB (C) (084071)
YtgC-R (M-R) (084072)
YtgD (M) (084073) 

 
3.A.1.15.13

The ZnuA18/ZnuA08/ZnuB/ZnuC zinc (Zn2+) uptake system (Hudek et al. 2013).  ZnuB (M) and ZnuC (C) can function with either of two zinc ion receptors, ZnuA18 (R) which is encoded in the znuACB operon, and ZnuA08 (R) which is encoded elsewhere on the chromosome.  ZnuA18 is more efficient that ZnuA08 in promoting uptake (Hudek et al. 2013).

Cyanobacteria

Zn2+ uptake system of Nostoc punctiforme
ZnuA18 (R) (B2IWS9)
ZnuA08 (R) (B2J0B7)
ZnuB (M) B2IWT1)
ZnuC (C) (B2IWT0)

 
3.A.1.15.14

High affinity Mn2+ uptake complex, PsaABC (Lisher et al. 2013).

Firmicutes

PsaABC of Streptococcus pneumoniae
PsaA (R; 309 aas)
PsaB (C; 240 aas)
PsaC (M; 282 aas)

 
3.A.1.15.15

High affinity Mn2+ uptake complex, MntABC.  The 3-d structure of MntC has been  solved to 2.2Å resolution (Gribenko et al. 2013).

Firmictues

MntABC of Staphylococcus aureus 
MntA of 247 aas (C)
MntB of 278 aas (M)
MntC of 309 aas (R)

 
3.A.1.15.16

ZnuABC Zinc/Manganese/iron uptake porter

ZnuABC of Leptospira sp.
ZnuA (R) 345 aas
ZnuB (M) 275 aas
ZnuC C) 210 aas

 
3.A.1.15.17

ZnuABC Zinc/Manganese/Iron uptake porter

 

ZnuABC of Bdellovibrio bacteriovorus
ZnuA (R)
ZnuB (M)
ZnuC (C)

 
3.A.1.15.18

ABC high affinity Zinc (Zn2+) uptake porter, ZnuABC.  The similar system from Y. pestis has been characterized (Bobrov et al. 2014; Neupane et al. 2018). ZnuA (R) of that systems can bind up to 5 zinc ions with high affinity.

ZnuABC of Yersinia pseudotuberculosis
ZnuA, 318 aas, Q66AT6
ZnuB, 261 aas, Q66AT8
ZnuC, 253 aas, Q66AT7

 
3.A.1.15.19

Zinc ion ABC uptake system, AztABCD, where AztD is a periplasmic chaparone protein that feeds Zn2+ into AztC, the periplasmic receptor/binding protein for the transporter (Neupane et al. 2018).

AztABCD of Paracoccus denitrificans
AztA, 309 aas, R, (A1B2F3)
AztB, 288 aas, 9 TMSs, M, (A1B2F2)
AztC. 263 aas, C, (A1B2F1)
AztD, 408 aas, Periplasmic chaparone (A1B2F4)

 
3.A.1.15.2Manganese (Mn2+) and zinc (Zn2+) porterFirmicutesScaABC of Streptococcus gordonii
ScaA (R)
ScaB (M)
ScaC (C)
 
3.A.1.15.3

Zinc (Zn2+) porter, AdcABC/AII

Firmicutes

AdcABC of Streptococcus pneumoniae
AdcA (R)
AdcB (M)
AdcC (C)
AdcAII (Lmb) (R)

 
3.A.1.15.4Iron and manganese porterProteobacteriaYfeABCD of Yersinia pestis
YfeA (R)
YfeB (C)
YfeC (M)
YfeD (M)
 
3.A.1.15.5

Zinc (Zn2+) porter of E. coli, ZnuABC.  Required for Zn2+ homeostasis and virulence in the close E. coli relative, Salmonella enterica (Ammendola et al., 2007).

Proteobacteria

ZnuABC (YebLMI) of E. coli
ZnuA (R)
ZnuC (C)
ZnuB (M)

 
3.A.1.15.6Iron (Fe2+)/Zinc (Zn2+)/Copper (Cu2+) porterFirmicutesMtsABC of Streptococcus pyogenes
MtsA (R)
MtsB (C)
MtsC (M)
 
3.A.1.15.7

Manganese (Mn2+) (Km=0.1 μM) and iron (Fe2+) (5 μM) porter (inhibited by Cd2+ > Co2+ > Ni2+, Cu2+) (most similar to YfeABCD of Yersinia pestis (TC #3.A.1.15.4)). Important for virulence in Salmonella (Karlinsey et al., 2010).

Proteobacteria

SitABCD of Salmonella typhimurium
SitA (R)
SitB (C)
SitC (M)
SitD (M)

 
3.A.1.15.8

Manganese (Mn2+), zinc (Zn2+) and possibly iron (Fe2+) uptake porter, TroABCD (Hazlett et al., 2003).  Transcription of the operon is controlled by the Mn2+-activated (not Zn2+- or Fe2+-activated) repressor, TroR (153 aas, acc# F7IW50;) TroR contains a metal-binding domain homologous to the YtgC-R protein (3.A.1.15.12) which has the membrane domain of this ABC transporter (N-terminus) fused to the repressor domain (C-terminus) (Liu et al. 2013).  TroA (Tromp1), the periplasmic metal binding protein, was originally reported to be an outer membrane porin (Zhang et al. 1999), but this proved to be incorrect.

Spirochaetes

TroABCD of Treponema pallidum
TroA (R) P96116
TroB (C) P96117
TroC (M) P96118
TroD (M) P96119

 
3.A.1.15.9Manganese (Mn2+) and Iron (Fe2+) porter, SitABCD (Davies and Walker, 2007)BacteriaSit ABCD of Sinorhizobium meliloti
SitA (R) - (Q92LL5)
SitB (M) - (Q92LL4)
SitC (C) - (Q92LL3)
SitD (M) - (Q92LL2)
 


3.A.1.150 Functionally Uncharacterized ABC2-6 (ABC2-6) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.150.1

Putative ABC transporter consisting of an ATPase and three membrane proteins having 4, 10 and 2 TMSs, respectively.  The structure of the ATPase is similar to those of ABC transorteers, and expression is down regulated in response to cold shock (Gerwe et al. 2007).

Putative ABC transporter of Pyrococcus furiosus

 
3.A.1.150.2

Putative ABC transporter consisting of an ATPase and 3 membrane proteins having 4, 10 and 2 TMSs.

Putative ABC transporter of Pyrococcus furiosus

 


3.A.1.151 Functionally Uncharacterized ABC2-7 (ABC2-7) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.151.1

3-component putative ABC transporter with two membrane proteins and an ATPase. These three genes are adjacent to a gene encoding a DegV domain-containing protein, a fatty acid binding domain, also found in PTS mannose EIIA proteins (TC# 4.A.6) and dihydrolyacetone kinases (Schulze-Gahmen et al. 2003; Kinch et al. 2005; Nan et al. 2009).

Putative ABC transporter of Halothermothrix orenii

 
3.A.1.151.2

Putative 3-compenent ABC transporter consisting of two membrane proteins and a cytoplasmic ATPase.  Adjacent to genes coding for a MoaJ/NirJ iron-sulfur nitrite-like oxidoreductase and an antilisterial bacteriocin biosynthetic enzyme, AlbA (B5YBB2 and 3, respectively).  The system could be a bacteriocin exporter.

ABC transporter of Dictyoglomus thermophilum
B5YBA9, M, 186 aas and 6 TMSs (may be N-terminally truncated)
B5YBB0, M, 223 aas and 6 TMSs (both in a 2 + 4 arrangement)
BSYBB1, C, 239 aas, ATPase

 


3.A.1.152 The lipopolysaccharide export (LptBFG) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.152.1

LPS export system, LptF (M), LptG (M) and LptB (C).  This system is also listed in TCDB under TC#1.B.42.1.2 as part of a multicomponent system.  The entire system is described in detail there. LptB2FG extracts LPSs from the IM and transports them to the outer membrane. Luo et al. 2017 reported the crystal structure of nucleotide-free LptB2FG from P. aeruginosa. It shows that LPS transport proteins LptF and LptG each contain a TM domain (TMD), a periplasmic beta-jellyroll-like domain and a coupling helix that interacts with LptB on the cytoplasmic side. The LptF and LptG TMDs form a large outward-facing V-shaped cavity in the IM. Mutational analyses suggested that LPS may enter the central cavity laterally, via the interface of the TMD domains of LptF and LptG, and is expelled into the beta-jellyroll-like domains upon ATP binding and hydrolysis by LptB. These studies suggest a mechanism for LPS extraction by LptB2FG that is distinct from those of classical ABC transporters that transport substrates across the IM (Luo et al. 2017). LptB2FG extracts LPS from the periplasmic face of the IM through a pair of lateral gates and then powers transperiplasmic transport to the OM through a slide formed by either of the periplasmic domains of LptF or LptG, LptC, LptA and the N-terminal domain of LptD. The structural and functional studies of the seven lipopolysaccharide transport proteins provide a platform to explore the unusual mechanisms of LPS extraction, transport and insertion from the inner membrane to the outer membrane (Dong et al. 2017). LptB2 binds novobiocin which stimulates its export activity and renders the membrane more impermeable to novobiocin (May et al. 2017).

LptFGB2 of Pseudomonas aeruginosa
LptF, M, Q9HXH4, 375 aas, 6 TMSs
LptG, M, Q9HXH5, 354 aas, 6 TMSs
LptB, C, Q9HVV6, 241 aas, ATPase

 
3.A.1.152.2

Putative ABC exporter of the YjgP/Q (LptFG) family.  The membrane protein has 772 aas and 12 TMSs in a (3 + 3)2 duplicated topology.  The gene adjacent to this membrane protein gene encodes an ABC1 ATPase of 583 aas and 6 N-terminal TMSs with a C-terminal ATPase domain. Most ATPases of family 3.A.1.152.  are of the ABC2-type.Thus, it is unlikely that this protein serves to energized the YjgP/Q-dependent transport process. This protein is in TCDB with TC# 3.A.1.106.17.

Putative ABC transporter of Acidobacterium ailaaui

 
3.A.1.152.3

Uncharacterized ABC system of the YjgP/Q family; the two membrane proteins are encoded by adjacent genes, but the gene for the ATPase was not found.  However, a soluble OstA homologue (Q5SL97) of 824 aas is encoded adjacent to the two membrane protein-encoding genes.

UP of Thermus thermophilus

 
3.A.1.152.4

Uncharacterized YjgP/YjgQ family homologue of 441 aas and 6 TMSs. No other YjgP homologue and no ATPase is encoded adjacent to the gene encoding this protein.

UP of Chlorobium phaeovibrioides (Prosthecochloris vibrioformis)

 
3.A.1.152.5

Uncharacterized YjgP/Q homologue of 266 aas and 6 TMSs. No ATPase or another YjgP homologue is encoded by a gene adjacent to this one.

YjgP homologue of Leptonema illini

 
3.A.1.152.6

YjgP/Q homologue of 584 aas an 8 TMSs in a 2 + 3 +3 arrangement.

YjgP homologue of Bizionia argentinensis

 
3.A.1.152.7

YjgP/Q family protein of 392 aas and 6 TMSs

YjgP homologue of Gimesia maris

 
3.A.1.152.8

Uncharacterized YgjP homologue of 585 aas and 6 TMSs; the central hydrophilic domain is 350 aas long, about twice that of many of the homologues.  It might be duplicated.

YgjP homologue of Niabella soli

 
3.A.1.152.9

Lipopolysaccharide transporter that exports LPS from the external surface of the cytoplasmic membrane to the outer membrane, LptB2FG. The 134-kDa protein complex is unique among ABC transporters because it extracts lipopolysaccharide from the external leaflet of the inner membrane and propels it along a filament that extends across the periplasm to directly deliver lipopolysaccharide into the external leaflet of the outer membrane. Dong et al. 2017 reported the crystal structure of this transporter in which both LptF and LptG are composed of a beta-jellyroll-like periplasmic domain and six TMSs. LptF and LptG together form a central cavity containing highly conserved hydrophobic residues. Structural and functional studies suggest that LptB2FG uses an alternating lateral access mechanism to extract lipopolysaccharide and traffic it along the hydrophobic cavity toward the transporter's periplasmic domains. The structure has been presented by Dong et al. 2017.

LptB2FG of Klebsiella pneumoniae
LptB, 241 aas; 0 TMSs, A6TEM0
LptF, 365 aas, 6 TMSs, A6THI3
LptG, 360 aas, 6 TMSs, A6THI4

 


3.A.1.153 The Functionally Uncharacterized ABC-X (ABC-X) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.153.1

ABC transporter complex YtrBCD that may play a role in acetoin utilization during stationary phase and sporulation (Yoshida et al. 2000). Expression is induced early in the stationary phase. The six ytr genes form a single operon, transcribed from a promoter present upstream of ytrA. YtrA, which possesses a helix-turn-helix motif of the GntR family, may be a repressor that regulates its own transcription as well as the whole operon. Inactivation of the operon led to a decrease in the maximal cell yield and less-efficient sporulation. B. subtilis produces acetoin as an external carbon storage compound and then reuses it later during stationary phase and sporulation. Possibly the Ytr porter plays a role (Yoshida et al. 2000). The YtrEF system, believed to be a distinct ABC efflux system (M. Saier, unpublished results), can be found under TC# 3.A.1.122.19.

YtrBCD of Bacillus subtilis
YtrB, 292 aas (C)
YtrC, 328 aas (M)
YtrD, 325 aas (M)

 
3.A.1.153.2

Putative ABC acetoin exporter, ABC-2-like protein (M) plus ATPase (C).

ABC porter of Bacillus thuringiensis
ABC2-2-like protein of 375 aas and 8 TMSs (A0RI83)
BAC-type ATPase of 298 aas (A0RI82)

 
Examples:

TC#NameOrganismal TypeExample
3.A.1.154.1

Uncharacterized protein

Actinobacteria

Uncharacterized protein of Streptomyces coelicolor (Q9K3K9)  

 
3.A.1.154.2

Uncharacterized protein of 316 aas and 6 TMSs.

UP of Hoyosella subflava (Amycolicicoccus subflavus)

 
3.A.1.154.3

Uncharacterized protein of 353 aas and 5 or 6 TMSs.

UP of Gordonia alkanivorans

 
3.A.1.154.4

Uncharacterized protein of 12 TMSs in a 1 + 5 + 1 +5 arrangement.  TMSs 5 and 6 as well as 11 and 12 are separated by about 30 - 50 residues.

UP of Mycobacterium abscessus

 
Examples:

TC#NameOrganismal TypeExample
3.A.1.155.1

The phage infection protein of 901 aas, PIP (Geller et al. 1993). The PIP family (3.A.1.155) includes large proteins with 1 N-terminal hydrophobic TMS, a hydrophilic domain of variable length, and 5 C-terminal putative TMSs. The functionally characterized protein from Lactococcus lactis is of 901 aas (Geller et al., 1993). Homologues obtained with one PSI-BLAST iteration include members of the MmpL family of the RND superfamily (e.g., a Bacillus protein, gi#89208076; 1038 aas). With poorer scores, a protein annotated as an ABC-2-like sequence (gi#89200681; 392 aas with 1 TMS followed by a 150 residue hydrophilic domain followed by a C-terminal 5 putative TMSs) was retrieved. Another protein annotated as ABC-2 was smaller with 6 putative TMSs in a 2 + 3 + 1 arrangement (gi#57234453; 241 aas). The hydrophilic domain in these proteins may show sequence similarity with the large periplasmic hydrophilic domains of RND porters (2.A.6.1 - 9).

Bacteria

PIP of Lactococcus lactis (P49022)

 
3.A.1.155.2The putative ABC-2-like protein of 678 aas (topology-like PIP) BacteriaABC-2-like protein of Arthrobacter sp. (gi#116669229)
 
3.A.1.155.3

Uncharacterized protein YhgE (ORFB)

Bacilli

YhgE of Bacillus subtilis

 
3.A.1.155.4

X(3)LX(2)G heptad repeat protein of 779 aas

Firmicutes

Heptad repeat protein of Lachnospiraceae bacterium 2_1_46FAA

 
3.A.1.155.5

Uncharacterized YhgE/Pip domain-containing protein of 432 aas and 6 TMSs.

UP of Streptomyces himastatinicus

 
3.A.1.155.6

Uncharacterized protein of 499 aas and 7 putative TMSs in a 1 + 5 + 1 TMS arrangement.  This protein may interrelate 9.B.74 and 2.A.6.10 (subfamily) which may NOT belong to the RND superfamily.

UP of Dietzia alimentaria

 
3.A.1.155.7

YhfE/Pip domain protein of 740 aas and 6 or 7 TMSs in a 1 + 5 or 6  arrangement.

YhfE protein of Gulosibacter molinativorax

 
3.A.1.155.8The ABC-2-like protein of 392 aas

Bacteria

ABC-2-like protein of Bacillus cereus (A7GKA4)

 
3.A.1.155.9

Uncharacterized protein of 397 aas and  6 TMSs in a 1 + 5 TMS arrangement

UP of Bacillus cereus

 
Examples:

TC#NameOrganismal TypeExample
3.A.1.156.1

ABC transporter permease

ABC permease of Rubeoparvulum massiliense
(M) 232 aas and 6 TMSs (WP_048600991.1)
(C) 244 aas (WP_048600992.1)

 
3.A.1.156.2

ABC transporter with a membrane protein of 219 aas and 6 TMSs and an ATP-binding protein, YxlF, of 316 aas.

ABC-2 transporter of Lokiarchaeum sp.
(M), 219 aas and 6 TMSs
(C), 316 aa

 
3.A.1.156.3

ABC2 transporter of unknown substrate specificity with two membrane constituents and one ATPase.

Tricomponent ABC exporter of Bacillus licheniformis
M1, 170 aas and 5 TMSs, ARC67021
M2, 212 aas and 5 TMSs, ARC67023
C, ATPase, YxlF, 307 aas, ARC67024

 
3.A.1.156.4

Two component ABC transporter with one M subunit and one C subunit.

ABC transporter of Clostridioides difficile

 
Examples:

TC#NameOrganismal TypeExample
3.A.1.157.1

Putative ABC3 porter with a 10 TMS membrane protein and an ATPase.  This system is encoded by genes that are adjacent to those encoding 3.A.1.207.7 and 3.A.1.207.9. It is not known if these three systems are distinct or function somehow together.

ABC3 porter of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)

 
3.A.1.157.1

Putative ABC3 porter with a 10 TMS membrane protein and an ATPase. This system is encoded by genes that are adjacent to those encoding 3.A.1.207.7 and 3.A.1.207.9. It is not known if these three systems are distinct or function somehow together.

ABC3 porter of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)

 
3.A.1.157.2

Putative ABC3-type porter of 956 aas with 10 TMSs in a 1 + 3 + 2 + 1 + 3 TMS arrangement. Two ABC-type ATPases are encoded by genes adjacent to the membrane protein, and on the other side is encoded a membrane protein of 509 aas with two TMSs, one N-termnal, and one C-terminal. This last protein is included here because if could be an auxilliary protein of the ABC exporter.

ABC3-type exporter of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)

 
3.A.1.157.3

Putative ABC3 transporter of two constituents

ABC3 porter of Candidatus Heimdallarchaeota archaeon

 


3.A.1.16 The Nitrate/Nitrite/Cyanate Uptake Transporter (NitT) Family (Similar to 3.A.1.12 and 3.A.1.17)


Examples:

TC#NameOrganismal TypeExample
3.A.1.16.1

Four component nitrate/nitrite porter (Kikuchi et al. 1996).  It's synthesis occurs in response to nitrite, not nitrate in a nitrate reductase mutant (Kikuchi et al. 1996).

Cyanobacteria

NrtABCD of Synechococcus sp. (PCC 7942)
NrtA (R)
NrtB (M)
NrtC (C)
NrtD (C)

 
3.A.1.16.2Bispecific cyanate/nitrite transporter (functions in both cyanate and nitrite assimilation; Maeda and Omata, 2009).
Cyanobacteria

CynABD of Synechococcus PCC7942
CynA (R)
CynB (M)
CynD (C)

 
3.A.1.16.3Bicarbonate porter (activated by low [CO2] mediated by CmpR; (Nishimura et al., 2008))CyanobacteriaCmpABCD of Synechococcus sp.
CmpA (R)
CmpB (M)
CmpC (C)
CmpD (C)
 
3.A.1.16.4

Nitrate uptake system, NrtABCD (Frías et al., 1997)

Cyanobacteria

NrtABCD of Anabaena (Nostoc) sp. PCC 7120
NrtA (R) (Q44292)
NrtB (M) (Q8YRV7)
NrtC (C-R) (Q8YRV8)
NrtD (C) (Q8YZ25)

 
Examples:

TC#NameOrganismal TypeExample
Examples:

TC#NameOrganismal TypeExample


3.A.1.17 The Taurine Uptake Transporter (TauT) Family (Similar to 3.A.1.12 and 3.A.1.16)


Examples:

TC#NameOrganismal TypeExample
3.A.1.17.1Taurine (2-aminoethane sulfonate) porterProteobacteriaTauABC of E. coli
TauA (R)
TauB (C)
TauC (M)
 
3.A.1.17.10

Aliphatic sulfonate (alkanesulfonate) import permease, SsuABC (YcbOEM) and is regluated by the transcriptional activator, Cbl (van Der Ploeg et al. 1999; Eichhorn and Leisinger 2001).

Proteobacteria

SsuABC of E. coli
SsuA (YcbO), (R), 319 aas
SsuB (YcbE), (C), 255 aas
SsuC (YcbM), (M), 263 aa

 

 
3.A.1.17.11

Putative ABC transporter specific for riboflavin, RibXYZ. RibY is called "NMT1/THI5 like domain protein" (Anderson et al. 2015).

Riboflavin transporter, RibXYZ, of Thermobaculum terrenum
RibY, 1 N-terminal TMS; R (D1CEG8)
RibX, 7 TMSs, M (D1CEG9)
RibZ, unknown

 
3.A.1.17.12

Sulfonate and sulfonate ester uptake transporter, SsuABC (Koch et al. 2005).

SsuABC of Corynebacterium glutamicum
SsuA (R)
SsuB (C)
SsuC (M)

 
3.A.1.17.13

Putative thiamine (vitamin B1)-specific transporter, ThiXYZ (Rodionova et al. 2015).

ThiXYZ of Chloroflexus aurantiacus
ThiX, (M, 5 TMSs) (A9WDS0)
ThiY, (R, 1 TMS) (A9WDR9)
ThiZ, (C, 0 TMSs) (A9WDR8)

 
3.A.1.17.14

Riboflavin uptake porter, RibXY (RibX, 168 aas and 6 TMSs; RibY, 351 aas) (Gutiérrez-Preciado et al. 2015).

RibXY of Chloroflexus aurantiacus

 
3.A.1.17.2Aromatic sulfonate porterProteobacteriaSsuABC of Pseudomonas putida
SsuA (R)
SsuB (C)
SsuC (M)
 
3.A.1.17.3

Putative hydroxymethylpyrimidine transport system, ThiXYZ (Rodionov et al., 2002). Regulated by TPP (thiamin) riboswitch. Potentially takes up a pyrimidine moiety of thiamin.

Bacteria

ThiXYZ of Haemophilus influenzae
ThiZ (C) (P44656)
ThiX (M) (Q57306)
ThiY (R) (P44658)

 
3.A.1.17.4

The taurine uptake system, TauABC (Krejcík et al., 2008).

Proteobacteria

TauABC of Neptuniibacter caesariensis
TauA (R) (Q2BM68)
TauB (C) (Q2BM69)
TauC (M) (Q2BM70)

 
3.A.1.17.5The phthalate uptake system, OphFGH (Chang et al. 2009).

Bacteria

OphFGH of Burkholderia capacia
OphF (R) (C0LZR7)
OphG (M) (C0LZR8)
OphH (C) (C0LZR9)

 
3.A.1.17.6

Putative hydroxymethylpyrimidine transport system, ThiXYZ (Rodionov et al., 2002). Regulated by TPP (thiamin) riboswitch. Potentially takes up a pyrimidine moiety of thiamin. ThiY is homologous to the yeast THI5 HMP-P synthase (P43534) (Bale et al., 2010).

Actinobacteria, Proteobacteria

ThiXYZ of Pasteurella multocida
ThiX (M) (Q9CLG9)
ThiY (R) (Q9CLH1)
ThiZ (C) (Q9CLG8)

 
3.A.1.17.7

Putative riboflavin transport system, RibXY. Regulated by FMN riboswitch (Vitreschak et al. 2002)

Chloroflexi

RibXY of Roseiflexus castenholzii

RibX (M) (A7NLS3)

RibY (R) (A7NLS2)

 
3.A.1.17.8

Putative thiamine transport system, ThiXYZ (Rodionov et al., 2002). Regulated by TPP (thiamin) riboswitch.

Chloroflexi

ThiXYZ of Roseiflexus castenholzi

ThiX (M) (A7NH43)

ThiY (R) (A7NH44)

ThiZ (C) (A7NH45)

 
3.A.1.17.9

Uncharacterized membrane protein of 733 aas and 12 TMSs. The other constituents of the system have not been identified.

Rhodophyta

UP of Chondrus crispus

 


3.A.1.18 The Cobalamin Precursor/Cobalt (CPC) Family

The putative cobalamin precursor/cobalt (CPC) transporter family includes proteins of about 190 aas with 4-6 TMSs. These proteins are encoded in operons that are subject to regulation by vitamin B12 (Rodionov et al. 2003). These and other ECF ABC families (3.A.1.18, 23, 25, 26, 28, 31 and 32) have been reviewed (Rempel et al. 2018).


Examples:

TC#NameOrganismal TypeExample
3.A.1.18.1

Putative ECF transporter, EcfSTA; regulated by a cobalamin riboswitch.

Bacteria

EcfSTA of Roseifluxes sp. RS-1
EcfS (S) (A5UXW2)
EcfT (T) (A5UXW1)
EcfA (A) (A5UXW0)

 
3.A.1.18.2

Putative Co2+ ECF transporter, EcfSTA

Bacteria

EcfSTA of Gloeobacter violaceus
EcfS (S) (Q7NIY0)
EcfT (T) (Q7NIX9)
EcfA (A) (Q7NIX8)

 
3.A.1.18.3

Putative Co2+ ECF transporter, EcfSTA

Bacteria

EcfSTA of Syntrophobotulus glycolicus
EcfS (S) (F0SWZ4)
EcfT (T) (F0SWZ5)
EcfA (A) (F0SWZ6)

 


3.A.1.19 The Thiamin Uptake Transporter (ThiT) Family (Most similar to 3.A.1.10, 3.A.1.6 and 3.A.1.8 in that order)


Examples:

TC#NameOrganismal TypeExample
3.A.1.19.1Thiamin, thiamin monophosphate and thiamin pyrophosphate porter. The 2.25 Å structure of ThiB (TbpA) has been solved (Soriano et al., 2008). ProteobacteriaThiBPQ of Salmonella typhimurium (functionally characterized and partially sequenced) and E. coli (fully sequenced but not functionally characterized)
ThiB; TbpA (R)
ThiP; YabK (M)
ThiQ; YabJ (C)
 
3.A.1.19.2

The thiamine pyrophosphate (TPP) uptake porter (Bian et al., 2011).

Bacteria

TPP transporter of Treponena denticola TDE0143/TDE0144/TDE0145
TDE0143 (R) (Q73RE6)
TDE0144 (M) (Q73RE5)
TDE0145 (C) (Q73RE4)

 
3.A.1.19.3

ABC transporter of unknown function. The three genes encoding this system are adjacent to a gene homologous to a mycothiol maleylpyruvate isomerase.

Actinobacteria

ABC transporter of Streptomyces hygroscopicus
Periplasmic binding protein (R) (H2JXL4)
Permease (M) (H2JXL5)
ATPase (C) (H2JXL6)

 
3.A.1.19.4

The putative sulfate/thiosulfate transporter, YnjBCD. YnjB has 12 TMSs. The three genes encoding this system are adjacent to one encoding a thiosulfate:sulfur transferase or a rhodanese (B7L6N1).  Also considered to be a thiamine transporter (Moussatova et al. 2008).

γ-Proteobacteria

YnjBCD of E. coli
YnjB (possible receptor, R) (B7L6M8)
YnjC (M) (B7L6M9)
YnjD (C) (B7L6N0)

 
3.A.1.19.5

Putative ABC transporter, WtpB1/C1: molybdate/tungstate transport system.

Deinococcus-Thermus

ABC transporter of Deinococcus deserti
Permesae (M) (C1CWI2)
ATPase (C) (C1CWI3)
Possible periplasmic receptor (R) (C1CWI4)

 
3.A.1.19.6

Probable 4 component ABC transporter with two ATPase of 387 and 368 aas, respectively, both annotated as MalK, one membrane protein that maps together with the two ATPases and is annotated CysW, and one receptor that maps separately for the other three and is designated MalE. It is not established that this repector maps with the other three constituents, but this has been inferred by the similarities of the two ATPases to MalK. 

Putative 4 component ABC uptake porter of unknown specificity, CysW/MalK/MalK/MalE of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)

 


3.A.1.2 The Carbohydrate Uptake Transporter-2 (CUT2) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.2.1

Ribose porter.  RbsA has two ATPase domains fused together; RbsB is the substrate receptor; RbsC has 10 TMSs with N- and C-termini in the cytoplasm and forms a dimer (Stewart and Hermodson, 2003).  ABC importers can be divided into two classes. Type I importers follow an alternating access mechanism driven by the presence of the substrate. Type II importers accept substrates in a nucleotide-free state, with hydrolysis driving an inward-facing conformation.  RbsABC2 seems to share functional traits with both type I and type II importers, as well as possessing unique features, and employs a distinct mechanism relative to other ABC transporters (Clifton et al. 2014).

Proteobacteria

RbsABC of E. coli
RbsA (C)
RbsB (R)
RbsC (M)

 
3.A.1.2.10The purine nucleoside permease (probably transports guanosine, adenosine, 2'-deoxyguanosine, inosine and xanthosine with decreasing affinity in this order) (Deka et al., 2006)SpirochaetesPnrA-E of Treponema pallidum
PnrA (R) (TmpC; Tp0319) (P29724)
PnrB (?51 aas; 1 TMS; Tp0320) (O83340)
PnrC (C) (533 aas; duplicated; Tp0321) (NP_218761)
PnrD (M) (400 aas; 10 TMSs; Tp0322) (NP_218762)
PnrE (M) (316 aas; 10 TMSs; Tp0323) (NP_218763)
 
3.A.1.2.11

The erythritol permease, EryEFG (Geddes et al., 2010) (probably orthologous to 3.A.1.2.16)

Bacteria

EryEFG of Sinorhizobium meliloti
EryE (C) (CAC48737)
EryF (M) (CAC48738)
EryG (R) (CAC48735)

 
3.A.1.2.12The (deoxy)ribonucleoside permease; probably takes up all deoxy- and ribonucleosides (cytidine, uridine, adenosine and toxic analogues, fluorocytidine and fluorouridine tested), but not ribose or nucleobases (Webb and Hosie, 2006)BacteriaRnsABCD of Streptococcus mutans
RnsA (R) (AAN58814)
RnsB (C) (AAN58813)
RnsC (M) (AAN58812)
RnsD (M) (AAN58811)
 
3.A.1.2.13

The probable autoinducer-2 (AI-2;, a furanosyl borate diester: 3aS,6S,6aR)-2,2,6,6a-tetrahydroxy-3a-methyltetrahydrofuro[3,2-d][1,3,2]dioxaborolan-2-uide) uptake porter (Shao et al., 2007) (50-70% identical to RbsABC of E. coli; TC# 3.A.1.2.1)

Bacteria

RbsABC of Aggregatibacter actinomycetemcomitans (Actinobacillus succinogens)
RbsA (C) (A6VKS8)
RbsB (R) (A6VKT0)
RbsC (M) (A6VKS9)

 
3.A.1.2.14

Putative L-arabinose porter (Rodionov et al. 2010).

Proteobacteria

AraUVWZ of Shewanella oneidensis
AraU (R) (Q0HIQ8)
AraV (C-C) (Q0HIQ7)
AraW (M; 10 TMSs) (Q0HIQ6)
AraZ (M; 9 TMSs) (Q0HIQ5)

 
3.A.1.2.15

The putative xylitol uptake porter, XltABC (Rodionov et al., 2010)

Proteobacteria

XltABC of Shewanella pealeana
XltA (C) (A8H4W7)
XltB (M; 9 TMSs) (A8H4W6)
XltC (R) (A8H4W5)

 
3.A.1.2.16

The erythritol uptake permease, EryEFG (Yost et al., 2006) (probably orthologous to 3.A.1.2.11)

Bacteria

EryEFG of Rhizobium leguminosarum
EryE (C) (Q1M4Q7)
EryF (M) (Q1M4Q8)
EryG (R) (Q1M4Q9)

 
3.A.1.2.17

General nucleoside uptake porter, NupABC/BmpA (transports all common nucleosides as well as 5-fluorocytidine, inosine, deoxyuridine and xanthosine) (Martinussen et al., 2010) (Most similar to 3.A.1.2.12). NupA is 506aas with two ABC (C) domains. NupB has 8 predicted TMSs, NupC has 9 or 10 predicted TMSs in a 4 + 1 (or 2) + 4 arrangement.

Bacteria

NupABC/BmpA of Lactococcus lactis
BmpA (R) (D2BKA1)
NupA (C) (A2RKA7)
NupB (M) (A2RKA6)
NupC (M) (A2RKA5)

 
3.A.1.2.18

Xylose porter (Nanavati et al. 2006). Regulated by xylose-responsive regulator XylR (Kazanov et al., 2012).

Thermotogae

XylFEK of Thermotoga maritima
XylF (M) (TM0112) (Q9WXW7)
XylE (R) (TM0114) (Q9WXW9)
XylK (C) (TM0115) (Q9WXW0)

 
3.A.1.2.19

D-ribose porter (Nanavati et al., 2006). Induced by ribose (Conners et al., 2005).

Thermotogae

RbsABC of Thermotoga maritima
RbsA (C) (TM0956) (Q9X051)
RbsB (R) (TM0958) (Q9X053)
RbsC (M) (TM0955) (Q9X050)

 

 
3.A.1.2.2

Arabinose porter (Horazdovsky and Hogg 1989).

Proteobacteria

AraFGH of E. coli
AraF (R)
AraG (C)
AraH (M)

 
3.A.1.2.20

Glucose porter. Also bind xylose (Boucher and Noll 2011). Induced by glucose (Frock et al. 2012). Directly regulated by glucose-responsive regulator GluR (Kazanov et al., 2012).

Thermotogae

GluEFK of Thermotoga maritima
GluE (

 

 

GluE (R) (ThemaDRAFT_1377) (G4FGN5)
GluF (M) (ThemaDRAFT_1376) (G4FGN4); 9 TMSs
GluK (C) (ThemaDRAFT_1375) (G4FGN3)

 

 
3.A.1.2.21

The myoinositol (high affinity)/ D-ribose (low affinity) transporter IatP/IatA/IbpA. The structure of IbpA with myoinositol bound has been solved (Herrou and Crosson 2013).

α-Proteobacteria

IatP/IatA/IbpA of Caulobacter crescentus
IatP (M) (B8H230)
IatA (C) (B8H229)
IbpA (R) (B8H228)

 
3.A.1.2.22

ABC sugar transporter that plays a role in the probiotic benefits through acetate production (Fukuda et al. 2012).

Actinobacteria

Sugar transporter of Bifidobacterium longum
BL1694, 385 aas (R) (Q8G3R1)
BL1695, 517 aas (C) (Q8G3R0)
BL1696, 405 aas (M) (Q8G3Q9)

 
3.A.1.2.23

ABC sugar transporter, FruEFGK, important for the probiotic effect of Bifidobacterium longum and involved in producing acetate (Fukuda et al. 2012).  The system is specific for fructose (highest affinity) ribose and xylose.  All three sugars induce the system (Wei et al. 2012). 

Actinobacteria

Sugar transporter of Bifidobacterium longum
BL0033 of 327 aas (R) (Q8G848)
BL0034 of 513 aas (C) (Q8G847)
BL0035 of 356 aas (M) (Q8G846)
BL0036 of 340 aas (M) (Q8G845)

 
3.A.1.2.24

XylFGH downstream of characterized transcriptional regulator, ROK7B7 (Sco6008); XylF (Sco6009); XylG (Sco6010); XylH (Sco6011)) (Świątek et al. 2013).

Actinobacteria

 

XylFGH of Streptomyces coelicolor 
XylF (R)
XylG (C)
XylH (M; 12 TMSs) 

 
3.A.1.2.25

Putative sugar uptake porter, YtfQRT/YjfF (Moussatova et al. 2008).

Proteobacteria

YtfQRT/YjfF of E. coli
YtfQ (R)
YtfR (C)
YtfT (M)
YjfF (M)

 
3.A.1.2.26

Xylose transporter, XylFGH (XylF (R), 359 aas; XylG (C), 525 aas; XylH (M), 389 aas.  Controlled by a 3 component sensor kinase/response regulator system (XylFII, sensor, A6LW07; LytS, SK, A6LW08; YesN, RR, A6LW09) (Sun et al. 2015). The XylFII-LytS complex provides the molecular basis for D-xylose utilization and metabolic modification (Li et al. 2017).

Firmicutes

XylFGH of Clostridium beijerinckii
XylF (R)
XylG (C)
XylH (M; 12 TMSs)

 
3.A.1.2.27

Sugar (pentose?) transport system, YphDEF

YphDEF of E. coli
YphD (M) 332 aas, 10 TMSs
YphE (C) 503 aas
YphF (R) 327 aas

 
3.A.1.2.28

Riboflavin uptake ABC transporter, RfuABCD.  The periplasmic binding protein (RfuA) has been crystallized at 1.3 Å resolution with riboflavin bound (Deka et al. 2013). Similar systems are found in other spirochetes such as Treponema denticola, and Borrelia burgdorferi (Deka et al. 2013).

RfuABCD of Treponema pallidum
RfuA, R, 343 aas and 1 N-terminal TMS
RfuB, C, 586 aas and 0 TMSs
RfuC, M, 377 aas and 9 or 10 TMSs
RfuD, M, 313 aas and 9 TMSs (may be N-terminally truncated)

 
3.A.1.2.29

High affinity fructose uptake porter, FrtABC, Km (fructose) = ~100μM; expression of the frtABC operon is regulated by the product of the upstream gene, frtR, FrtR, a LacI/GalR-type repressor that allows activation in the presence of fructose (Ungerer et al. 2008). When FruR is eliminated, the cells become hypersensitive to fructose, and the level of fruABC expression is much higher than in the presence of wild type cells grown on fructose (Ungerer et al. 2008).

FrtABC of Anabaena (Nostoc) variabilis
FrtA, Ava2171, Q3MB45, 341 aas with 1 N-terminal TMS (R)
FrtB, Ava2172, Q3MB44, 517 aas and 0 TMSs (C)
FrtC, Ava2173, Q3MB43, 332 aas and 8 TMSs (M)

 
3.A.1.2.3Galactose/glucose (methyl galactoside) porterProteobacteriaMglABC of E. coli
MglA (C)
MglB (R)
MglC (M)
 
3.A.1.2.30

3-component ABC-type putative general nucleoside uptake porter consisting of a receptor, a putative lipoprotein with two N- and C-terminal TMSs (R; 405 aas), an integral membrane protein of about 20 TMSs in a 1 + 4 (tight) + 4 (loose) +2 +1 + 4 (tight) +4 (loose) TMS arrangement (M; 864 aas), and a cytoplasmic ATPase (C; 563 aas).  It appears that the membrane protein contains a 9 (or 10) TMS repeat unit, and that there are two extra TMSs separating the two repeat units.  These are homologous to the two membrane constituents of TC# 3.A.1.2.17.

ABC uptake porter of Candidatus Heimdallarchaeota
OLS24537, R
OLS24538, C
OLS24539, M

 
3.A.1.2.31

Putative purine porter with 4 components (Chandravanshi et al. 2019).

Putative purine porter of Thermus thermophilus
R, 379 aas and 1 TMS (Q5SIR3)
M, 277 aas and 9 TMSs
(Q5SIR2)
M, 349 aas and 8 - 10 TMSs
(Q5SIR1)
C, 489 aas and 0 TMSs
(Q5SIR0)

 
3.A.1.2.4Xylose porterProteobacteriaXylFGH of E. coli
XylF (R)
XylG (C)
XylH (M)
 
3.A.1.2.5Multiple sugar (arabinose, xylose, galactose, glucose, fucose) putative porterProteobacteriaChvE, GguAB of Agrobacterium tumefaciens
ChvE (R)
GguA (C)
GguB (M)
 
3.A.1.2.6

D-allose porter.  The structure of AlsB has been solved at 1.8 Å resolution (Chaudhuri et al. 1999). Ten residues from both the domains form 14 hydrogen bonds with the sugar. 6-Deoxy-allose, 3-deoxy-glucose and ribose bind with reduced affinity so AlbP can function as a low affinity transporter for D-ribose (Chaudhuri et al. 1999).

Proteobacteria

AlsABC of E. coli
AlsB (R)
AlsA (C)
AlsC (M)

 
3.A.1.2.7Fructose/mannose/ribose porterProteobacteriaFrcABC of Sinorhizobium meliloti
FrcA (C)
FrcB (R)
FrcC (M)
 
3.A.1.2.8

Autoinducer-2 (AI-2, a furanosyl borate diester: (3aS,6S,6aR)-2,2,6,6a-tetrahydroxy-3a-methyltetrahydrofuro[3,2-d][1,3,2]dioxaborolan-2-uide) uptake porter (Taga et al., 2001, 2003)

Proteobacteria

LsrACDB of E. coli
LsrB (R) AAC74589
LsrA (C) AAC74586
LsrC (M) AAC74587
LsrD (M) AAC74588

 
3.A.1.2.9Rhamnose porter (Richardson et al., 2004) (Transport activity is dependent on rhamnokinase (RhaK; AAQ92412) activity (Richardson and Oresnik, 2007) This could be an example of group translocation!)ProteobacteriaRhaSTP of Rhizobium leguminosarum bv. trifolii
RhaS (R) AAQ92407
RhaT (C) AAQ92408
RhaP (M) AAQ92409
 


3.A.1.20 The Brachyspira Iron Transporter (BIT) Family (Most similar to 3.A.1.6, 3.A.1.8 and 3.A.1.11)


Examples:

TC#NameOrganismal TypeExample
3.A.1.20.1

The iron transporter, BitABCDEF (Dugourd et al. 1999).

Spirochaetes

BitABCDEF of Brachyspira (Serpulina) hyodysenteriae
BitA (R)
BitB (R)
BitC (R)
BitD (C)
BitE (M)
BitF (M)

 
3.A.1.20.2

Hexose-phosphate transporter.  Transports glucose-6-phosphate (Km = 0.3 υM) and fructose-6-phosphate (1.3 υM).  Sugar phsophates can be used as both carbon and phosphate sources (Moisi et al. 2013).

Proteobacteria

Sugar phosphate uptake permease, FbpABC of Vibrio cholerae
FbpA 344 aas (R) (Q9KLQ7)
FbpB 700 aas (M) (Q9KLQ6)
FbpC 351 aas (C) (Q9KLQ5)

 
3.A.1.20.3

Iron (Fe3+) uptake porter, AfuABC (FbpABC) (Chin et al. 1996).

Proteobacteria

AfuABC (FbpABC) of Actinobacillus pleuropneumoniae
AfuA (R)
AfuB (M)
AfuC (C)

 

 
3.A.1.20.4

Putative glycerol phosphodiester uptake transporter.  The three genes encoding this system are in an operon with a gene encoding a glycerophosphodiester phosphodiesterase, providing the evidence that this transporter might function to take up such substrates.

Putative glycerol phosphodiester uptake porter of Bdellovibrio exovorus

A11Q_2445 (R), 344 aas and 1 TMS
A11Q_2446 (M), 541 aas and 12 TMSs
A11Q_2447 (C), 245 aas and 0 TM

 

 
3.A.1.20.5

Possibly a Mg2+-citrate uptake porter with three components, R, M and C, as suggested by Mandal et al. 2019.  However, this system appears more likely to be a ferric iron uptake system, based on sequence similarity studies (see other members of TC sub-family 3.A.1.20).

Fe3+ or Mg2+-citrate porter of Thermus thermophilus

 


3.A.1.201 The Multidrug Resistance Exporter (MDR) Family (ABCB)


Examples:

TC#NameOrganismal TypeExample
3.A.1.201.1

Broad specificity multidrug resistance (MDR1; MDR-1; Pgp; P-gp; ABCB1; P-glycoprotein) efflux pump. It exports organic cations and amphiphilic compounds of unrelated chemical structure.  These include: antibiotics, anti-viral agents, cancer chemotheraputic agents, hypertensives, depressants, histamines, emetics, and the protease inhibitor, lopinavir. Pgp also exports immunosuppressants, detergents, long-chain fatty acids, HIV protease inhibitors, synthetic tetramethylrosamine analogues, calcein M, etc.); it is also a peptide efflux pump, and peptide inhibitors have been designed (Tarasova et al. 2005). It is also a phospholipid (e.g., phosphatidyl serine), cholesterol and sterol flippase. It binds and probably transports inhibitors and agonists of SUR (3.A.1.208.4) (Bessadok et al., 2011). The 3-d structure has been determined (Aller et al., 2009). It can pump from the cytoplasmic leaflet to either the outer leaflet or the outer medium (Katzir et al., 2010). The inhibitor, 5''-fluorosulfonylbenzoyl 5''-adenosine, an ATP analogue, interacts with both drug-substrate- and nucleotide-binding sites (Ohnuma et al., 2011). Inhibited by sildenafil (Shi et al., 2011), verapamil, indomethacin, probenecid, cetirizine (He et al. 2010), and lapatinib derivatives (Sodani et al., 2012), several of which are also substrates. HG-829 is a potent non-competitive inhibitor (Caceres et al., 2012).  Berberine, palmatine, jateorhizine, cetirizine and coptisine are all P-gp substrates, and cyclosporin A and verapamil are potent inhibitors (He et al. 2010; Zhang et al., 2011).  Transports clarithromycin (CAM), a macrolide antibiotic used to treat lung infections, more effectively than azithromycin (AZM) or telithromycin (TEL) (Togami et al. 2012).  Nucleotides, lipids and drugs bind synergistically to the pump (Marcoux et al. 2013).  Fluorescent substrates have been identified (Strouse et al. 2013).  The central cavity undergoes alternating access during ATP hydrolysis (van Wonderen et al. 2014).  Structural data suggest that signals are transduced through intracellular loops of the TMSs that slot into grooves on the NBDs. The Q loops at the base of these grooves are required to couple drug binding to the ATP catalytic cycle of drug export (Zolnerciks et al. 2014). Ocotillol analogues are strong competitive inhibitors (Zhang et al. 2015).  Durmus et al. 2015 have reviewed PGP transport of cancer chemotheraputic agents.  ABCB1 variants modulate therapeutic responses to modafinil and may partly explain pharmacoresistance in Narcolepse type 1 (NT1) patients (Moresco et al. 2016).  Many inhibitors have been identified (Hemmer et al. 2015).  The open-and-close motion of the protein alters the surface topology of P-gp within the drug-binding pocket, explaining its polyspecificity (Esser et al. 2016). The ATP- and substrate-coupled conformational cycle of the mouse Pgp transporter have been defined, showing that the energy released by ATP hydrolysis is harnessed in the NBDs in a two-stroke cycle (Verhalen et al. 2017).  Rilpivirine inhibits MDR1- and BCRP-mediated efflux of abacavir and increases its transmembrane transport (Reznicek et al. 2017).  It transports Huerzine A in the brain, a drug that is used for the treatment of Alzheimer's disease (Li et al. 2017). AbcB1 acts in concert with ABCA1, ABCG2 and ABCG4 to efflux amyloid-β peptide (Aβ) from the brain across the blood-brain barrier (BBB) (Kuai et al. 2018).The structure has been determined with the ABCB1 inhibitor, zosuquidar, bound.  This structure reveals the transporter in an occluded conformation with a central, enclosed, inhibitor-binding pocket lined by residues from all TMSs. The pocket spans almost the entire width of the lipid membrane and is occupied exclusively by two closely interacting zosuquidar molecules (Alam et al. 2018).  Iit is also inhibited by dacomitinib (Fan et al. 2018). Moreover, Kim and Chen 2018 presented the structure of human P-glycoprotein in the outward-facing conformation, determined by cryo-electron microscopy at 3.4-Å resolution. The two nucleotide-binding domains form a closed dimer occluding two ATP molecules. The drug-binding cavity observed in the inward-facing structures is reorientated toward the extracellular space and is compressed to preclude substrate binding. This observation indicates that ATP binding, not hydrolysis, promotes substrate release (Kim and Chen 2018). P-gp also transports opioid peptides (Ganapathy and Miyauchi 2005). MDR1 has been quantified in primary human renal cell carcinoma cells and corresponding normal tissue, and down-regulation or expression loss was documented in tumor tissues, corroborating its importance in drug resistance and efficacy (Poetz et al. 2018). Regarding the conformational transitions, first the transition is driven by the NBDs, then transmitted to the cytoplasmic parts of TMSs, and finally to the periplasmic parts. The trajectories show that besides the translational motions, the NBDs undergo a rotation movement (Zhang et al. 2018). Isoxanthohumol is a substrate and competitive inhibitor which reverses ABCB1-mediated doxorubicin resistance (Liu et al. 2017). Tariquidar is a potent inhibitor, even when taken orally (Matzneller et al. 2018). Combined oral administration of the ovarian hormones, ethinyl estradiol and progesterone, significantly lowered both MDR-1 mRNA and MDR-1 protein in the ovary (Brayboy et al. 2018). Its expression in immune cells plays a protective role from xenobiotics and toxins (Bossennec et al. 2018). Oxypeucedanin reverses P-gp-mediated drug transport by inhibition of P-gp activity and P-gp protein expression as well as downregulation of P-gp mRNA levels (Dong et al. 2018). Alam et al. 2019 determined the 3.5-Å cryo-EM structure of substrate-bound human ABCB1 reconstituted in lipidic nanodiscs, revealing a single molecule of the chemotherapeutic compound paclitaxel (Taxol) bound in a central, occluded pocket. A second structure of inhibited, human-mouse chimeric ABCB1 revealed two molecules of zosuquidar occupying the same drug-binding pocket. Minor structural differences between substrate- and inhibitor-bound ABCB1 sites are amplified toward the nucleotide-binding domains (NBDs), revealing how the plasticity of the drug-binding site controls the dynamics of the ATP-hydrolyzing NBDs. Ordered cholesterol and phospholipid molecules suggest how the membrane modulates the conformational changes associated with drug binding and transport (Alam et al. 2019). The TMS4/6 cleft may be an energetically favorable entrance gate for ligand entry into the binding pocket of P-gp (Xing et al. 2019). The epigallocatechin gallate derivative Y6 reverses drug resistance mediated by ABCB1 (Wen et al. 2019). Substrate-induced acceleration of ATP hydrolysis correlates with stabilization of a high-energy, post-ATP hydrolysis state characterized by structurally asymmetric nucleotide-binding sites, but this state is destabilized in the substrate-free cycle and by high-affinity inhibitors in favor of structurally symmetric nucleotide binding sites (Dastvan et al. 2019). It transports temozolomide (TMZ) which is used as a treatment of glioblasomas (Malmström et al. 2019).

Animals, fungi, bacteria

MDR1 of Homo sapiens

 
3.A.1.201.10

Mdr1; resistance to Cilofungin and other drugs (Lamping et al., 2010)

Fungi

Mdr1 (MCMC) of Aspergillus fumigatus (B0Y3B6)

 
3.A.1.201.11

Mdr1 azole resistance efflux pump (Lamping et al., 2010)

Fungi

Mdr1 (MCMC) of Cryptococcus (Filobasidiella) neoformans (O43140)

 
3.A.1.201.12

California mussel ABCB/MDR multixenobiotic resistance efflux pump (Luckenbach and Epel, 2008).

Animals

ABCB/MDR transporter of Mytilus californianus (MCMC) (B2WTH9)

 
3.A.1.201.13

Plasma membrane AbcB5, of 812 aas and 6 TMSs, mediates resistance of tumor cells to doxorubicin and other drugs including taxanes and anthracyclines (Kawanobe et al. 2012) by catalyzing efflux of these drugs (Sakamoto et al. 2019).  Expression in metastatic melanoma cells is affected by nano-TiO2 exposure, which as a sunscreen ingredient, may play a role in metastatic melanoma progression (Zdravkovic et al. 2019).

Animals

ABCB5 of Homo sapiens (Q2M3G0)

 
3.A.1.201.14

P-glycoprotein-1 MDR exporter.  Transports multiple drugs, cancer chemotherapy agents, cancer unrelated compounds and many xenobiotics including ivermectin (Ardelli 2013).  The crystal structure at 3.4 A resolution is available (Jin et al. 2012).  It has 4,000x higher affinity for actinomycin D in the membrane bilayers than in detergent.  A "ball and socket joint" and salt bridges similar to ABC importers suggested that both types of systems, importers and exporters, use the same mechanism to interconnect ATP hydrolysis with transport and achieve alternating access of the substrate binding site to the two sides of the membrane. 

Animals

P-glycoprotein-1 of Caenorhabditis elegans

 
3.A.1.201.15

MDR efflux pump, ABCB1a.  Exports canonical MDR susbtrates such as calcein-AM, bodipy-verapamil, bodipy-vinblastine and mitoxantrone (Gokirmak et al. 2012).

Animals

ABCB1a of Stronglycentrotus purpuratus

 
3.A.1.201.16

MDR efflux pump, ABCB4a.  Exports canonical MDR susbtrates such as calcein-AM, bodipy-verapamil, bodipy-vinblastine and mitoxantrone (Gokirmak et al. 2012).

Animals

ABCB4a of Stronglycentrotus purpuratus

 
3.A.1.201.17

Mitochondrial ABCB10 transporter.  Essential for erythropoiesis, and for protection of mitochondria against oxidative stress.  The 3-d structures of several conformations are available (3ZDQ; Shintre et al. 2013). May be required for heme biosynthesis (Sakamoto et al. 2019).

Animals

ABCB10 of Homo sapiens

 
3.A.1.201.18

Leptomycin B resistance protein 1, Pmd1 of 1362 aas and 13 predicted TMSs (Nishi et al. 1992).

Yeast

Pmd1 of Schizosaccharomyces pombe

 
3.A.1.201.19

Mitochondrial iron/sulfur complex transporter, AbcB13 of 663 aas (Xiong et al. 2010).

Alveolata (Ciliates)

AbcB13 (M-C) of Tetrahymena thermophila

 
3.A.1.201.2

Bile salt export pump, BSEP, ABCB11 or SPGP in the canalicular membrane of liver cells, is associated with progressive familial intrahepatic cholestasis-2 and benign recurrent intrahepatic cholestasis (Kagawa et al., 2008; Stindt et al. 2013; Park et al. 2016). It exports unconjugaged bile salts and glycine conjugates > taurine conjugates as well as the statin, pravastatin (Nigam 2015). BSEP mediates biliary excretion of bile acids from hepatocytes. Compounds based on GW4064 (Q96RI1), a representative farnesoid X receptor (RXR) agonist, enhance E297G BSEP transport activity (Misawa et al., 2012).

Animals

BSEP of Homo sapiens

 
3.A.1.201.20

12 TMS multidrug resistance transprter of 1318 aas, AbcB15 (Xiong et al. 2010) is the probable exporter of dichlorodiphenyltrichloroethane (DDT). Expression is induced by treatment with DDT, and this transporter appears to be responsible for DDT tolerance by pumping it out of the cell (Ning et al. 2014).

Alveolata (Ciliates)

AbcB15 (M-C-M-C) of Tetrahymena thermophila

 
3.A.1.201.21

Half sized ABCB1 drug (verapamil; rhodamine 6G) exporter of specificity similar to that of P-glycoprotein (3.A.1.201.1).  The 3-d structures of the unbound (2.6 Å) and the allosteric inhibitor-bound (2.4 Å) forms have been determined (Kodan et al. 2014).  The outward opening motion is required for ATP hydrolysis. Kodan et al. 2019 have reported a pair of structures of this homodimeric P-glycoprotein: an outward-facing conformational state with bound nucleotide, and an inward-facing apo state, at resolutions of 1.9 Å and 3.0 Å, respectively. Features that can be clearly visualized include ATP binding with octahedral coordination of Mg2+; an inner chamber that significantly changes in volume with the aid of tight connections among TMSs 1, 3, and 6; a glutamate-arginine interaction that stabilizes the outward-facing conformation; and extensive interactions between TMS1 and TMS3, a property that distinguishes multidrug transporters from floppases (Kodan et al. 2019).

Rhodophyta (Algae)

ABCB1 of Cyanidioschyzon merolae

 
3.A.1.201.22

Mitochondrial ATP-binding cassette 1, ABCB8.  Mediates doxorubicin resistance in melanoma cells (Elliott and Al-Hajj 2009).  Regulated by the Sp1 transcription factor and down regulated by mthramycin A which blocks Sp1 binding to the DNA (Sachrajda and Ratajewski 2011). It is regulated by neuropilin-1, NRP1 (TC# 8.A.47.1.5) (Issitt et al. 2018).

Animals

ABCB8 of Homo sapiens

 
3.A.1.201.23

The cyclic AMP efflux pump of 1432 aas, ABCB3 (Miranda et al. 2015).

Slime molds

ABCB3 of Dictyostelium discoideum

 
3.A.1.201.24

Multidrug exporter, MDR49 or Pgp of 1302 aas and 12 TMSs.  Exports many drugs as well as pollutants such as polycyclic aromatic hydrocarbons (PAHs) which are major sources of air, water and soil pollution.  MDR49 is expressed at all developmental stages of the life cycle and in many tissues (Vache et al. 2007). It is essential for early development, probably because Drosophila germ cell migration depends on lipid-modified peptides that are secreted by MDR49 (Ricardo and Lehmann 2009).

MDR49 of Drosophila melanogaster (Fruit fly)

 
3.A.1.201.25

MDR transporter, Crmdr1 of 1266 aas and 12 TMSs.  Crmdr1 is constitutively expressed in the root, stem and leaf with lower expression in leaf. It has two transmembrane domains (TMDs) and two nucleotide binding domains (NBDs) arranging in "TMD1-NBD1-TMD2-NBD2" direction (Jin et al. 2007).

 

Crmdr1 of Catharanthus roseus (Madagascar periwinkle) (Vinca rosea)

 
3.A.1.201.26

ABC multidrug exporter, MDR1 of 1341 aas, 12 TMSs and two ATPase domains in an MCMC arrangement.  Miltefosine (hexadecylphosphocholine), the first orally available drug available to treat leishmaniasis, is pumped out of the parasite by MDR1, a P-glycoprotein-like transporter. Overexpression of LtrMDR1 increases miltefosine efflux, leading to a decrease in drug accumulation in the parasites and resistance (Pérez-Victoria et al. 2006).

MDR1 of Leishmania major

 
3.A.1.201.27

Multidrug resistance exporter of 1331 aas and 12 TMSs, TratrD or MDR2. Almost identical throughout must of its length to F2PRR1 from T equinum of 1235 aas and 12 TMSs (Martins et al. 2016). Displays increased levels of transcription of the TruMDR2 gene when mycelia were exposed to acriflavine, benomyl, ethidium bromide, ketoconazole, chloramphenicol, griseofulvin, fluconazole, imazalil, itraconazole, methotrexate, 4-nitroquinoline N-oxide (4NQO) or tioconazole. Disruption of the TruMDR2 gene rendered the mutant more sensitive to terbinafine, 4NQO and ethidium bromide than the control strain, suggesting that this transporter plays a role in modulating drug susceptibility in T. rubrum (Fachin et al. 2006).

TratrD or MDR2 of Trichophyton rubrum (Athlete's foot fungus) (Epidermophyton rubrum)

 
3.A.1.201.28

MDR1 alkaloid/multiple drug efflux transporter of 1292 aas and 12 TMSs (Shitan et al. 2003). 

CjMDR1 of Coptis japonica (Japanese goldthread)

 
3.A.1.201.29

ABC transporter B family member 11 isoform X1 or ABCB11 of 1303 aas and 12 TMSs. Functions to export shikonin (Zhu et al. 2017). Shikonin is a naphthoquinone secondary metabolite with  medicinal value, found in Lithospermum erythrorhizon.

ABCB11 of Jatropha curcas (Barbados nut) (closely related to Lithospermum erythrorhizon)

 
3.A.1.201.3

Short chain fatty acid phosphatidylcholine translocase (phospholipid flippase), MDR3; AbcB4; Pgy3 (associated with progressive familial intrahepatic cholestasis type 3 (PFIC3) (Degiorgio et al. 2007) and progressive intrafamilial hepatic disease (Quazi and Molday, 2011)). ABCB4 exhibits narrow drug specificity relative to MDR1. Exports digoxin, paclitaxel, vinblastin and bile acids). ABCB4 regulates phosphatidylcholine secretion into bile and its translocation across the plasma membrane in hepatocytes (Voloshyna and Reiss, 2011; Kluth et al. 2014). Functions as a floppase (Sakamoto et al. 2019).

Animals

MDR3 of Homo sapiens

 
3.A.1.201.30

ABCB10 transporter of 655 aas and 6 TMSs.  Functions in resistance to acaricides (Koh-Tan et al. 2016).

ABCB10 of Rhipicephalus microplus (Cattle tick) (Boophilus microplus)

 
3.A.1.201.31

Permeability glycoprotein, P-Glycoprotein 65, P-GP65, MDR65 of 1302 aas and 12 TMSs. a detoxification efflux pump transporting various lipophilic xenobiotics out of the cells. Exports Polycyclic aromatic hydrocarbons (PAHs), ubiquitous environmental contaminants (Vaché et al. 2006). When flies are exposed to benzo[a]pyrene or to ambient air polluted by higher or lower PAH concentrations, P-gp expression was induced (Vaché et al. 2006).

PGP65 of Drosophila melanogaster (Fruit fly)

 
3.A.1.201.33

ABCB14 of 1247 aas and an MCMC domain arrangement. Transports malate and auxins (Lefèvre and Boutry 2018).

ABCB14 of Arabidopsis thaliana (Mouse-ear cress)

 
3.A.1.201.34

ABCB15 of 1240 aas with a domain order of MCMC.

ABCB15 of Arabidopsis thaliana (Mouse-ear cress)

 
3.A.1.201.35

P-glycoprotein, Pgp, ABCB1, of 1241 aas and 12 TMSs with a domain order MCMC.  Exports geraniol and other monoterpenes. Demissie et al. 2018 reported two structures of this homodimeric P-glycoprotein: an outward-facing conformational state with bound nucleotide and an inward-facing apo state, at resolutions of 1.9 Å and 3.0 Å, respectively. Features that could be clearly visualized include ATP binding with octahedral coordination of Mg2+; an inner chamber that significantly changes in volume with the aid of tight connections among transmembrane helices (TMSs) 1, 3, and 6; a glutamate-arginine interaction that stabilizes the outward-facing conformation; and extensive interactions between TMS1 and TMS3, a property that distinguishes multidrug transporters from floppases. These structural elements were proposed to participate in the mechanism of the transporter (Demissie et al. 2018).

ABCB1 of Lavandula angustifolia

 
3.A.1.201.36

ABCB21 of 1296 aas and a domain order of MCMC. Transports auxins (Lefèvre and Boutry 2018).

ABCB21 of Arabidopsis thaliana (Mouse-ear cress)

 
3.A.1.201.37

ABC protei, MDR1 of 1288 aas with 12 TMSs and a domain order of MCMC. Transports alkaloids (Lefèvre and Boutry 2018).

MDR1 of Coptis japonica

 
3.A.1.201.38

Fusion protein with a complete ABC transporter (domain order MCMC) followed by a complete probable phosphate uptake transpoter, a member of the DASS family (TC# 2.A.47).  Many fusion proteins of this type are present in the NCBI protein database.

Fusion protein of Pochonia chlamydosporia

 
3.A.1.201.39

Multidrug resistance-1, Mdr1, of 1464 aas and 12 TMSs in a 6 +6 TMS arrangement (domain order: M-C-M-C).  Confers resistance to chloroquine (CQ) and primaquine (PQ), but mutations decrease resistance (Kittichai et al. 2018).

Mdr-1 of Plasmodium vivax

 
3.A.1.201.4

The multidrug resistance/chloroquine resistance protein, PfMdr1.  PfMdr1 is the central system in P. falciparum artemisinin therapy regimen resistance (Gil and Krishna 2017).  PfMDR1 is inhibited by 4 nM actelion (ACT)-213615 and actelion (ACT)-451840 (Brunner et al. 2012, Brunner et al. 2013, Krause et al. 2016),

Protozoa

Pfmdr1 of Plasmodium falciparum (P13568)

 
3.A.1.201.40

Serine protease/ABC transporter B family protein TagA of 1752 aas and 9 putative TMSs with one N-terminal TMS followed by a large hydrophilic region that may correspond to the protease domain, followed by 8 putative TMSs in a 2 + 2 + 2 + 2 TMS arrangement and the ATPase domain. It is required for general cell fate determination at the onset of development andis required for the specification of an initial population of prespore cells in which tagA is expressed. It is also required for normal SDF-2 signaling during spore encapsulation (Good et al. 2003; Cabral et al. 2006).

TagA of Dictyostelium discoideum (Slime mold)

 
3.A.1.201.5

Auxin efflux pump Pgp1 (MDR1; ABCB1) (Carraro et al. 2012). Regulated by Twd1, an FK506-binding protein immunophilin prolyl/peptidyl isomerase; 8.A.11.1.1 (Bouchard et al., 2006).  Involved in light-dependent hypocotyl elongation (Sidler et al. 1998). The combination of ibrutinib and paclitaxel can effectively antagonize ABCB1- or ABCC10-mediated paclitaxel resistance (Zhang et al. 2017). Pgp1 also confers herbicide tolerance to cycloheximide, toxic leves of the plant hormone N6-[2-isopentyl]adenine (2iP) and multiple herbicides (Windsor et al. 2003). It is up-regulated under salt stress conditions (Yang et al. 2018).

Plants

Pgp1 of Arabidopsis thaliana (Q9ZR72)

 
3.A.1.201.6

Auxin efflux pump Pgp19 (MDR11; ABCB19; ABCB21) (regulated by Twd1, an FK506-binding protein immunophilin prolyl/peptidyl isomerase (TC# 8.A.11.1.1) (Bouchard et al., 2006).

Plants

Pgp19 of Arabidopsis thaliana (Q9LJX2)

 
3.A.1.201.7

Auxin efflux pump Pgp4; AbcB4; MDR4; PGP4 (Lefèvre and Boutry 2018) of 1286 aas and 12 TMSs in a MCMC domain arrangement.  Functions in the basipetal redirection of auxin from the root tip. Strongly expressed in root cap and epidermal cells (Terasaka et al., 2005).  Contributes to the basipetal transport in hypocotyls and root tips by establishing an auxin uptake sink in the root cap. Confers sensitivity to 1-N-naphthylphthalamic acid (NPA). Regulates root elongation, the initiation of lateral roots and the development of root hairs. Can transport IAA, indole-3-propionic acid, NPA syringic acid, vanillic acid and some auxin metabolites, but not 2,4-D and 1-naphthaleneacetic acid (Terasaka et al., 2005). Pgps and PINs (TC# 2.A.69) function in coordinated but independent auxin transport but also function interactively in a tissue-specific manner (Blakeslee et al. 2007). Found in the plasma membranes of root hair cells (Cho et al. 2012).

Plants

Pgp4 of Arabidopsis thaliana (MCMC) O80725

 
3.A.1.201.8The aluminum chelate (aluminum sensitivity (ALS1)) protein; expressed in root vacuoles half-type ABC transporter (not induced by aluminum; Larsen et al., 2007).PlantsALS1 (M-C) of Arabidopsis thaliana (Q0WML0)
 
3.A.1.201.9Marine skate liver bile salt exporter, BSEP (1348 aas) (transports taurocholine in an ATP-dependent fashion (Cai et al., 2001)) (Most similar to 3.A.1.201.2)AnimalsBSEP of Raja erinacea (MC MC) (Q90Z35)
 


3.A.1.202 The Cystic Fibrosis Transmembrane Conductance Exporter (CFTR) Family (ABCC)


Examples:

TC#NameOrganismal TypeExample
3.A.1.202.1

Cystic fibrosis transmembrane conductance regulator (CFTR) (also called ABCC7); cyclic AMP-dependent chloride channel; also catalyzes nucleotide (ATP-ADP)-dependent glutathione and glutathione-conjugate flux (Kogan et al., 2003) (may also activate inward rectifying K+ channels). The underlying mechanism by which ATP hydrolysis controls channel opening is described by Gadsby et al., 2006. The most common cause of cystic fibrosis (CF) is defective folding of a cystic fibrosis transmembrane conductance regulator (CFTR) mutant lacking Phe508 (DeltaF508)(Riordan, 2008). The DeltaF508 protein appears to be trapped in a prefolded state with incomplete packing of the transmembrane segments, a defect that can be repaired by direct interaction with correctors such as corr-4a, VRT-325, and VRT-532 (Wang et al., 2007). CFTR interacts directly with MRP4 (3.A.1.208.7) to control Cl- secretion (Li et al., 2007). It has intrinsic adenylate kinase activity that may be of functional importance (Randak and Welsh, 2007). The intact CFTR protein mediates ATPase rather than adenylate kinase activity (Ramjeesingh et al., 2008). Regulated by Na+/H+ exchange regulatory cofactors (NHERF; O14745; TC #8.A.24.1.1) (Seidler et al., 2009). Regulated by protein kinase A and C phosphorylation (Csanády et al., 2010). It is also activated by membrane stretch induced by negative pressures (Zhang et al., 2010). TMS6 plays roles in gating and permeation (Bai et al., 2010; 2011). The 3-D structure revealed the probable location of the channel gate (Rosenberg et al., 2011). Conformational changes opening the CFTR chloride channel pore, coupled to ATP-dependent gating, have been studied (Wang and Linsdell, 2012). Alternating access to the transmembrane domain of CFTR has been demonstrated (Wang and Linsdell, 2012). MRP4 and CFTR function in the regulation of cAMP and beta-adrenergic contraction in cardiac myocytes (Sellers et al., 2012). An asymmetric hourglass, comprising a shallow outward-facing vestibule that tapers toward a narrow "bottleneck" linking the outer vestibule to a large inner cavity extending toward the cytoplasmic extent of the lipid bilayer has been proposed (Norimatsu et al., 2012). Small molecule CFTR potentiators and correctors that overcome the efects of deleterious mutations have been identified (Kym et al. 2018).  The intracellular processing, trafficking, apical membrane localization, and channel function of CFTR are regulated by dynamic protein-protein interactions in a complex network. Zhang et al. 2017 reviewed the macromolecular complex of CFTR, Na⁺/H⁺ exchanger regulatory factor 2 (NHERF2; TC# 8.A.24.1.2), and lysophosphatidic acids (LPA) receptor 2 (LPA2; see TC# 9.A.14.2.5) at the apical plasma membrane of airway and gut epithelial cells.  The structure, gating and regulation of the CFTR anion channel has been reviewed (Csanády et al. 2019). Mutants impairing ion conductance giving rise to CF, are partially corrected using the drug ivacaftor, and the structure of CFTR bound to this drug, which keeps the channel open has been solved by cryoEM (Liu et al. 2019). The drug binds to a site with a hinge involved in channel gating.

Zhang et al. 2017

Animals

CFTR of Homo sapiens

 
3.A.1.202.2

CFTR of    Epithelial ion channel that plays a role in the regulation of epithelial ion and water transport and fluid homeostasis (Bagnat et al. 2010; Navis et al. 2013; Navis and Bagnat 2015). It mediates the transport of chloride ions across the cell membrane. Channel activity is coupled to ATP hydrolysis. The ion channel is also permeable to HCO3-; selectivity depends on the extracellular chloride concentration. CFTR exerts its function in part by modulating the activity of other ion channels and transporters, and it contributes to the regulation of the pH and the ion content of the epithelial fluid layer. Required for normal fluid homeostasis in the gut (Bagnat et al. 2010) and for normal volume expansion of Kupffer's vesicle during embryonic development as well as for normal establishment of left-right body patterning (Navis et al. 2013; Roxo-Rosa et al. 2015). It is also required for normal resistance to infection by Pseudomonas aeruginosa  (Phennicie et al. 2010).

CFTR of Danio rerio (Zebrafish) (Brachydanio rerio)

 


3.A.1.203 The Peroxysomal Fatty Acyl CoA Transporter (P-FAT) Family (ABCD)


Examples:

TC#NameOrganismal TypeExample
3.A.1.203.1

Peroxisomal long chain fatty acyl (LCFA; especially branched chain fatty acids) transporter of 659 aas; associated with Zellweger Syndrome, ABCD3, PMP70, PXMP1.  Can form heterodimers with ABCD1/ALD and ABCD2/ALDR, but the transporter is perdominantly a homodimer (Hillebrand et al. 2007). Dimerization is necessary to form an active transporter. It interacts with PEX19.  abcd3-knockout mice accumulate bile acid precursors suggesting that Abcd3 imports these compounds as CoA derivatives into peroxisomes (Visser et al. 2007).  These mutants also accumulate pristanic acid suggesting that Abcd3 also imports branched chain substrates into peroxisomes (Sakamoto et al. 2019). The unfolded protein response (UPR) detects and restores deficits in the endoplasmic reticulum (ER) protein folding capacity (Torres et al. 2019). Ceapins are aromatic compounds that specifically inhibit the UPR sensor ATF6alpha, an ER-tethered transcription factor, by retaining it at the ER. Ceapin's function is dependent on ABCD3. ABCD3 physically associates with ER-resident ATF6alpha in cells and in vitro in a Ceapin-dependent manner. Ceapins induce the neomorphic association of ER and peroxisomes by directly tethering the cytosolic domain of ATF6alpha to ABCD3's transmembrane regions without inhibiting or depending on ABCD3 transport activity (Torres et al. 2019).  Ceapins act through ABCD3 which binds to ATF6α. causing the ER to be tethered to the peroxysome, preventing ATF6α from carrying out its function as the unfolded protein response sensor (Torres et al. 2019).

Animals

PMP70 of Homo sapiens

 
3.A.1.203.10

Long chain fatty acid transporter consisting of a heterodimer of AbcD1 (719 aas) and AbcD2 (694 aas) (Xiong et al. 2010).

Alveolata (ciliates)

AbcD1/AbcD2 of Tetrahymena thermophila

 
3.A.1.203.11

Putative fatty acid exporter; homodimer (Moussatova et al. 2008).

Proteobacteria

YddA (M-C) of E. coli; 561 aas

 
3.A.1.203.12

ABC transporter, BclA, of 586 aas and 6 TMSs in a 2 + 2 + 2 arrangement in the N-terminus and the ABC domain in the C-terminus.  It is a peptide transprter required for bacteroid differentiation.  It catalyzes import of peptides called nodule-specific cysteine-rich (NCR) peptides in the symbiotic nodule cells which house the bacteroids. NCR peptides are related to antimicrobial peptides of innate immunity, but they induce the endosymbionts into a differentiated, enlarged, and polyploid state (Guefrachi et al. 2015). BclA is required for the formation of differentiated and functional bacteroids in the nodules of the NCR peptide-producing Aeschynomene legumes. BclA catalyzes import of NCR peptides and provides protection against the antimicrobial activity of these peptides. Moreover, BclA can complement the role of the related BacA transporter of Sinorhizobium meliloti, which has a similar symbiotic function in the interaction with Medicago legumes (Guefrachi et al. 2015).

BclA of Bradyrhizobium sp. ORS 285

 
3.A.1.203.13

Glycosomal ABC transporter of 683 aas and 6 N-terminal TMSs followed by the ATPase domain. Insertion into the glycosomal membrane is facilitated by the chaparone/receptor, Pex19 (Yernaux et al. 2006).

Glycosomal ABC half transporter of Trypanosoma brucei

 
3.A.1.203.14

Glycosomal ABC transporter of 641 aas and 6 N-terminal TMSs followed by the ATPase domain. Insertion into the glycosomal membrane is facilitated by the chaparone/receptor, Pex19 (Yernaux et al. 2006).

ABC half transporter of Trypanosoma brucei

 
3.A.1.203.15

ABCD1 transporter of 766 aas and 6 TMSs. Similar to human patients with X-linked adrenoleukodystrophy (ALD), zebrafish abcd1 mutants have elevated very long chain fatty acid levels, and CNS development was disrupted, with hypomyelination in the spinal cord, abnormal patterning, decreased numbers of oligodendrocytes, and impaired motor function followed by increased cell death (Strachan et al. 2017). Expression of human ABCD1 in zebrafish oligodendrocytes rescued apoptosis in the abcd1 mutant (Strachan et al. 2017).

ABCD1 of Danio rerio (Zebrafish) (Brachydanio rerio)

 
3.A.1.203.3

The peroxysomal long chain fatty acid (LCFA) half transporter, ABCD1 (ALD, the X-linked adrenoleukodystrophy (X-ALD or ALDP) protein) (functions as a homodimer and accepts acyl-CoA esters (van Roermund et al. 2008)). Transports C24:0 and C26:0 as substrates (van Roermund et al., 2011).  ABCD1 deficiency or mutation is associated with plasma and tissue elevation of C24:0 and C26:0 accompanied by demyelination and inflamation (Baarine et al. 2012).  X-ALD is a recessive neurodegenerative disorder that affects the brain's white matter and is associated with adrenal insufficiency. It is characterized by abnormal function of peroxisomes, which leads to an accumulation of very long-chain fatty acids (VLCFA) in plasma and tissues, especially in the cortex of the adrenal glands and the white matter of the central nervous system, causing demyelinating disease and adrenocortical insufficiency (Addison's disease or X-linked adrenoleukodystrophy (X-ALD) (Kallabi et al. 2013; Andreoletti et al. 2017) Forms heterodimers with PMP70 (ABCD3; TC#3.A.1.203.1) (Hillebrand et al. 2007). X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, results from mutations in the ABCD1 (ALDP) (Margoni et al. 2017).

Animals

LCFA transporter of Homo sapiens

 
3.A.1.203.4

The BacA (Rv1819c) porter (selective for the uptake of bleomycin and antimicrobial peptides) (essential for maintenance of extended chronic infection) (Domenech et al., 2009).

Actinobacteria

BacA of Mycobacterium tuberculosis (M-C) (Q50614)

 
3.A.1.203.5

Peroxisomal importer, Comatose, of substrates for β-oxidation (transports fatty acids and precursors 2,4-dichlorophenoxybutyric acid (2,4-DB) and indole butyric acid (IBA) (Dietrich et al., 2009; Visser et al. 2007). The peroxisomal fatty acyl-CoA transporter, Comatose (CTS, ABCD1, ABCD1, ABCC1, PED3, Pxa1; 1337aas) (Nyathi et al., 2010) determines germination potential and fertility and is essential for acetate metabolism (Linka and Esser 2012).  It associates with long chain fatty acyl-CoA synthetases (LACS6 (Q8LPS1) and LACS7 (Q8LKS5) and has intrinsic acyl CoA thiesterase activity (De Marcos Lousa et al. 2013). It has been proposed that it transports and hydrolyzes acyl-CoA esters, releasing a non-esterified fatty acid into the peroxisomal matrix which then needs to be re-activated by peroxisomal LACS6 or LACS7 (Visser et al. 2007). Mutagenesis of three residues in TMS 9 differentially affected the ATPase and thioesterase activities (Carrier et al. 2019).

Plants

Comatose of Arabidopsis thaliana (Q94FB9)

 
3.A.1.203.6

Peroxisomal long-chain fatty acid/oleic acid importer, PXA1 (Pat2)/PXA2 (Pat1) (Lamping et al., 2010; van Roermund et al., 2011).  PXA1 and PXA2 are two half-ABC transport subunits that can form a heterodimer. They are of 870 and 853 aas, respectively, both probably with 6 TMSs in a 1 + 2 + 2 + 1 TMS arrangement. Oxidation of its substrates requires the peroxysomal fatty acyl CoA ligase, suggesting that the free acids are the transported substrates.   

Yeast

PXA1/PXA2 of Saccharomyces cerevisiae
PXA1 (MC) (P41909)
PXA2 (MC) (P34230)

 
3.A.1.203.7

Peroxisomal fatty acid transporter, ABCD2, ALD1, ALDL1, ALDR, or ALDRP. Transports C22:0 and different unsaturated very long-chain fatty acyl-CoA derivatives including C24:6 and especially C22:6 (van Roermund et al., 2011). The loss of AbcD2 results in greater oxidative stress in murine adrenal cells than the loss of abcd1 (Lu et al. 2007). Based on the 2.85 Å resolution crystal structure of the mitochondrial ABC transporter, ABCB10, Andreoletti et al. 2017 proposed structural models for all three peroxisomal ABCD proteins. The model specifies the positions of the transmembrane and coupling helices and highlights functional motifs and putatively important amino acyl residues.

Animals

ABCD2 (M-C) of Homo sapiens (Q9UBJ2)

 
3.A.1.203.8

Peroxisomal/chloroplast fatty acyl CoA transporter, ABCD2 (Linka and Esser 2012).

Plants

ABCD2 of Arabidopsis thaliana

 
3.A.1.203.9

ABCD4, PMP70-related, P70R, PMP69 or PXMP1L of 606 aas.  Forms homo- and heterodimers.  May be involved in intracellular processing of vitamin B12 (cobalamin), possibly by playing a role in the lysosomal release of vitamin B12 into the cytoplasm.  Defects cause Methylmalonic aciduria and homocystinuria type cblJ (MAHCJ), a disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) (Coelho et al. 2012).  The amino treminal region determines the subcellular localization of this and other ABC subfamily D proteins (Kashiwayama et al. 2009). Maybe involved in intracelluar processing of Vitamin D (Sakamoto et al. 2019).

Animals

ABCD4 of Homo sapiens

 


3.A.1.204 The Eye Pigment Precursor Transporter (EPP) Family (ABCG)


Examples:

TC#NameOrganismal TypeExample
3.A.1.204.1

Eye pigment precursor transporter, White.  Part of a membrane-spanning permease system necessary for the transport of pigment precursors into pigment cells responsible for eye color. White dimerize with Brown for the transport of guanine. The Scarlet (TC# 3.A.1.204.17) and White complex transports a metabolic intermediate (such as 3-hydroxy kynurenine) from the cytoplasm into the pigment granules (Mackenzie et al. 2000).  The White and Scarlet proteins are located in the membranes of pigment granules within pigment cells and retinula cells of the compound eye.  Somatic knockouts of white in the noctuid moth, Helicoverpa armigera block pigmentation of the egg, first instar larva and adult eye, but germ-line knockouts of white are recessive lethal in the embryo (Khan et al. 2017).

Animals, yeast

White of Drosophila melanogaster

 
3.A.1.204.10

AbcH homologue

Animals

AbcH homologue of Caernorhabditis elegans (Q18900)

 
3.A.1.204.11

AbcG Homologue

Plants

AbcG of Physcomitrella patens (A9SCA8) 

 
3.A.1.204.12

The intracellular sterol transporter, ABCG1 (Tarling and Edwards, 2011). Involved in cell signalling, creation of membrane asymmetry and apoptosis (Quazi and Molday, 2011). Promotes cholesterol efflux from macrophages to the mature forms of HDL (HDL2 and HDL3) (Voloshyna and Reiss, 2011).  Plays a role in arteriosclerosis (Münch et al. 2012).  The diverse functions invarious cell types have been reviewed by Tarling (2013).  Many mammals have two isoforms, long and short, but mice have only the short isoform (Burns et al. 2013).  Residues have been identified that play roles in stability, oligomerization and trafficking (Wang et al. 2013).  Both the full-length and the short isoforms of ABCG1 can dimerize with ABCG4 (3.A.1.204.20) (Hegyi and Homolya 2016). Cholesterol-binding motifs in the membrane may allow transport of different cholesterol pools (Dergunov et al. 2018).

Animals

ABCG1 of Homo sapiens (P45844)

 
3.A.1.204.13

The ABCG1 transporter homologue 

Slime Molds

ABCG1 of Dictyostelium discoideum (Q55DW4)

 
3.A.1.204.14

ABC transporter-like protein ECU11_1340

Fungi

ECU11_1340 of Encephalitozoon cuniculi

 
3.A.1.204.15

MDR efflux pump, ABCG2a.  Exports canonical MDR susbtrates such as calcein-AM, bodipy-verapamil, bodipy-vinblastine and mitoxantrone (Gokirmak et al. 2012).

Animals

ABCG2a of Stronglycentrotus purpuratus

 
3.A.1.204.16

Half ABC transporter, ABCG10.  Secretes isoflavinoids including precursors of the phytoalexin, medicarpin (Banasiak et al. 2013).

Plants

ABCG10 of Medicago truncatula

 
3.A.1.204.17

Scarlet.  Part of a membrane-spanning permease system necessary for the transport of pigment precursors into pigment cells responsible for eye color. The scarlet and white (TC# 3.A.1.204.1) complex probably transports a metabolic intermediate (such as 3-hydroxy kynurenine) from the cytoplasm into the pigment granules (Tearle et al. 1989). These proteins are located in the membranes of pigment granules within pigment cells and retinula cells of the compound eye (Mackenzie et al. 2000). Knockouts of scarlet in the noctuid moth, Helicoverpa armigera, are viable and produce pigmentless first instar larvae and yellow adult eyes lacking xanthommatin (Khan et al. 2017).

Animals

Scarlet of Drosophila melanogaster

 
3.A.1.204.18

Brown.  Part of a membrane-spanning permease system necessary for the transport of pigment precursors into pigment cells responsible for eye color. Brown and white (TC# 3.A.1.204.1) dimerize for the transport of guanine (Campbell and Nash 2001).  Knockouts of brown in the noctuid moth, Helicoverpa armigera, show no phenotypic effects on viability or pigmentation (Khan et al. 2017).

Animals

Brown of Drosophila melanogaster

 
3.A.1.204.19

ABC transporter G family member 3, ABCG3; ABCG.3. Also called the white-brown complex homologue protein 3, WBC3, of 730 aas. Homologue of animal eye pigment precursor uptake porters.  The white, scarlet (TC# 3.A.1.204.17), and brown (3.A.1.204.18) genes of Drosophila melanogaster encode ABC transporter proteins involved with the uptake and storage of metabolic precursors to the red and brown eye colour pigments (Mackenzie et al. 2000). May also transport sesquiterpenes, defensive agents or pheromones. (Lefèvre and Boutry 2018).

Plants

ABCG3 of Arabidopsis thaliana

 
3.A.1.204.2

Drug resistance transporter, ABCG2 (MXR; ABCP) (human breast cancer resistance protein, BCRP) (Moitra et al., 2011). It exports urate and haem in haempoietic cells (Latunde-Dada et al., 2006) as well as cytotoxic agents (mitoxantrone, flavopiridol, methotrexate, 7-hydroxymethotrexate, methotrexate diglutamate, topotecan, rosurvastatin, and resveratrol), fluorescent dyes (Hoechst 33342) and other toxic substances (PhIP and pheophorbide a) (Özvegy-Laczka et al., 2005; Nigam 2015). It also transports folate and sterols: estradiol, and probably cholesterol, progesterone, testosterone and tamoxifen (Janvilisri et al., 2003; Breedveld et al., 2007). It is a homotetramer (Xu et al., 2004). It forms a homodimer bound via a disulfide bond at Cys-603 which stabilizes the protein against ubiquitin-mediated degradation in proteosomes (Wakabayashi et al., 2007), and can for dodecamers with 12 subunits (Xu et al. 2007). It has 6 established TMSs with the N- and C- termini inside (Wang et al., 2008). The following drugs are exported from human breast cancer cell line MCF-7: miloxantrone, daunorubicin, doxorubicin and rhodamine123). Also transports reduced folates and mono-, di- and tri-glutamate derivatives of folic acid and methotrexate (Assaraf et al., 2006). It is an active glutathione efflux pump (Brechbuhl et al., 2010). Mutations in ABCG2 cause hyperuricemia and gout , which led to the identification of urate as a physiological subsrate for ABCG2; it catalyzes elimination of urate across the renal tubular apical membrane (Prestin et al. 2014). Zafirlukast antagonizes ABCG2 multidrug resistance (Sun et al., 2012). Inhibited by Sildenafil (Shi et al., 2011) and lapatinib derivatives (Sodani et al., 2012).  Mutation of basic residues can increase or decrease drug efflux activities (Cai et al. 2010).  A substrate of ABCG2 is d-luciferin, allowing bioluminescent immaging of drug efflux across the blood-brain barrier.  Inhibitors include Ko143, gefetinib and nilotinib (Bakhsheshian et al. 2013).  Fluorescent substrates have been identified (Strouse et al. 2013).  Telabinib reverses chemotheraputic MDR mediated by ABCG2 (Sodani et al. 2014).  Residues involved in protein trafficking and drug transport activity have been identified (Haider et al. 2015).  The 3-d structure in the inward facing conformation has been solved (Rosenberg et al. 2015). Durmus et al. 2015 and Westover and Li 2015 have reviewed BCRP-mediated transport of cancer chemotheraputic agents.  A role for the C2-sequence of the ABCG2 linker region in ATP binding and/or hydrolysis coupled to drug efflux has been proposed (Macalou et al. 2015).  Functions at the blood:placenta barrier of the mouse (Kumar et al. 2016). The Q141K variant exhibits decreased functional expression and thus increased drug accumulation and decreased urate secretion, and the R482 position, which plays a role the substrate specificity, is located in one of the substrate binding pockets (László et al. 2016). Naturally occurring single nucleotide polymorphisms in humans giving rise to amino acyl residue substitutions in the transmembrane domains result in impared transport of Lucifer Yellow and estrone sulfate (Sjöstedt et al. 2017). A cryoEM structure revealed two cholesterol molecules bound in the multidrug-binding pocket that is located in a central, hydrophobic, inward-facing translocation pathway between TMSs. A multidrug recognition and transport mechanism was proposed, and disease-causing single nucleotide polymorphisms were rationalized. The structural basis of cholesterol recognition by G-subfamily ABC transporters was also revealed (Taylor et al. 2017). Catalyzes efflux of ochratoxin A (OTA) (Qi et al. 2017). Penylheteroaryl-phenylamide scaffold allows ABCG2 inhibition. 4-Methoxy-N-(2-(2-(6-methoxypyridin-3-yl)-2H-tetrazol-5-yl)phenyl)benzamide (43) exhibited a highest potency (IC50=61nM)), selectivity, low intrinsic toxicity, and it reversed the ABCG2-mediated drug resistance at 0.1muM (Köhler et al. 2018). ABCG2 acts in concert with ABCA1, ABCB1 and ABCG4 to efflux amyloid-β peptide (Aβ) from the brain across the blood-brain barrier (BBB) (Kuai et al. 2018). Inhibited by dacomitinib (Fan et al. 2018). A specific inhibitor, CCTA-1523, is a potent, selective and reversible modulator of ABCG2 (Patel et al. 2017). Exports uric acid (urate), and its loss promotes onset of hyperuricemia.  It has potential as a regulator of Gout (Fujita and Ichida 2018). High resolution cryo-EM structures of human ABCG2 bound to synthetic derivatives of the fumitremorgin C-related inhibitor Ko143 or the multidrug resistance modulator tariquidar have been solved (Jackson et al. 2018). Both compounds are bound to the central, inward-facing cavity of ABCG2, blocking access for substrates and preventing conformational changes required for ATP hydrolysis. The high resolutions allowed for de novo building of the entire transporter and also revealed tightly bound phospholipids and cholesterol interacting with the lipid-exposed surface of the TMSs (Jackson et al. 2018). Multiple drug binding pockets and residues involved in binding have been identified (Cox et al. 2018). The third transmembrane helix and adjacent regions of ABCG2 may interact with AT1 receptor antagonists, giving rise to drug-drug interactions in multi-drug regimens (Ripperger et al. 2018). The system is inhibitied by hetero aryl phenyl inhititors (Köhler et al. 2018). It is present in the blood-brain, blood-testis and maternal-fetal barriers, and cryoEM of a mutant shows the protein in a substrate-bound pre-translocation state and an ATP-bound post-translocation state (Manolaridis et al. 2018). A single molecule of estrone-3-sulfate (E1S) is bound in a central, hydrophobic, cytoplasm-facing cavity about halfway across the membrane. Only one molecule of E1S can bind in the observed binding mode. In the ATP-bound state, the substrate-binding cavity has collapsed while an external cavity has opened to the extracellular side of the membrane. The ATP-induced conformational changes include rigid-body shifts of the transmembrane domains, pivoting of the nucleotide-binding domains (NBDs), and a change in the relative orientation of the NBD subdomains (Manolaridis et al. 2018). This shows how the energy of ATP binding extrudes E1S and other substrates, and suggests that the size and binding affinity of compounds are important for distinguishing substrates from inhibitors. Its structure, mechanism and inhibitory propensity have been reviewed (Kapoor et al. 2018). Y6, an Epigallocatechin Gallate Derivative, Reverses ABCG2-Mediated Mitoxantrone Resistance (Zhao et al. 2018). ABCG2 confers resistance to several cancer treatments. Photodynamic therapy (PDT) is an anti-cancer method involving the use of light-activated photosensitisers to induce oxidative stress and cell death in cancers, but ABCG2 can efflux photosensitisers (Khot et al. 2019). Regorafenib sensitized MDR colon cancer cells to BCRP substrates by increasing  intracellular accumulation without changes in the expression level or the subcellular distribution of BCRP in the cells exposed to regorafenib. Regorafenib stimulates BCRP ATPase activity and promotes a stable interaction between regorafenib and the transmembrane domain of BCRP (Zhang et al. 2019).

	

Animals, yeast

ABCG2 (ABCP) of Homo sapiens (Q9UNQ0)

 
3.A.1.204.20

ATP-binding cassette sub-family G member 4, ABCG4, half transporter of 646 aas.  ABCG4 can form homodimers, but also heterodimers with its closest relative, ABCG1. Both the full-length and the short isoforms of ABCG1 can dimerize with ABCG4, whereas the ABCG2 multidrug transporter is unable to form a heterodimer with ABCG4 (Hegyi and Homolya 2016). ABCG4 is predominantly localized to the plasma membrane. AbcG4 acts in concert with ABCA1, ABCB1 and ABCG2 to efflux amyloid-β peptide (Aβ) from the brain across the blood-brain barrier (BBB) (Kuai et al. 2018). It is involved in macrophage lipid homeostasis (Sakamoto et al. 2019).

Animals

ABCG4 of Homo sapiens

 
3.A.1.204.21

Pigment precursor transporter of 644 aas, Ok. In the noctuid moth, Helicoverpa armigera, Ok transports precursors from the cytoplasm into the pigment granules. Knockouts of Ok are viable and produce translucent larval cuticle and black eyes (Khan et al. 2017).

Ok of Bombyx mori

 
3.A.1.204.22

Root heterodimeric half ABCG subfamily lipid  exporter, STR (817 aas)/STR2 (727 aas). Each protein has an ATPase domain followed by a 6 TMS membrane domain.  Exports lipids made from RAM2 (glycerol-3-phosphate acyltransferase)-catalyzed monoacylglycerols, allowing accumulation of extracellular lipids, possibly 2-monopalmitin (Luginbuehl et al. 2017).  Found in the peri-arbuscular membrane and required for colonization by mutualistic mycorrhizal and parasitic fungi (Jiang et al. 2017). Arbuscular mycorrhizal (AM) fungi facilitate plant uptake of mineral nutrients and obtain organic nutrients such as sugars and fatty acids, from the plant, and this ABCG transporter is required to form the symbiosis. Co-overexpressing STR and STR2 led to higher accumulation of extracelular unstaurated lipid polyesters such as cutin monomers (Jiang et al. 2017).

STR/STR2 of Medicago truncatula (Barrel medic) (Medicago tribuloides)

 
3.A.1.204.23

Homo dimeric plasma membrane AbcG1 half ABC transporter of 633 aas and 6 TMSs.  Actively exports volatile organic compounds (Benzenoids and phenylpropanoids such as methylbenzoate and benzyl alcohol, major VOC constituents emitted by flowers) from the flower cell cytoplasm to the external environment (Adebesin et al. 2017).  May also export alcohol glycosides.  Up regulated 100-fold in petunia flowers within the 24 hour period between bud and flower opening stages. Regulated by the ODORANT1 transcription factor (Adebesin et al. 2017).

AbcG1 of Petunia hybrida

 
3.A.1.204.24

Wax precursor (cuticular lipid) exporter of 678 aas and 6 TMSs, AbcG13 (Adebesin et al. 2017).

AbcG13 of Arabidopsis thaliana

 
3.A.1.204.25

ABCG6 of 546 aas and 4 TMSs involved in phosholipid trafficing and drug export in Leishmania tarentolae (Gonzalez-Lobato et al. 2016).

ABCG6 of Trypanosoma grayi (C-M)

 
3.A.1.204.26

ABC transporter G family member 26, ABCG.26; AtABCG26 of 685 aas and 6 TMSs. Putative white-brown complex homolog protein 27.  May function in vacuolar arsenic accumulation with potential for bioremediation (Potdukhe et al. 2018).

ABCG26 (C-M) of Arabidopsis thaliana (Mouse-ear cress)

 
3.A.1.204.27

Multidrug resistancd protein, ABCG19 (Wbc19), of 725 aas and 6 TMSs with a domain order C-M. Confers resistance to kanamycin (Mentewab and Stewart 2005).

ABCG19 of Arabidopsis thaliana (Mouse-ear cress)

 
3.A.1.204.28

ABCG25 of 662 aas and 6 TMSs in a C-M domain arrangement.  Transports abscisic acid, ABA, a plant hormone that influences developmental processes, including seed and bud dormancy, the control of organ size and stomatal closure (Lefèvre and Boutry 2018).

ABCG25 of Arabidopsis thaliana (Mouse-ear cress)

 
3.A.1.204.29

ABCG14 of 648 aas and 6 TMSs in a C + M domain arrangement.  May transport cytokinins (Lefèvre and Boutry 2018).

ABCG14 of Arabidopsis thaliana (Mouse-ear cress)

 
3.A.1.204.3

Putative ABC Transporter WHT-1

Worm

WHT-1 of Caenorhabditis elegans (Q11180)

 
3.A.1.204.30

ABCG16 of 736 aas and 6 TMSs in a C-M domain arrangement.  Transports jasmonic acid (Lefèvre and Boutry 2018).

ABCG16 of Arabidopsis thaliana (Mouse-ear cress)

 
3.A.1.204.31

ABCG6 of 727 aas and 6 TMSs in a CM domain arrangement. This transporter is an ABCG half-transporters that is required for synthesis of an effective suberin barrier in roots and seed coats, while ABCG2 and ABCG20 may serve the same function (Yadav et al. 2014).  Seed coats of abcg2 abcg6 abcg20 triple mutant plants had increased permeability to tetrazolium red and decreased suberin content. The root system of triple mutant plants was more permeable to water and salts in a zone complementary to that affected by the Casparian strip. Suberin of mutant roots and seed coats had distorted lamellar structure and reduced proportions of aliphatic components. Root wax from the mutant was deficient in alkylhydroxycinnamate esters (Yadav et al. 2014).

ABCG6 of Arabidopsis thaliana (Mouse-ear cress)

 
3.A.1.204.32

ABC exporter, ABCG1 of 415 aas and 3 C-terminal TMSs.  This sequence may be incomplete, being C-terminally truncated. The protein is necessary of microsporidal infections in the midguts of silkworms (He et al. 2018).

ABCG1 of Nosema bombycis

 
3.A.1.204.33

Uncharacterized ABC transporter-like protein of 640 aas with a C-terminal membrane domain with 8 putative TMSs in a 2 + 5 + 1 TMS arrangement. This protein is a full length homologue of 3.A.1.204.32 which is C-terminally truncacted.

UP of Papilio xuthus (Asian swallowtail)

 
3.A.1.204.34

Uncharacterized membrane protein of 324 aas with 6 - 8 TMSs with homology to the membrane parts of the proteins listed under TC#s 3.A.1.204.32 and .33. 

UP of Nosema pernyi

 
3.A.1.204.35

Uncharacterized membrane protein of 389 aas of 7 - 8 TMSs, homologous to the membrane parts of TC#s 3.A.1.204.32, 33, and 34.

UP of Nosema bombycis

 
3.A.1.204.36

AbcG4 of 549 aas and 6 C-terminal TMSs (domain order C-M).  Insecticides, including permethrin and other pyrethroids, are exported by ABCG4, which is also up-regulated in response to insecticide treatments (Negri et al. 2019).

AbcG4 of Anopheles stephensi (a mosquito malaria vector)

 
3.A.1.204.37

ABC transporter, White, of 685 aas and 6 C-terminal TMSs.  Loss gave rise to the white phenotype in embryonic eye pigmentation (Sumitani et al. 2005).

White of Athalia rosae (Turnip sawfly)

 
3.A.1.204.4

The plant cuticular wax and/or lipid metabolite exporter, CER5; ABCG12; WBC12 (in the plasma membrane of epidermal cells; secretes wax to the plant surface) (Pighin et al., 2004; Panikashvili and Aharoni 2008).

Plants

CER5 (C-M) of Arabidopsis thaliana (Q9C8K2)

 
3.A.1.204.5

The ABCG5 (sterolin-1)/ABCG8 (sterolin-2) heterodimeric neutral sterol (cholesterol and plant sterols) (e.g., sitosterol) (phosphoryl donors ATP > CTP > GTP > UTP) exporter; present in the apical membranes of enterocytes and hepatocytes. Cholesteryl oleate, phosphatidyl choline and enantiomeric cholesterol are poorly transported (mutation of either ABCG5 or ABCG8 cause sitosterolemia and coronary atherosclerosis) (Zhang et al., 2006; Wang et al., 2006; 2011). Involved in cell signalling, creation of membrane asymmetry and apoptosis (Quazi and Molday, 2011). The ABCG5/ABCG8 heterodimer (G5G8) mediates excretion of neutral sterols as well as the drug, Marinobufagenin, a Na+/K+-ATPase inhibitor, in the liver and intestine (Lan et al. 2018). Mutations disrupting G5G8 cause sitosterolaemia, a disorder characterized by sterol accumulation and premature atherosclerosis. Lee et al. 2016 used crystallization in lipid bilayers to determine the X-ray structure in a nucleotide-free state at 3.9 A resolution. The structure reveals a new transmembrane fold that is present in a large and functionally diverse superfamily of ABC transporters. The transmembrane domains are coupled to the nucleotide-binding sites by networks of interactions that differ between the active and inactive ATPases, reflecting the catalytic asymmetry of the transporter (Lee et al. 2016). High expression levels of both ABCG5 and ABCG8 were observed in liver, the digestive tract and the mammary gland. The system plays roles in lipid and sterol intestinal absorption, biliary excretion, and lipid trafficking and excretion during lactation (Viturro et al. 2006).

Animals

ABCG5/ABCG8 of Homo sapiens
ABCG5 (Q9H222)
ABCG8 (Q9H221)

 
3.A.1.204.6

The efflux porter for phosphatidylcholine and its analogues as well as toxic alkyl phospholipids, ABCG4 (Castanys-Munoz et al., 2007). Also promotes cholesterol efflux to the mature forms of HDL (HDL2 and HDL3) (Voloshyna and Reiss, 2011).

Protozoa

ABCG4 of Leishmania infantum (A4HWI7)

 
3.A.1.204.7

Multidrug resistance efflux pump, AbcG6, causes camptothecin-resistant parasites (Bosedasgupta et al., 2008)

Euglenozoa

AbcG6 of Leishmania donovani (A8WEV1)

 
3.A.1.204.8

The epidermal plasma membrane cuticular lipid (wax) exporters, ABCG11/ABCG11 and ABCG11/ABCG12; ABCG11 is also called Wbc11; Desperado (DSO); COF1; PEL1. ABCG12 is also called CER5, WBC12 and D3 (Panikashvili and Aharoni 2008).  Required for the cuticle and pollen coat development by controlling cutin and possibly wax transport to the extracellular matrix. Involved in developmental plasticity and stress responses (Bird et al. 2007).  ABCG11 can traffic to the plasma membrane in the absence of ABCG12 and can form flexible dimers. By contrast, ABCG12 was retained in the endoplasmic reticulum in the absence of ABCG11, indicating that ABCG12 can only form dimers with ABCG11 in the plasm membrane of epidermal cells. Some ABCG proteins may be promiscuous, having multiple partnerships, while others may form obligate heterodimers for specialized functions (McFarlane et al. 2010).

ABCG11 of Arabidopsis thaliana

 
3.A.1.204.9

The putative multidrug/pigment exporter, Adp1 (Lamping et al., 2010)

Yeast

Adp1 (C-M) of Saccharomyces cerevisiae (P25371)

 


3.A.1.205 The Pleiotropic Drug Resistance (PDR) Family (ABCG)


Examples:

TC#NameOrganismal TypeExample
3.A.1.205.1

Pleiotropic drug resistance (PDR; Pdr5) exporter; steroid exporter; sporidesmin toxicity suppressor (Sts1); MDR; cyclic nucleotide exporter; amphipathic anion exporter. Its ATPase activity is inhibited by its substrate, clotrimazole; can use ATP, GTP and maybe UTP to drive efflux (Golin et al., 2007).  Molecular modeling revealed aspects of the binding pocket and mechanism of action (Rutledge et al. 2011).  Charged residues at the end of TMS2 affect transport (Dou et al. 2016). The 23-membered-ring macrolide tacrolimus, a commonly used immunosuppressant, also known as FK506, is a broad-spectrum inhibitor and an efflux pump substrate, and mutations that minimize its export have been isolated (Tanabe et al. 2018). An A666G mutation in TMS 5 of Pdr5 increases drug efflux by enhancing cooperativity between transport sites (Arya et al. 2019). Mutations in the yeast multidrug resistance ABC transporter Pdr5 give rise to altered drug specificity (Tutulan-Cunita et al. 2005).

Yeast

Pdr5 (Sts1; Ydr1) (C-M-C-M) of Saccharomyces cerevisiae (P33302)

 
3.A.1.205.10

Pleiotropic drug resistance (PDR) exporter, named ABCG40, PDR9 or PDR12, 1423 aas with 12 - 14 TMSs. It functions as a pump to exclude Pb2+ ions and/or Pb2+- containing toxin compounds) (Lee et al., 2005). It may also export abscisic acid (ABA) (Lefèvre and Boutry 2018).

Plants

PDR12 of Arabidopsis thaliana (Q9M9E1)

 
3.A.1.205.11The brefeldin resistance protein, Bfr1, (also exports actinomycin D, cerulenin, and cytochalasin B) (Turi and Rose, 1995; Nagao et al., 1995).YeastBfr1 of Schizosaccharomyces pombe (P41820)
 
3.A.1.205.12The plasma membrane Pdr10, a negative regulator for incorporation of Pdr12 (TC# 3.A.1.205.3) into detergent-resistant membranes, a novel role for members of the ABC transporter superfamily (Rockwell et al., 2009) (most like 3.A.1.205.1; 67% identity).

Yeast

PDR10 of Saccharomyces cerevisiae (P51533)

 
3.A.1.205.13

The putative sterol uptake transporter, Aus1 (also protects against antifungal azoles such as fluconazole and itraconazole; (Nakayama et al., 2007).

Yeast

Aus1 of Candida glabrata (Q6FUR1)

 
3.A.1.205.15

Anaerobically-induced AusI. Specifically stimulated by phosphatidylserine in proteoliposomes. May translocate cholestrol and derivatives (Marek et al., 2011).

Yeast

AusI of Saccharomyces cerevisiae (Q08409)

 
3.A.1.205.16

ABCG32/PEC1 transporter.  Required for plant cuticle production (Bessire et al. 2011).

Plants

ABCG32/PEC1 of Arabidopsis thaliana

 
3.A.1.205.17

ABC transporter, PDR1.  Secretes phytohormones such as strigolactones that regulate plant shoot architecture and stimulate germination (Kretzschmar et al. 2012).

Plants

PDR1 of Petunia hybrida

 
3.A.1.205.18

The monolignol (p-coumaryl alcohol) transporter, ABCG29 or PDR1. In addition to this precursor of lignin biosynthesis, this transporter may transport various phenolic compounds and glucosinolates (Alejandro et al. 2012).  Reported to be required for normal meiotic double strand DNA break formation resulting from interaction with SPO11-1 (De Muyt et al. 2007).

Plants

ABCG29 of Arabidopsis thaliana

 
3.A.1.205.19

Small molecule transporter, ABCG10.  Poorly expressed in an lrrB mutant (Sugden et al. 2010).

Slime molds

ABCG10 of Dictyostelium discoideum

 
3.A.1.205.2Drug/Sterol/Mutagen exporter, Snq2pYeastSnq2p of Saccharomyces cerevisiae (P32568)
 
3.A.1.205.20

TUR2 transporter.  May be a general defense protein. Involved in turion (dormant buds) formation. Confers resistance to the diterpenoid antifungal agent sclareol (van den Brûle et al. 2002).  Induced by abiotic stresses such as cold-stress, cycloheximide and sodium chloride (NaCl). Induction by abscisic acid (ABA) is repressed by cytokinin such as kinetin (Crouzet et al. 2006).

Plants (Aquaphytes)

TUR2 of Spirodela polyrrhiza

 
3.A.1.205.21

ABC1 transporter.  Excretes secondary metabolites such as terpenes. Involved in both constitutive and jasmonic acid-dependent induced defense. Secretes the terpenes, sclareol and sclareolide and thereby confers resistance to the fungus, B.cinerea (Stukkens et al. 2005).  Induced by sclareolide and sclareol, and by some phytohormones such as jasmonic acid (JA) and ethylene. Strongly induced by compatible pathogens such as B. cinerea and the bacterium, Pseudomonas syringae pv tabaci, as well as by non pathogenic bacteria such as P. fluorescens, and P. marginalis pv marginalis (Grec et al. 2003).

Plants

ABC1 of Nicotiana plumbaginifolia

 
3.A.1.205.22

Plasma membrane ABC family G member 39 (ABCG39; PDR11) paraquot uptake transporter of 1454 aas and 12 - 16 TMSs.  Also called pleiotropic drug resistance protein, PDR11 or PDR13 (Fujita and Shinozaki 2014). It may export a variety of xenobiotics (Lefèvre and Boutry 2018).

Plants

PDR11 of Arabidopsis thaliana

 
3.A.1.205.23

AbcG34 of 1453 aas and 12 TMSs.  Secretes a major phytoalexin, camalexin, which on the leaf surface protects the plant against necrotophic pathogens (Khare et al. 2017). Also protects against the antifungal agent, sclareol. AtABCG34 expression was induced by Abrassicicola inoculation as well as by methyl-jasmonate, a defense-related phytohormone, and AtABCG34 was polarly localized at the external face of the plasma membrane of epidermal cells of leaves and roots (Khare et al. 2017). Probably transports a variety of alkaloids v(Lefèvre and Boutry 2018).

AbcG34 of Arabidopsis thaliana (Mouse-ear cress)

 
3.A.1.205.24

Multidrug resistance (MDR) exporter, (Np)AbcG5/PDR5 of 1498 aas and 12 TMSs.  NpABCG5/NpPDR5 is barely expressed in leaf tissues under normal conditions, but its expression is induced by the biotic stress hormone methyl jasmonate, or when tissues are wounded or chewed by an insect. NpABCG5/NpPDR5 confers resistance to the herbivore Manduca sexta (Toussaint et al. 2017).

PDR5 of Nicotiana plumbaginifolia (Leadwort-leaved tobacco) (Tex-Mex tobacco)

 
3.A.1.205.25

Plasma membrane ABCG1 or PDR1a of 1434 aas and 12 TMSs.  85% identical to TC# 3.A.1.205.21. PDR1 secretes plastid-produced diterpene(s) that are the antimicrobial compounds active in preinvasion defense, as well as the sesquiterpenoid, capsidiol, the major phytoalexin produced by Nicotiana and Capsicum species. Capsidiol is produced in plant tissues attacked by pathogens and plays a major role in postinvasion defense by inhibiting pathogen growth (Shibata et al. 2016).   This protein and ABCG2/PDR2, a close paralogue, export the same compounds and are essential for resistance to the potato late blight pathogen Phytophthora infestans. Thus, ABCG1/2 are involved in the export of both antimicrobial diterpene(s) for preinvasion defense and capsidiol for postinvasion defense against P. infestans.

PDR1 of Nicotiana benthamiana (wild tobacco)

 
3.A.1.205.26

ABC transporter, AtrB or BcatrB, that catalyzes efflux of fungitoxic compounds including the phytoalexin, camalexin.  Camalexin also induces its synthesis (Stefanato et al. 2009).

AtrB of Botryotinia fuckeliana (Noble rot fungus) (Botrytis cinerea)

 
3.A.1.205.27

Multidrug resistance efflux pump of 1567 aas and 12 TMSs. Probably exports many drugs including griseofulvin, itraconazole, terbinafine and amphotericin B (Martins et al. 2016).

MDR of Trichophyton rubrum (Athlete's foot fungus)

 
3.A.1.205.28

ABCG30 or PDR2 of 1400 aas and 12 TMSs in a C-M-C-M domain arrangement.  Responds to abiotic stresses such as heavy metals (Cd2+, Pb2+, etc), and is regulated by hormones related to pathogenic defenses (Crouzet et al. 2006) . It may be a heavy metal efflux pump, but may also transport abscisic acid, influencing developmental processes, including seed and bud dormancy, the control of organ size and stomatal closure (Lefèvre and Boutry 2018).

PDR2 of Arabidopsis thaliana (Mouse-ear cress)

 
3.A.1.205.29

ABCG37 (PDR9; PDR12) of 1450 aas and 12 TMSs in a CMCM domain arrangement.  Confers resistance to auxinic herbicides (Ito and Gray 2006) and contributes oxygenated coumarins to root exudates (Ziegler et al. 2017). Responds to abiotic stresses such as heavy metals (Cd2+ and lead) and is regulated by pathogenic defense hormones (Kim et al. 2007). It probably exports a wide range of compounds including monolignols (Lefèvre and Boutry 2018).

ABCG37 of Arabidopsis thaliana (Mouse-ear cress)

 
3.A.1.205.3Weak acid exporter, Pdr12p (exports preservative anions including propionate, sorbate and benzoate) (Mollapour et al., 2008)YeastPdr12p of Saccharomyces cerevisiae (Q02785)
 
3.A.1.205.30

Multidrug exporter, AtrF, of 1547 aas and 14 TMSs in a CMCM domain order with a 6 + 6 +2 TMS arrangement. It is a pleiotropic efflux pump that confers resistance to azoles such as fluconazole, voriconazole, and itraconazole (Meneau et al. 2016 Li et al. 2017).

AtrF of Neosartorya fumigata (Aspergillus fumigatus)

 
3.A.1.205.31

Pdr18 ABC pump of 1333 aas and 12 TMSs in a C-M-C-M domain arrangement. It functions to insert sterols such as ergosterol into the membrane, and Pdr18-mediated multistress resistance is linked to the status of plasma membrane lipid environment related with ergosterol content and the associated plasma membrane properties (Godinho et al. 2018).

Pdr18 of Saccharomyces cerevisiae

 
3.A.1.205.4

Multidrug resistance protein, Cdr1 (Candida drug resistance 1) confers resistance to cycloheximide, xenobiotics and antifungal agents such as azoles and terbinafine (Holmes et al., 2006; Schuetzer-Muehlbauer et al., 2003); also, transports phospholipids (Shukla et al., 2007). It is the major fluconazole efflux system in fluconazole-resistant C. albicans (Holmes et al., 2008; Basso et al., 2010). Similar to Cdr2. For additional details of both systems, as well as other MDR pumps in various Candida species, see Cannon et al., 1998. Chimeras between Cdr1 and Cdr2 revealed regions determining substrate specificity (Tanabe et al., 2011).  The protein has a large polyspecific drug-binding pocket formed by many of the TMSs (Rawal et al. 2013).  The macrocyclic polyketide, FK520, an analologue of antifungal FK506, and a potent immunosuppressant that prevents T-cell proliferation, displays fungicidal synergism with azoles in Candida albicans and inhibits drug efflux mediated by ABC multidrug transporters including Cdr (Nim et al. 2014).  TMS 5 residues impart substrate specificity and selectively act as a communication link between ATP hydrolysis and drug transport (Puri et al. 2009).  The 4 domains (2Cs and 2 Ms) are connected by intracellular loops that allow coupling between ATP hydrolysis and transport  (Shah et al. 2015) and faciliitate membrane targetting (Shah et al. 2015). Multiple drug binding sites have been identified (Nim et al. 2016). The system also transports steroid hormones such as β-estradiol and corticosterone as well as rhodamine 6G using specific but overlapping binding sites (Baghel et al. 2017). The 23-membered-ring macrolide, tacrolimus, a commonly used immunosuppressant also known as FK506, is a broad-spectrum inhibitor and an efflux pump substrate, and mutations that minimize its export have been isolated (Tanabe et al. 2018). A structural motif, called the E-helix, plays a role in the maintenance of proper structural fold and/or inter-domain contacts (Vishwakarma et al. 2019).

Yeast

Cdr1 (C-M-C-M) of Candida albicans (P43071)

 
3.A.1.205.5

Multidrug resistance protein, Cdr2 (confers resistance to azole and other antifungal agents/terbinafine, amorolfine, aspofungin, etc. as well as a variety of metabolic inhibitors) (Schuetzer-Muehlbauer et al., 2003; Basso et al., 2010). Chimeras between Cdr1 an Cdr2 revealed regions determining substrate specificity (Tanabe et al., 2011). Has an external binding site for an inhibiting octapeptide derivative (Niimi et al., 2012).

Yeast

Cdr2 of Candida albicans (P78595)

 
3.A.1.205.6

Multidrug resistance protein, Cn Afr1 (confers resistance to azole antifungal drugs including fluconazole) (Posteraro et al., 2003)

Fungi

CnAFR1 (C-M-C-M) of Cryptococcus neoformans (Q8X0Z3)

 
3.A.1.205.7The multidrug resistance protein, AtrB (confers resistance to all major classes of fungicides as well as natural toxic compounds substrates include: anilinopyrimidine, benzimidazole, phenylpyrrole, phenylpyridylamine, strobirulin, azoles, dicarboximides, quintozene, acriflavin, and rhodamine 6G as well as natural toxins such as camptothecin (an alkaloid) and the stilbene phytoalexin, resveratrol) (Andrade et al., 2000). FungiAtrB of Aspergillus nidulans (P78577)
 
3.A.1.205.8The multidrug resistance protein, Pdr11p, mediates sterol uptake by promoting movement of sterols from the plasma membrane to the endoplasmic reticulum where esterification occurs (Li and Prinz, 2004).YeastPdr11p of Saccharomyces cerevisiae (P40550)
 
3.A.1.205.9

The plasma membrane Cd2+/Pb2+ efflux pump (heavy metal resistance pump), PDR8 (ABCG36; PEN30, present in root hair and epidermal cells; it may export a broad range of substrates (Kim et al., 2007).  Also reported to transport flavonoid glycosides (phytoalexins) as well as quercitin, kaempeferol, 4-methoxy-indol-3-ylmethylglucosinolate and salicylate (Badri et al. 2012; Stein et al. 2006).  Key factor that controls the extent of cell death in the defense response (Kobae et al. 2006). Necessary for both callose deposition and glucosinolate activation in response to pathogens. Required for limiting invasion by nonadapted powdery mildews (Consonni et al. 2006).

Plants

PDR8 of Arabidopsis thaliana (Q9XIE2)

 


3.A.1.206 The a-Factor Sex Pheromone Exporter (STE) Family (ABCB)


Examples:

TC#NameOrganismal TypeExample
3.A.1.206.1

a-Factor sex pheromone (a hydrophobic isoprenylated (farnesylated) carboxymethylated peptide) exporter, Ste6 (Michaelis and Barrowman 2012).

Yeast

Ste6 of Saccharomyces cerevisiae

 
3.A.1.206.2

Mating factor M secretion protein, Mam1 of 1336 aas and 13 predicted TMSs.  Mam1 ABC protein is a promiscuous peptide transporter that can accommodate globular proteins of a relatively large size being capable of exporting a mating factor M- GFP fusion protein (Kjaerulff et al. 2005).

Yeast

Mam1 of Schizosaccharomyces pombe

 


3.A.1.207 The Eukaryotic ABC3 (E-ABC3) Family

(functions unknown; ABC-type ATPases have not been identified.)

Examples:

TC#NameOrganismal TypeExample
3.A.1.207.1The hypothetical protein, HP (1209aas; 10TMSs:1+6+3; 2-4 are homologous to 8-10; the FtsX domain) (P. tetraurelia has at least 5 paralogues.)CiliatesHP of Paramecium tetraurelia (M) (A0ECD9)
 
3.A.1.207.2Putative permeases; Duf214 protein (1234aas; 10TMSs: 1+6+3; 2-4 are homologous to 8-10 (the FtsX domain))CiliatesPutative permease of Tetrahymena thermophila (M) (Q22NS1)
 
3.A.1.207.3Hypothetical protein, HP (1465aas; 8TMSs:1+6+1) (D. discoideum has several paralogues)Slime moldHP of Dictyostelium discoideum (M) - Q8ST07
 
3.A.1.207.4

Hypothetical protein, HP, 1129aas (homologous are found in many unicellular eukaryotes)

Amoeba

HP of Entamoeba histolytica (M) (C4LT38)

 
3.A.1.207.5

Putative uncharacterized ABC exporter with two constituents, a membrane porter with 10 TMSs in a 1 + 3 + 2 + 1 + 3 TMS arrangement, typical of a full length ABC3 porter, and an ATPase encoded by the adjacent gene. This is the first example of this type of protein, belonging to this ABC subfamily, in a prokaryote.

ABC porter of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)

 


3.A.1.208 The Drug Conjugate Transporter (DCT) Family (ABCC) (Dębska et al., 2011)

Dębska et al., 2011


Examples:

TC#NameOrganismal TypeExample
3.A.1.208.1Multi-drug resistance-associated protein, MRP1-like protein (MLP1 or MRP1) (Exporter of leukotrienes, glutathione and cysteinyl conjugates of organic anions, drugs, unmodified hydrophobic xenobiotics and hydrophilic conjugated endobiotics). Vincristine and glutathione are co-transported. MRP1 catalyzes export of glutathione during apoptosis (Hammond et al., 2007). Also transports reduced folates as well as mono-, di- and tri-glutamate derivatives of folic acid and methotrexate (Assaraf et al., 2006).AnimalsMRP1 of Rattus norvegicus (O88269)
 
3.A.1.208.10

Multidrug (anthracycline) resistance organic anion efflux pump (ABC-C6; MRP6; MOAT-E - the ectopic mineralization disorder, pseudoxanthoma elasticum disease (PXE), protein (Vanakker et al. 2013; Rasmussen et al. 2013) exports glutathione conjugates including leukotriene C4, DNP, and N-ethylmaleimide S-glutathione; also exports anthracyclines, epipodophyllotoxins, cisplatin, and probably exports probenecid, benzbromarone and indomethacin (Chen and Tiwari, 2011).  The system participates in networds of complex diseases (De Vilder et al. 2015). This transporter has an extra N-terminal domain (TMD0) and a loop, L0.  TMD0 is not required for transport function, but L0 maintains ABCC6 in a targeting-competent state for the basolateral membrane and might be involved in regulating the NBDs (Miglionico et al. 2016). PXE is a disease of altered elastic properties in multiple tissues. Many of these mutations influence various steps in the biosynthetic pathway, minimally altering local domain structure but adversely impacting ABCC6 assembly and trafficking (Ran and Thibodeau 2016). PXE is an ectopic, metabolic mineralization disorder that affects the skin, eye, and vessels. ABCC6 is assumed to mediate efflux of one or several small molecule compounds from the liver cytosol to the circulation. In mice, abrogating ABCC6 function causes alterations in the liver metabolic profile, suggesting that PXE is a metabolic disease originating from a liver disturbance (Rasmussen et al. 2016). Thus, MRP6 is involved in the regulation of tissue calcification in mammals, and mutations are associated with human ectopic calcification disorders. Comparative analyses of the ABCC6 and ABCC1 from invertebrates to vertebrates where a bony endoskeleton first evolved. The ABCC6 gene was only found in bony vertebrate genomes (Parreira et al. 2018).

Animals

ABCC6 (MRP6) of Homo sapiens (O95255)

 
3.A.1.208.11

Vacuolar metal resistance and drug detoxification protein, yeast cadmium factor (YCF1); transports cadmium-glutathione conjugates, glutathione S-conjugated leukotriene C4, organic glutathione S-conjugates, selenodigluthatione, unconjugated bilirubin, reduced glutathione, and diazaborine (Lazard et al., 2011). Mediates arsenite expulsion, possibly as a glutathione conjugate. Activity is dependent on Tus1p, a guanine nucleotide exchange factor (GEF) for the small GTPase Rho1p and a Rho1p-dependent-positive regulator of Ycf1p (Paumi et al. 2007).

 

Yeast

YCF1 of Saccharomyces cerevisiae (P39109)

 
3.A.1.208.12Bile acid transporter, BAT1 (in vacuoles)YeastBAT1 of Saccharomyces cerevisiae (P32386)
 
3.A.1.208.13

Cyclic nucleotide (cAMP and cGMP) efflux pump, MRP8 (ABCC11); also exports other nucleoside and nucleotide analogues, and confers resistance to fluoropyrimidines and the anti-AIDS drug, 2',3'-dideoxycytidine (Guo et al., 2003). Human earwax consists of wet and dry types. Dry earwax is frequent in East Asians, whereas wet earwax is common in other populations. A SNP, 538G --> A (rs17822931), in the ABCC11 gene is responsible for determination of earwax type. Cells with allele A show a lower excretory activity for cGMP than those with allele G. The 538G --> A SNP is the first example of DNA polymorphism determining a visible genetic trait (Yoshiura et al., 2006).  Binding sites in ABCC11 for cGMP (cyclic guanosine monophosphate) and 5FdUMP (5-fluoro-2'-deoxyuridine-5'-monophosphate), the active metabolite of the anticancer drug 5-fluoro-uracil, have been identified (Honorat et al. 2013).  MRP8 generally exports a variety of anionic lipophilic compounds including antiviral and anticancer agents (Arlanov et al. 2015).

Animals

MRP8 (ABCC11) of Homo sapiens (Q9BX80)

 
3.A.1.208.14

The vacuole (tonoplast) ZmMrp3 anthocyanin pigment transporter (ABCF) (Goodman et al., 2004)

Plants

ZmMrp3 of Zea mays
ZmMrp3 (MC-MC) (Q6J0P5)

 
3.A.1.208.15

The general organic anion exporter, MRP5 (MOATC). It exports cyclic AMP, cyclic GMP, 5'-FUMP, glutathione and glutathione conjugates and antimonial tartrate). Also transports reduced folates as well as mono-, di- and tri-glutamate derivatives of folic acid and methotrexate (Assaraf et al., 2006). When overexpressed, it can lower the intracellular concentration of nucleoside/nucleotide analogs, such as the antiviral compounds PMEA (9-(2-phosphonylmethoxyethyl)adenine) or ganciclovir, and of anticancer nucleobase analogues, such as 6-mercaptopurine, after their conversion into the respective nucleotides (Ritter et al., 2005).

Animals

MRP5 of Homo sapiens (O15440)

 
3.A.1.208.16The vacuolar Abc2p (SPAC3F10.11c) transporter for xenobiotics, glutathione S-conjugates and monochlorobimane (Iwaki et al., 2006)YeastAbc2p of Schizosaccharomyces pombe (MCMC; 1478 aas) (Q10185)
 
3.A.1.208.17

The vacuolar glutathione-conjugate and chlorophyll catabolite transporter, MRP3 (Tommasini et al., 1998).  This protein appears to have an M-M-C-M-C domain order, possibly a characteristic of this ABC subfamily.  It exports reduced and oxidized glutathione (GSH) as well as GSH conjugates of cadmium, dinitrophenol, metolachlor, herbicies and anthocyanins (Lu et al. 1997).

Plants

MRP3 of Arabidopsis thaliana (Q9LK64)

 
3.A.1.208.18Vacuolar glutathione conjugate, glutathione exporter; mediates cadmium detoxification and ade2 pigmentation in vivo (Sharma et al., 2002). (Most similar to Ycf1 of S. cerevisiae (TC# 3.A.1.208.11; 41% identity))PlantsBpt1 of Saccharomyces cerevisiae (P14772)
 
3.A.1.208.19

The possible HCO3- transporter, HLA3 (Duanmu et al., 2009).  Activation of HLA3 expression in high CO2 acclimated cells, where HLA3 is not expressed, resulted in increased Ci accumulation and Ci-dependent photosynthetic O2 evolution specifically in very low CO2 concentrations, which confirms that HLA3 is indeed involved in Ci uptake.  It also suggests that HLA3 is mainly associated with HCO3- transport in very low CO2 concentrations, conditions in which active CO2 uptake is limited (Gao et al. 2015).

Algae

HLA3 of Chlamydomonas reinhardtii (A8I268)

 
3.A.1.208.2

Hepatic canalicular conjugate exporter, ABCC2. cMRP, MRP2, CMOAT (the Dubin-Johnson Syndrome protein) (transports bilirubin glucuronides; E2 17 β glucuronide, dianionic bile salts such as taurocholate, taurochenodeoxycholate sulfate and taurolithocholate sulfate; reduced glutathione; glutathione conjugates; glucuronides; cysteinyl leukotrienes; arsenic-glutathione complexes and glutathione disulfide; also exports anthracyclines, epipodophyllotosine, Vinca alkaloids, cisplatin, methotrexate, and the protease inhibitor, lopinavir) (Chen and Tiwari, 2011; Krumpochova et al., 2012).  MK-571 is an inhibitor (Zhang et al., 2011).  Sterol sensing residues have been identified (Gál et al. 2015). Catalyzes efflux of ochratoxin A (OTA) (Qi et al. 2017). ABCC2 polymorphism and gender correlate with the high-density lipoprotein/ cholesterol response to simvastatin (Liu et al. 2018).

Animals

cMRP (MRP2; cMOAT) of Homo sapiens (Q92887)

 
3.A.1.208.20

The vacuolar MRP1 of 1622 aas. Also called ABCC1 and EST1. It has 17 TMSs in a 5 + 6 + 6 arrangement with an N-terminal transmembrane domain of 5 TMSs.  The domain order is N - MCMC, and it transports xenobiotics (Lefèvre and Boutry 2018) It sequesters in the vacuole glutathione conjugates, folate mono-glutamates (pteroyl-1-glutamate) and antifolates (methotrexate); (Raichaudhuri et al. 2009) (86% identical to MRP2 (3.A.1.208.5). ABCC1 and ABCC2 confer tolerance to cadmium and mercury, in addition to their role in arsenic detoxification. MRP1 of Lithospermum erythrorhizon may play a direct or indirect role in transmembrane transport  of shikonin (Zhu et al. 2017). ABCC1 and ABCC2 regulate stomatal closing and opening as well as anthocyanin transport (Frelet-Barrand et al. 2008). ABCC1 of 1622 aas and 17 TMSs in a 5 + 6 + 6 arrangement with an N-terminal transmembrane domain of 5 TMSs.  The domain order is N - MCMC.  Transports xenobiotics (Lefèvre and Boutry 2018)

Plants

MRP1 of Arabidopsis thaliana (Q9C8G9)

 
3.A.1.208.21

The thale cress protein atMRP5 (atABCC5), a high-affinity inositol hexakisphosphate transporter; involved in guard cell signaling and phytate storage (Nagy et al., 2009). Transports organic anions and phytate (Lefèvre and Boutry 2018).

Plants

MRP5/ABCC5 of Arabidopsis thaliana (Q7GB25)

 
3.A.1.208.22

California mussel ABCC/MRP-type multixenobiotic resistance efflux pump (Luckenbach and Epel, 2008).

Animals

ABCC/MRP-type exporter of Mytilus californianus (B2WTI0)

 
3.A.1.208.23

The Sur2B (ABCC9) sulfonylurea receptor. The amino-terminal transmembrane domain of Sur2B binds Kir6.2 (Winkler et al., 2011). Dominant missense mutations in ABCC9, promoting open channel formation, cause Cantú syndrome (Harakalova et al., 2012; van Bon et al., 2012). This protein is part of an ATP-dependent potassium (K(ATP)) channel that couples the metabolic state of a cell with its electrical activity.  Associated with early repolarization (ERS) and Brugada (BrS) syndromes (Hu et al. 2014).  This ATP-sensitive potassium (K(ATP)) channel couples glucose metabolism to insulin secretion in pancreatic beta-cells (de Wet et al. 2007).

Animals

Sur2B of Homo sapiens (O60706)

 
3.A.1.208.24

Similar to MRP4 of man (TC#3.A.1.208.7). A single amino acid mutation causes resistance to Bt toxin Cry1Ab in the silkworm, Bombyx mori (Atsumi et al., 2012). 83% identical to 3.A.1.208.6.

Insects

MRP4-like ABC transporter of Bombyx mori (G1UHW7)

 
3.A.1.208.25

The ABC-thiol (cysteine; glutathione) exporter, MrpA (Mukherjee et al., 2007). 83% identical to 3.A.1.208.6.

Kinetoplastid protozoans

MrpA of Leishmania donovani

 
3.A.1.208.26

Mrp2 of 2133 aas.  Confers resistance to quinolone drugs including chloroquine, mefloquine and quinine (Mok et al. 2013).

Alveolata

Mrp2 of Plasmodium falciparum

 
3.A.1.208.27

Multidrug (e.g., ivermectin) exporter, MRP-1 isoform a (Ardelli 2013).

Animals

MRP-1 of Ceanorhabditis elegans

 
3.A.1.208.28

Vacuolar iron transporter, Abc3(+) of 1465 aas.  Induced by low iron and repressed by high iron.  Required for growth in a low iron medium.  Probably mobilizes stored vacuolar iron (Pouliot et al. 2010).

Yeast

Abc3 of Schizosaccharomyces pombe

 
3.A.1.208.29

Multidrug resistance-associated protein 9, MRP9 of 1359 aas. Also called ABCC12. Expressed in testis, but widely expressed in other tissues at low levels. Isoform 5 is specifically expressed in brain, testis and breast cancer cells.

Animals

MRP9 or ABCC12 of Homo sapiens

 
3.A.1.208.3

Oligomycin-resistance protein YOR1 in plasma membrane (confers resistance to oligomycin, rhodamine B, tetracycline, verapamil, eosin Y and ethidium bromide; Grigoras et al., 2007)).

Yeast

YOR1 (M-C-M-C) of Saccharomyces cerevisiae (P53049)

 
3.A.1.208.30

Animals

ABCC13 of Macaca mulatta

(Rhesus macaque)

 
3.A.1.208.31

Multidrug resistance-associated protein 7, MRP7 or ABCC10 of 1492 aas. Probably involved in cellular detoxification through lipophilic anion extrusion. Isoform 1 is specifically expressed in spleen; isoform 2 is more widely expressed. The combination of ibrutinib and paclitaxel can effectively antagonize ABCB1- or ABCC10-mediated paclitaxel resistance (Zhang et al. 2017).

Animals

MRP7 of Homo sapiens

 
3.A.1.208.32

MRP-like ABC transporter of 1513 aas.  Induced by copper, cadmium and oxidative stress (González-Guerrero et al. 2010).

Fungi

ABC1 of Rhizophagus irregularis (Arbuscular mycorrhizal fungus) (Glomus intraradices)

 
3.A.1.208.33

Multidrug resistance export pump, ABCC or MRP1 of 1822 aas (González-Pons et al. 2009).

Alveolata

Mrp1 of Plasmodium falciparum

 
3.A.1.208.34

ABCC13 of 1505 aas.  Required for phytic acid accumulation in developing seeds. Phytic acid is the primary storage form of phosphorus in cereal grains and other plant seeds (Xu et al. 2009).

ABCC13 of Oryza sativa

 
3.A.1.208.35

MDR1 (ABCC1) of 1514 aas; 96% identical to the characterized protein of the same length from Rhopalosiphum padi (Bird cherry-oat aphid) (Aphis padi), which exports the insecticides, imidacloprid and chlorpyrifos (Kang et al. 2016).

ABCC1 of Acyrthosiphon pisum (Pea aphid)

 
3.A.1.208.36

ABC transporter with two components, one of 551 aas and 6 TMSs and the other of 585 aas and 6 TMSs; both have the M-C domain order.

ABC transporter of Bdellovibrio exovorus

 
3.A.1.208.37

ABC-type multidrug transporter with two fused ATPases and two fused permease domains; of 1228 aas and 12 TMSs.

Possible MDR pump of Bdellovibrio bacteriovorus

 
3.A.1.208.38

ABC transporter, a 2 component system, both proteins with the M-C domain order.

ABC transporter of Bdellovibrio bacteriovorus

 
3.A.1.208.39

dMDR of 1548 aas; exports daunorubicin (Chahine et al. 2012).

MDR of Drosophila melanogaster (Fruit fly)

 
3.A.1.208.4

SUR1 sulfonylurea receptor; subunit and regulator of α-cell ATP-sensitive K+ channel (TC #1.A.2); determines ATP sensitivity; no inherent transport function known; associated with persistent hyperinsulinemic hypoglycemia of infancy due to focal adenomatous hyperplasia (also called ABCC8). Gain-of-function mutations in the genes encoding the ATP-sensitive potassium (K(ATP)) channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) cause neonatal diabetes mellitus. Because mutant channels are inhibited less strongly by MgATP, this increases K(ATP) currents in pancreatic beta cells, thus reducing insulin secretion and producing diabetes (de Wet et al., 2007). Binds ligands (blockers): glibenclamide, tolbutamide, and meglitinide as well as agonists, SR47063 (a cromakalim analog), P1075 (a pinacidil analog), and diazoxide (Bessadok et al., 2011). ATP activates ATP-sensitive potassium channels composed of mutant sulfonylurea receptor 1 and Kir6.2 with diminished PIP2 sensitivity (Pratt and Shyng, 2011). Dominant missense mutations in ABCC9, promoting open channel formation, cause Cantú syndrome (Harakalova et al., 2012; van Bon et al., 2012). The N-terminal transmembrane domain of SUR1 controls gating of Kir6.2 by modulating channel sensitivity to PIP2 (Pratt et al., 2011). Familial mild hyperglycemia is due to the ABCC8-V84I mutation (Gonsorcikova et al., 2011). ATP regulates KATP channels by promoting dimerization and conformational switching (Ortiz et al. 2013).  Mutations causing neonatal diabetes are attributed to alterations in the affinites for ATP and ADP (Ortiz and Bryan 2015).  Two groups of mutations with different cellular mechanisms have been identified. 1) Channel complexes with mutations in NBD2 of SUR1 traffic normally but are unable to be activated by MgADP. 2) Channel mutations in the TMS domains of SUR1 are retained in the ER and have variable functional impairment (Nessa et al. 2015). KATP channels (Kir6.2/SUR1) in the brain and endocrine pancreas  couple metabolic status to the membrane potential. In beta-cells, increases in cytosolic [ATP/ADP] inhibit KATP channel activity, leading to membrane depolarization and exocytosis of insulin granules. Mutations in ABCC8 (SUR1) or KCNJ11 (Kir6.2) can result in gain or loss of channel activity and cause neonatal diabetes (ND) or congenital hyperinsulinism (CHI), respectively.  Nucleotide binding without hydrolysis switches SUR1 to stimulatory conformations.  Increased affinity for ATP gives rise to ND while decreased affinty gives rise to CHI (Ortiz and Bryan 2015). SUR1 mutations constitute a genetic aetiology for neonatal diabetes, and they act by reducing the KATP channel's ATP sensitivity (Proks et al. 2006). Polymorphic ABCC8 isoforms are key regulatory proteins of cerebral oedema in many neurological disorders including traumatic brain injury (Jha et al. 2018). In polymorphisms predictive of oedema, variant alleles/genotypes confer increased risk while different variant polymorphisms are associated with favourable outcome, potentially suggesting distinct mechanisms (Jha et al. 2018).

Animals

SUR1 of Homo sapiens (Q09428)

 
3.A.1.208.40

Putative fumonisin (mycotoxin) exporter of 1489 aas and about 16 TMSs, Fum19.  Present in an operon with fumonisin biosynthetic enzymes (Proctor et al. 2003).

Fum19 of Gibberella moniliformis (Maize ear and stalk rot fungus) (Fusarium verticillioides)

 
3.A.1.208.41

The antifungal agent, EchonocandinB, exporter, EcdL of 1479 aas and 16 TMSs (Bera et al. 2017).

EcdL of Aspergillus rugulosus

 
3.A.1.208.42

MRP4 ABC anthocyanin/phytic acid efflux porter of 1510 aas and 12 TMSs.  It exports anthocyanin in aleurone tissues ().  ABC transporter that may affect phytic acid transport and compartmentalization. It function directly or indirectly in removing phytic acid from the cytosol. and is required for phytic acid accumulation in developing seeds. It is expressed most highly in embryos, but also in immature endosperm, germinating seed and vegetative tissues. Silencing expression of this transporter in an embryo-specific manner produced low-phytic-acid, high-Pi transgenic maize seeds that germinate normally (Shi et al. 2007). Phytic acid is the primary storage form of phosphorus in cereal grains and other plant seeds.

MRP4 of Zea mays

 
3.A.1.208.43

Arsenate/thioarsentate exporter, MRP12 or ABCC12

AbcC12 of Arabidopsis thaliana (Mouse-ear cress)

 
3.A.1.208.44

Pytate exporter of 1537 aas and 18 TMSs, ABCC5 (Pandey et al. 2018). 

ABCC5 of Glycine max

 
3.A.1.208.45

Multidrug resistance pump, MRP1 or ABCC1 of 1515 aas and 17 putative TMSs. The ABCC1 gene is expressed at all larval stages and in at least nine different tissues, particularly in the fifth-instar larvae and Malpighian tubules (Chen et al. 2018). MRP1 (ABCC1) serves as a functional receptor for the insect toxins, Cry1A and Cry2Ab (Chen et al. 2018).

ABCC1 of Helicoverpa armigera (Cotton bollworm) (Heliothis armigera)

 
3.A.1.208.47

Vacuolar ABCC1 of 1480 aas and 17 TMSs in a 5 + 6 + 6 TMS arrangement. Transports anthocyanins including anthocyanodin 3-O-glucosides such as malvidin 3-O-glucoside (Francisco et al. 2013; Lefèvre and Boutry 2018). Also transports glutathione (Francisco et al. 2013).

ABCC1 of Vitis vinifera

 
3.A.1.208.48

Multidrug resistance protein, MRP4 or ABCC4, of 1349 aas and 12 TMSs in an M-C-M-C domain order. The non-steroidal anti-inflammatory drug (NSAID) diclofenac, known to cause hyperuricemia and concomitant visceral gout in Gyps vultures may be a result of interference with renal uric acid excretion. Three species of Gyps vultures are on the verge of extinction due to nephrotoxic veterinary diclofenac having entered the food chain, and because the toxicity of different avian species to the NSAIDs like diclofenac varies. MRP4, an organic anion transporter in birds, plays a unique role in unidirectional efflux of urate into the proximal renal tubular lumen for excretion and maintenance of homeostasis. Barik et al. 2019 characterized the MRP4 channel at the molecular level to predict its structural based ligand binding properties in Gallus domesticus (Indian domestic chicken) and Gyps himalayensis (the Himalayan griffon vulture)including point and insertional mutational variants.

MDR4 of Gyps himalayensis (vulture)

 
3.A.1.208.5Vacuolar multidrug resistance efflux pump, AtMRP2 (catalyzes vacuolar uptake of glutathione conjugates (i.e., 2,4-dinitrophenyl-GS), glucuronide conjugates (i.e., 17 β-estradiol 17(β-D-glucuronide), and reduced glutathione). Also exports the herbicide, 1-chloro-2, 4-dinitrobenzene, and chlorophyll degradation catabolites (Frelet-Barrand et al., 2008).PlantsAtMRP2 of Arabidopsis thaliana (O64590)
 
3.A.1.208.6Metal-thiol conjugate exporter, PgpA; glutathione and trypanothione conjugates are exported; confers arsenite and antimonite resistance (trypanothione is glutathione-spermidine). ProtozoaPgpA of Leishmania tarentolae (P21441)
 
3.A.1.208.7

MRP4 (ABCC4); exporter of cyclic nucleotides (cAMP, cGMP and other nucleotide analogues, particularly purine analogues, methotrexate, bile acids, prostaglandins E1 and E2, reduced folates, 9-(2-phosphonylmethyoxyethyl)adenine, leukotrienes, estradiol 17-β-D-glucuronide) and drug sulfate conjugates (inhibited by nonsteroidal antiinflammatory drugs Reid et al., 2003; Rius et al., 2008)). When overexpressed, it can lower the intracellular concentration of nucleoside/nucleotide analogs, such as the antiviral compounds PMEA (9-(2-phosphonylmethoxyethyl)adenine), adefovir, or ganciclovir (Nigam 2015), and of anticancer nucleobase analogs, such as 6-mercaptopurine, after their conversion into the respective nucleotides. MRP4 interacts directly with CFTR (3.A.1.202.1) to control Cl- secretion (Li et al., 2007). It also functions in urate elimination across the renal tubule apical membrane (Prestin et al. 2014). Thus, MRP4 is a broad specificity organic anion exporter (Ritter et al., 2005). MRP4 and CFTR together function in the regulation of cAMP and beta-adrenergic contraction in cardiac myocytes (Sellers et al., 2012). Amino acid changes can alter the uptake of drugs such as 6-mercaptopurine (6-MP) and 9-(2-phosphonyl methoxyethyl) adenine (PMEA) (Janke et al. 2008).  Positions of L1 (the linker between the two halves of the exporter), L0 (the N-terminal domain), and the zipper helices (between the two NBDs) have been suggested (Chantemargue et al. 2018). ABCC4 exports proinflammatory molecules including leukotriene, prostaglandin and sphingosine-1-phosphate across the plasma membrane. These metabolites play roles in asthma (Palikhe et al. 2017).

Animals

MRP4 (MOAT-B; ABCC4) of Homo sapiens (O15439)

 
3.A.1.208.8

Drug resistance pump; ABCC1 (MRP1), exports chemotherapeutic agents, organic anions such as leukotriene C4 (LTC4), 17-β-estradiol 17-β-D-glucuronide, glucuronide-X (E217βG, etoposide-glucuronide), estrone-3-sulfate, folic acid and methotrexate, arsenic triglutathione, arsenic and antimonial oxyanions, glutathione (GSH), GSSG, glutathione conjugates (GSH-X; LTC4, DNP-SG, EA-SG, NEH-SG), sulfate-X (E1S, DHEAS), HIV protease inhibitors, anthracyclines, epipodophyllotoxins, and Vinca alkaloids. Changing charged residues in TMS6 (K332, H335 and D336) gave rise to specific changes in specificity (Chen et al., 2006; Haimeur et al., 2002; Leslie et al., 2004).  Also, mutations in TMS 10 alter substrate binding and export of drugs (Zhang et al. 2006). MDR1 also exports cobalamine (Vitamin B12) (Beedholm-Ebsen et al., 2010) and cytotoxic metals including antimony, mercuric ions, arsenate and arsenite, but not copper, chromium, cobalt and aluminum, often as glutathione conjugates (Aleo et al., 2005; Vernhet et al., 2000). Notch1 regulates the expression in cultured cancer cells (Cho et al., 2011).  Structural and functional properties of MRP1 have been reviewed comprehensively (He et al. 2011).  Fluorescent substrates have been identified (Strouse et al. 2013).  It pumps out sulfur mustards and nitrogen mustards (mechlorethamine, HN2), potent vesicants developed as chemical warfare agents (Udasin et al. 2015). It has 3 membrane domains with a total of 17 TMSs. Loss of the aromatic side chain at position 583 impairs the release of ADP and thus effectively locks the transporter in a low-affinity solute binding state (Weigl et al. 2018).

Animals

MRP1 of Homo sapiens (P33527)

 
3.A.1.208.9

Canicular multispecific organic anion MDR transporter, MRP3 (also called ABCC3) (most similar in sequence to MRP2). MRP3 exports epipodophyllotoxins, etoposide and teniposide, estradiol 17-β-D-glucuronide, leukotriene C4, dinitrophenyl S-glutathione, epoposide glucuronide, methotrexate, bilirubin-glucuronides, bile acids, GSH-X (LTC4, DNP-SG) and sulfate-X (taurolithocholate-3-sulfate).  Substrate translocation and stimulated ATP hydrolysis show positive cooperativity (Hill coefficient = 2) and are half-coupled (Seelheim et al. 2012).  ABCC3 is overexpressed in various types of cancer including carcinogenic stem cells, and plays a role in liver cancer progression (Carrasco-Torres et al. 2015).

Animals

MRP3 of Homo sapiens (O15438)

 


3.A.1.209 The MHC Peptide Transporter (TAP) Family (ABCB)


Examples:

TC#NameOrganismal TypeExample
3.A.1.209.1

MHC heterodimeric peptide exporter (TAP) (from cytoplasm to the endoplasmic reticulum) (TAP1=ABCB2; TAP2=ABCB3) (defects in TAP1 or TAP2 cause immunodeficiency) (TAP1/TAP2 is stabilized by tapasin isoforms 1, 2 and 3) (Raghuraman et al., 2002). TAP1 has 10 TMSs, 4 unique N-terminal TMSs and 6 TMSs that form the translocation pore with N- and C-termini in the cytosol (Schrodt et al., 2006). The TAP2 nucleotide binding site appears to be the main catalytic active site driving transport suggesting asymmetry in the transporter (Perria et al., 2006). The TAP complex shows strict coupling between peptide binding and ATP hydrolysis, revealing no basal ATPase activity in the absence of peptides (Herget et al., 2009).  There are three binding sites on TAP1 for tapasis which interconnects TAP and MHC class I, promotes TAP stability and facilitates heterodimerization (Leonhardt et al. 2014).  TAP is the target of GN1 (TC#8.B.25.1.1), a virally encoded protein inhibitor of viral peptide exposure on the cell surface (Verweij et al. 2008; Rufer et al. 2015). Tapasin (448 aas; O15533) stabilizes TAP2 (Papadopoulos and Momburg 2007). Tapasin is involved in the association of MHC class I with the transporter associated with antigen processing (TAP) and in the assembly of MHC class I with peptide (peptide loading). TAP plays a key role in the adaptive immune defense against infected or malignantly transformed cells by translocating proteasomal degradation products into the lumen of the endoplasmic reticulum for loading onto MHC class I molecules. TAP transports peptides from 8 to 40 residues, including even branched or modified molecules, suggestive of structural flexibility of the substrate-binding pocket. The bound peptides in side-chains' mobility was strongly restricted at the ends of the peptide, whereas the central region was flexible. Peptides bind to TAP in an extended kinked structure, analogous to those bound to MHC class I proteins (Herget et al., 2011). TAP translocates proteasomal degradation products from the cytosol into the lumen of the endoplasmic reticulum, where these peptides are loaded onto MHC class I molecules by a macromolecular peptide-loading complex (PLC) and subsequently shuttled to the cell surface for inspection by cytotoxic T lymphocytes. As a central adapter protein, tapasin (O15533) (Li et al. 2000) recruits other components of the PLC at the N-terminal domains of TAP. Koch et al. 2006 found that the N-terminal domains of human TAP1 and TAP2 independently bind to tapasin, thus providing two separate loading platforms for PLC assembly. Tapasin binding is dependent on the first N-terminal TMS of TAP1 and TAP2, demonstrating that these two helices contribute independently to the recruitment of tapasin and associated factors (Koch et al. 2006). The endoplasmic reticulum-resident human cytomegalovirus glycoprotein US6 (gpUS6) inhibits peptide translocation by the transporter associated with antigen processing (TAP) to prevent loading of major histocompatibility complex class I molecules and antigen presentation to CD8+ T cells. gpUS6 associates with preformed TAP1/2 heterodimers (Halenius et al. 2006).

Animals, yeast

TAP1/TAP2 of Homo sapiens

 
3.A.1.209.2

Homodimeric transporter ABCB9 or TAPL. Transports a broad spectrum of peptides (low affinity) from the cytosol to the lysosomal lumen. It exists in two forms (812 aas and 1257 aas). The latter full length protein confers resistance to taxanes and anthracyclines (Kawanobe et al., 2012). Resistance and transport were demonstrated for paclitaxel and docetaxel. TapL transports a broad range of peptides of 6-60aas (23aas optimal). It has also been detected in the ER. It is stabilized by interaction with LAMP-1 and LAMP-2 (see 9.A.16) (Demirel et al., 2012).  The protein consists of a core transporter plus an N-terminal transmembrane domain (TMD0) required to tageting to the lysosome and for interactions with LAMP-1 and -2 (Tumulka et al. 2013). TMD0 has a four transmembrane helix topology with a short helical segment in a lysosomal loop (Bock et al. 2018). Lysosomal targeting is determined by membrane localized charged residues (Graab et al. 2019).

Animals

TAPL or ABCB9 of Homo sapiens (Q9NP78)

 
3.A.1.209.3

Haf-4/Haf-9 heterodimeric half transporter of 787 aas and 815 aas, respectively.  Probably tranports antigenic peptides. Both proteins localize to the membrane of nonacidic, lysosome-associated, membrane protein homologue (LMP-1)-positive intestinal granules from larval to adult stages. Mutants of haf-4 and haf-9 exhibited granular defects in late larval and young adult intestinal cells, associated with decreased brood size, prolonged defecation cycle, and slow growth (Kawai et al. 2009). Thus they may mediate intestinal granular formation. HAF-4-HAF-9 heterodimer formation is required for their stabilization (Tanji et al. 2013). The HAF-4- and HAF-9-localizing organelles are distinct intestinal organelles associated with the endocytic pathway (Tanji et al. 2016; Tanji et al. 2017).

Haf-4/Haf-9 of Caenorhabditis elegans

 


3.A.1.21 The Siderophore-Fe3+ Uptake Transporter (SIUT) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.21.1The Fe3+-Yersiniabactin uptake transporter, YbtPQ (Brem et al., 2001; Fetherston et al., 1999)ProteobacteriaYbtPQ of Yersinia pestis
YbtP (M-C)
YbtQ (M-C)
 
3.A.1.21.2

The Fe3+-carboxymycobactin transporter, IrtAB (Rodriguez and Smith, 2006). IrtA contains an FAD-binding domain (Ryndak et al., 2010).

Actinobacteria

IrtAB of Mycobacterium tuberculosis
IrtA (M-C) (P63391)
IrtB (M-C) (P63393)

 


3.A.1.210 The Heavy Metal Transporter (HMT) Family (ABCB)


Examples:

TC#NameOrganismal TypeExample
3.A.1.210.1

The mitochondrial iron transporter, ATM1.  The crystal structures of the nucleotide-free and glutathione-bound inward facing, open conformations have been solved at 3.1 and 3.4 Å resolution respectively (Srinivasan et al. 2014).  The glutathione binding site is near the inner membrane surface in a large cavity.  An unknown sulfur compound appears to be exported by Atm1 and used for the synthesis of iron/sulfur centers in the cytoplasm.  This compound also signals iron sufficiency/deficiency to the nucleus (Philpott et al. 2012). [But see also, 3.A.210.15].

Fungi

ATM1 of Saccharomyces cerevisiae

 
3.A.1.210.10

Mitochondrial ABC iron/sulfur complex transporter, AbcB12 of 542 aas.

Alveolata (Ciliates)

AbcB12 (M-C) of Tetrahymena thermophila

 
3.A.1.210.11

Inner membrane miltochondrial homodimeric Atm1 of 608 aas and 6 TMSs per subunit.  The structure has been solved to 2.4 Å resolution (Lee et al. 2014).  Required for the formation of cytosolic iron-sulfur cluster-containing proteins (Lill et al. 2012); but see also, 3.A.210.15.

Proteobacteria

Atm1 of Novosphingobium aromaticivorans

 
3.A.1.210.12

ABCB3 of 704 aas and 6 TMSs.  Essential for the biosynthesis of heme in mitochondria, and of iron-sulfur centers (ISC) in the cytoplasm. The protein is an ABC half-transporter that has an N-terminal extension required to target LmABCB3 to the mitochondrion.  Martínez-García et al. 2016 showed that LmABCB3 interacts with porphyrins and is required for the mitochondrial synthesis of heme from a host precursor. It complements the severe growth defect in yeast lacking ATM1, an orthologue of human ABCB7, involved in exporting from mitochondria a gluthatione-containing compound required for the generation of cytosolic ISC. Docking analyzes using trypanothione, the main thiol in the parasite, showed how both, LmABCB3 and yeast ATM1, contain a similar thiol-binding pocket. LmABCB3 is an essential gene as dominant negative inhibition of LmABCB3 is lethal for the parasite. The abrogation of only one allele of the gene did not impede promastigote growth in axenic culture but prevented the replication of intracellular amastigotes and the virulence of the parasites in a mouse model of cutaneous leishmaniasis.

ABCB3 of Leishmania major

 
3.A.1.210.13

ABCB6 of 585 aas and about 6 TMSs with an M-C domain order. 

AbcB6 of Enterocytozoon hepatopenaei

 
3.A.1.210.15

ABC exporter, ABCB7; PexA; Atm1, of 612 aas and 6 N-terminal TMSs with an ATPase domain C-terminal (M-C), probably specific for polysulfides, being exported from the cytooplasm to the periplasm. I is 47% identical to PexA (ABCB7) of humans (Riedel et al. 2019).

ABCB7 of Rhodobacter capsulatus

 
3.A.1.210.2The vacuolar heavy metal tolerance protein precursor, HMT1 (transports phytochelins and Cd2+·phytochelin complexes) (Prévéral et al., 2009).

Yeast; animals, protozoa bacteria

HMT1 of Schizosaccharomyces pombe

 
3.A.1.210.3The ABC transporter homologueYeast; animals, protozoa bacteriaABC transporter homologue in Rickettsia prowazekii
 
3.A.1.210.4

ABC7 or ABCB7 iron transporter (X-linked sideroblastis anemia protein, XLSA/A (Fujiwara and Harigae 2013)).  Glutathione-complexed [2Fe-2S] stimulates the ATPase activity in both solution and proteoliposome-bound forms (Kd ∼ 68 μM). This cluster is a likely natural substrate for this transporter, which has been implicated in cytosolic Fe-S cluster protein maturation (Qi et al. 2014). It is a homodimer that may also transport heme from mitocondria to the cytosol (Sakamoto et al. 2019).

Yeast; animals, protozoa bacteria

ABC7 iron transporter of Homo sapiens

 
3.A.1.210.5Multidrug resistance homologues, Pfmdr2, proteinYeast; animals, protozoa bacteriaPfmdr2 protein of Plasmodium falciparum
 
3.A.1.210.6

Mitochondrial outer membrane/lysosome anionic porphyrin uptake half ABC transporter, ABCB6. Expressed in many mammalian tissues (including fetal liver) in response to intracellular porphyrin. Porphyrin uptake activates de novo porphyrin (haem) biosynthesis (Krishnamurthy et al., 2006).  The first TMS contains a lysosomal targetting signal (Kiss et al. 2015).

Animals

ABCB6 of Homo sapiens (Q9NP58; 842 aas)

 
3.A.1.210.7

The homodimeric heavy metal tolerance protein 1, CeHMT-1 (AbcB6) (exports phytochelatin ((γ-Glu-Cys)n)-Cd2+ complexes as well as glutathione complexes of copper and arsenic) (Vatamaniuk et al., 2005).  The N-terminal hydrophobic extension domain is required (but not sufficient) for dimerization and therefore is essential for normal function (Kim et al. 2010, Kim et al. 2018). Both the N- and C-terminal domains are required for proper localization in the endosomes of liver-like coelomocytes, head neurons and intestine (Kim et al. 2018).

Animals

CeHMT-1 of Caenorhabditis elegans (AAM33380)

 
3.A.1.210.8

Mitochondrial ABC transporter, ATM3, involved in iron homeostasis (Chen et al. 2007) and heavy metal resistance (Kim et al. 2006). There are three isoforms: ATM1, ATM2 and ATM3 (Chen et al., 2007). ATM3 can replace the yeast iron/sulfur cluster exporter better than ATM1 or ATM2. Atm3 is most similar to the human and yeast homologues, TC# 3.A.1.210.4 and 3.A.1.210.1, 51% and 47% identical, respectively.  It may function in cytosolic iron-sulfur cluster biogenesis (Bernard et al. 2009) as well as molybdenum cofactor biosynthesis (Teschner et al. 2010).  It performs an essential function in the generation of cytoplasmic iron-sulfur proteins by mediating export of Fe/S cluster precursors. Not required for mitochondrial and plastid Fe-S enzymes. Probably involved in the export of cyclic pyranopterin monophosphate (cPMP) from mitochondria into the cytosol. Mediates glutathione-dependent resistance to heavy metals such as cadmium and lead, as well as their transport from roots to leaves. Regulates nonprotein thiols (NPSH) and the cellular level of glutathione (GSH); but see also, 3.A.210.15.  This protein, also called ABCB25, is of 728 aas with 6 TMSs and a domain order of MC.  It transports glutathione poly sulfides (Lefèvre and Boutry 2018).

Plants

ATM3 of Arabidopsis thaliana (Q9LVM1)

 
3.A.1.210.9

The Ni2+/Co2+ exporter AtmA.  Repressed by Zn2+, but not induced by Ni2+ or Co2+ (Mikolay and Nies, 2009).

Bacteria

AtmA of Cuperiavidus metallidurans (Q1LRE9).

 


3.A.1.211 The Cholesterol/Phospholipid/Retinal (CPR) Flippase Family (ABCA)


Examples:

TC#NameOrganismal TypeExample
3.A.1.211.1

The cholesterol/phospholipid flippase, ABC1 (called ABCA1 in humans; Tangier disease proteins; 2261 aas; sp: O95477). An amphipathic helical region of the N-terminal barrel of the phospholipid transfer protein (PLTP) is critical for ABCA1-dependent cholesterol efflux (Oram et al., 2008). PLTP helix 144-163 removes lipid domains formed by ABCA1, stabilizing ABCA1, interacting with phospholipids, and promoting phospholipid transfer by direct interactions with ABCA1. May transport sphingosine-1-phosphate (Kobayashi et al., 2009). May protect from cardiovascular disease and diabetes (Tang and Oram, 2009). Mediates efflux of cellular cholesterol and phospholipids to apoA-I (Voloshyna and Reiss, 2011).  Hyperglycemia accelerates ABCA1 degradation (Chang et al. 2013).  Human ABCA1 is down regulated upon infection with Chlamydia pneumoniae which inhibits bacterial growth (Korhonen et al. 2013).  Curcumin induces expression of ABCA1 (Tian et al. 2013).

Animals and plants

ABC1 of Mus musculus

 
3.A.1.211.10

ABCA7. Regulates cellular efflux of phospholipids but not cholesterol, to apo A-1 (Voloshyna and Reiss, 2011).  Associated with late-onset Alzheimer's disease, possibly by influencing amyloid-β (Abeta) accumulation (Zhao et al. 2014).  Known functions of ABCA7 are summarized in Zhao et al. 2014 and Sakamoto et al. 2019.

Animals

ABCA7 of Homo sapiens (Q8IZY2)

 
3.A.1.211.11

AOH1; ABCA1 transporter.  Substrates unknown.

Plants

ABCA1 of Arabidopsis thaliana

 
3.A.1.211.12

ABCA12 transporter of 917 aas. 

Plants

ABCA12 of Arabidopsis thaliana

 
3.A.1.211.13

ABCA12 keratinocyte lipid transporter of 2595 aas (Shimizu et al. 2014).  Functions in epidermal lipid barrier formation and keratinocyte differentiation (Akiyama 2013).  Defects cause a form of autosomal recessive congenital ichthyosis, a disorder of keratinization with abnormal differentiation and desquamation of the epidermis, resulting in abnormal skin scaling over the whole body. The main skin phenotypes are lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE) (Akiyama 2013). ABCA12 plays a role in lipid transport from the Golgi apparatus to lamellar granule in human granular layer keratinocytes (Sakai et al. 2007).  ABCA12‑associated mutations or alterations in expression  exhibit causative or contributive effects to the development of keratinized dermatoses, including KP and NC (Liu et al. 2018).

Animals

ABCA12 of Homo sapiens

 
3.A.1.211.14

cAMP-dependent and sulfonylurea-sensitive anion transporter, ABCA1 of 2261 aas. Key gatekeeper influencing and possibly catalyzing intracellular phospholipid and cholesterol transport (Orlowski et al. 2007).  Interacts with the MEGF10 protein.  95% identical to the mouse orthologue, 3.A.1.211.1.  Cholesterol efflux from THP-1 macrophages decreases in the presence of plasma obtained from humans and rats with mild hyperbilirubinemia. A direct effect of unconjugated bilirubin on cholesterol efflux was demonstrated and is associated with decreased ABCA1 protein expression (Wang et al. 2017). The cryoEM struction (4.1 Å) revealed that the two transmembrane domains contact each other through a narrow interface in the intracellular leaflet of the membrane, and two extracellular domains of ABCA1 enclose an elongated hydrophobic tunnel. Structural mapping of dozens of disease-related mutations allowed potential interpretation of their diverse pathogenic mechanisms. Structural-based analyses suggested a plausible """"lateral access"""" mechanism for ABCA1-mediated lipid export that may be distinct from the conventional alternating-access paradigm. AbcA1 acts in concert with ABCB1, ABCG2 and ABCG4 to efflux amyloid-β peptide (Aβ) from the brain across the blood-brain barrier (BBB) (Kuai et al. 2018). One substrate of systems ABCA1, ABCB1 and ABCC1 is arsenate, where ABCC1 is most effective while ABCA1 and ABCB1 are less effective (Zhou et al. 2018). ABCA1 transports lipids and cholesterol onto apolipoprotein E (APOE( (Castranio et al. 2018). Cholesterol binding to the ABCA1 may interfere with ATP binding in both nucleotide-binding domains of the ABCA1 structure (Dergunov et al. 2018).  Adiponectin, possibly acting through AdipoR1 and AdipoR2, plays a key role in promoting ABCA1-dependent cholesterol efflux (Hafiane et al. 2019).

Animals

ABCA1 of Homo sapiens

 
3.A.1.211.15

ATP-binding cassette sub-family A member 6, ABCA6 of 1617 aas. This transporter may play a role in macrophage lipid homeostasis. It is up-regulated during monocyte differentiation into macrophages but down-regulated by cholesterol loading of macrophages (Sakamoto et al. 2019).

Animals

ABCA6 of Homo sapiens

 
3.A.1.211.16

ATP-binding cassette sub-family A member 9, ABCA9 of 1624 aas. May play a role in monocyte differentiation and lipid homeostasis. Expressed in fetal tissues with highest expression in fetal heart and kidney. Up-regulated during monocyte differentiation into macrophages. Down-regulated by cholesterol loading of macrophages (Sakamoto et al. 2019).

Animals

ABCA9 of Homo sapiens

 
3.A.1.211.17

ATP-binding cassette sub-family A member 10, ABCA10 of 1543 aas. May play a role in macrophage lipid homeostasis. Highly expressed in skeletal muscle, heart, brain and gastrointestinal tract. Down-regulated by cholesterol loading of macrophages (Sakamoto et al. 2019).

Animals

ABCA10 of Homo sapiens

 
3.A.1.211.18

ATP-binding cassette sub-family A member 13, ABCA13, of 5058 aas. Expressed in testis, bone marrow and trachea (Sakamoto et al. 2019).

Animals

ABCA13 of Homo sapiens

 
3.A.1.211.19
ABC transporter A family member 2, ABCA2 or ABCA.2 of 1621 aas.

Amoebozoa (Slime molds)

ABCA2 of Dictyostelium discoideum

 
3.A.1.211.2

The retinal-specific ABC transporter (RIM protein, ABCR or ABCA4) (Stargardt's disease protein, involved in retinal/macular degeneration) in the rod outer segment. Changes in the oligomeric state of the nucleotide binding domains of ABCR are coupled to ATP hydrolysis and might represent a signal for the TMDs of ABCR to export the bound substrate (Biswas-Fiss 2006). The ABCA4 porter flips N-retinylidene-phosphatidylethanolamine, a product generated from the photobleaching of rhodopsin, from the lumen to the cytoplasmic side of disc membranes following the photobleaching of rhodopsin, insuring that retinoids do not accumulate in disc membranes (Molday, 2007; Molday et al. 2009; Tsybovsky et al. 2013). It also transports several vitamin A derivatives (Sun, 2011) and phosphatidylethanolamine in the same direction. Mutations, known to cause Stargardt disease, decrease N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine transport activities (Quazi et al. 2012). It functions as an inwardly directed retinoid flippase in the visual cycle (Sakamoto et al. 2019).

Animals

RIM protein (ABCR) of Homo sapiens

 
3.A.1.211.20

ABCA9 of 950 aas with an M-C domain order.  Transports fatty acids and acyl CoA derivatives (Lefèvre and Boutry 2018).

ABCA9 of Arabidopsis thaliana (Mouse-ear cress)

 
3.A.1.211.21

Putative ATP-binding cassette transporter pf 1384 aas and 14 TMSs in a 1 + 6 + 1 + 6 arrangement (Greiner et al. 2018).

 

ABC exporter of Amsacta moorei entomopoxvirus

 
3.A.1.211.22

Putative ATP-binding cassette transporterof 1506 aas and 19 TMSs in an MCMC domain arrangement.

ABC exporter of Anomala cuprea entomopoxvirus

 
3.A.1.211.23

ATP-binding cassette sub-family A member 3-like isoform X1of 1571 aas and 13 or 14

ABC exporter of Onthophagus taurus

 
3.A.1.211.24

ABCF3 or ABC50 of 712 aas and 0 TMSs. ABC50 plays a key role in translation initiation and has functions that are distinct from those of other non-membrane ABC proteins (Paytubi et al. 2009).

ABCF3 of Caenorhabditis elegans

 
3.A.1.211.25

ABC protein, OptrA, of 619 aas and 0 TMSs, having the domain order of C-C.  It is not involved in the export of drugs (oxazolidinones and phenicols)out of the cell and may confer ribosomal protection (Wang et al. 2018).

.

OptrA of Enterococcus faecalis

 
3.A.1.211.26

ABCA17 or ABCAH or 1733 aas and 12 TMSs in a MCMC domain arrangement. ABCA17 mRNA is expressed exclusively in the testis, ABCA17 mRNA is expressed in germ cells, mainly spermatocytes, in the seminiferous tubule. It is localized in the endoplasmic reticulum, and intracellular esterified lipids, including cholesteryl esters, fatty acid esters and triacylglycerols, were decreased in cells stably expressing ABCA17. Thus, ABCA17 may play a role in regulating the lipid composition in sperm (Ban et al. 2005).

ABCA17 of Mus musculus

 
3.A.1.211.3

Multidrug resistance pump, ABCA2 (ABC2). Mediates trafficking of LDL-derived free cholesterol (Voloshyna and Reiss, 2011). Transports endogenous lipids such as myelin (Soichi et al. 2007).

Animals

ABCA2 of Homo sapiens

 
3.A.1.211.4The aced cell death 7 (ced-7) protein (translocates molecules that mediate adhesion between dying and engulfing embryonic cells during programmed death). AnimalsCed-7 of Caenorhabditis elegans (P34358)
 
3.A.1.211.5

The surfactant-secreting porter, ABCA3 (exports lipids and proteins into lamellar bodies). Fatal surfactant deficiency (FSD) can result from mutations in ABCA3, causing abnormal intracellular localization (type I) or decreased ATP hydrolysis (type II). Other mutations cause pediatric interstitial lung disease (pILD) (Matsumura et al. 2008).  ABCA3 is found in lamellar bodies of lung alveolar type II cells where it probably secretes surfactants (mixture of lipids; e.g., PC) and proteins (e.g., surfactant proteins A, B, C and D) stored in lamellar bodies and exocytosed (Matsumura et al., 2006). ABCA3 plays an essential role in pulmonary surfactant lipid metabolism and lamellar body biogenesis, probably by transporting these lipids as substrates (Ban et al., 2007). Cheong et al., 2007 have shown that ABCA3 is critical for lamellar body biogenesis in mice. They suggest it functions in surfactant-protein B processing and lung development late in gestation. Lymphoma exosomes shield target cells from antibody attack, and exosome biogenesis is modulated by lysosome-associated ABCA3 which mediates resistance to chemotherapy. Silencing ABCA3 enhances susceptability of target cells to antibody-mediated lysis. Mechanisms of cancer cell resistance to drugs and antibodies are linked in an ABCA3-dependent pathway of exosome secretion (Aung et al., 2011). 

Animals

ABCA3 of Homo sapiens (Q99758)

 
3.A.1.211.6

Xenobiotic transporter, ABCA8 (transports estradiol-β-glucuronide, taurocholate, LTC4, para-amino-hippurate, ochratoxin-A and hydrophilic drugs (Tsuruoka et al., 2002), (Sakamoto et al. 2019).

Animals

ABCA8 of Homo sapiens (O94911)

 
3.A.1.211.7Half sized ABCA exporter, AbcAAmoebaAbcA of Dictyostelium discoideum
M-C 655 aas; (Q94479)
 
3.A.1.211.8

AbcA12 Keratinocyte lipid transporter.  Transports lipids in lamellar granules to the apical surface of granular layer keratinocytes. Extracellular lipids, including ceramide, are thought to be essential for skin barrier function. ABCA12 mutations underlie the three main types of autosomal recessive congenital ichthyoses: harlequin ichthyosis, lamellar ichthyosis and congenital ichthyosiform erythroderma. ABCA12 mutations lead to defective lipid transport via lamellar granules in the keratinocytes, resulting in malformation of the epidermal lipid barrier and ichthyosis phenotypes. Lipid transport by ABCA12 is indispensable for intact differentiation of keratinocytes (Akiyama, 2011). 

Animals

AbcA12 of Mus musculus (B9EKF0)

 
3.A.1.211.9

ABCA5. Mediates cholesterol efflux to HDL3 (Voloshyna and Reiss, 2011). Functions in autolysosomes (Sakamoto et al. 2019).

Animals

ABCA5 of Homo sapiens (Q8WWZ7)

 


3.A.1.212 The Mitochondrial Peptide Exporter (MPE) Family (ABCB)


Examples:

TC#NameOrganismal TypeExample
3.A.1.212.1The mitochondrial peptide exporter, Mdl1p (exports peptides of 6-21 amino acyl residues from the mitochondrial matrix as well as degradation products of misassembled respiratory chain complexes) (Janas et al., 2003; van der Does et al., 2006; Gompf et al., 2007). A leaderless Mdl1p targets to the ER membrane instead of to the mitochondria (Gompf et al., 2007).YeastMdl1p of Saccharomyces cerevisiae (P33310)
 
3.A.1.212.2ABC mitochondrial peptide/MDR half transporter, MdlB. High copy number suppressor of ATM1 [iron-sulfur cluster transporter (3.A.1.210.1)]BacteriaMd1B of Saccharomyces cerevisiae (M-C) (P33311)
 
3.A.1.212.3

ABC-type MDR2 of 802 aas and 6 TMSs.  Exports many drugs including antifungal agents (Martins et al. 2016).

MDR of Trichophyton tonsurans (Scalp ringworm fungus)

 


3.A.1.22 The Nickel Uptake Transporter (NiT) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.22.1

Putative nickel (Ni2+)and/or Cobalt (Co2+) porter with 4 components, CbiKMQO.

Proteobacteria

CbiKMQO of Actinobacillus pleuropneumoniae
CbiK (R)
CbiM (M)
CbiQ (M)
CbiO (C)

 
Examples:

TC#NameOrganismal TypeExample


3.A.1.23 The Nickel/Cobalt Uptake Transporter (NiCoT) Family

This and other ECF ABC families (3.A.1.18, 23, 25, 26, 28, 31 and 32) have been reviewed (Rempel et al. 2018).


Examples:

TC#NameOrganismal TypeExample
3.A.1.23.1

Nickel (Ni2+) porter (Chen and Burne, 2003)

Firmicutes

UreMQO of Streptococcus salivarius
UreM (M) (Q79CJ1)
UreQ (M) (Q79CJ0)
UreO (C) (Q79CI9)

 
3.A.1.23.2Putative cobalt (Co2+) porter (Chen and Burne, 2003)Firmicutes

CbiMQOK of Clostridium acetobutylicum
CbiM (M) (AAK79333)
CbiQ (M) (AAK79335)
CbiO (C) (AAK79336)
CbiK (Auxiliary?) (AAK79334)

 
3.A.1.23.3

Cobalt (Co2+) porter 

δ-Proteobacteria

Cbi M(N)OQ of Geobacter sulfurreducens 
Cbi M(N) (D7AE13)
CbiO (D7AE10)
CbiQ (D7AE11) 

 
3.A.1.23.4

The NikM2 (230 aas; 5 TMSs)/NikN2 (110 aas; 2 TMSs) pair is part or all of a nickel transporter.  The crystal structure of NikM2 is known (PDB 4M5C; 4M58).  It possesses an additional TMS at its N-terminal region not present on other ECF transporter of known structure, resulting in an extracellular N-terminus. The highly conserved N-terminal loop inserts into the center of NikM2 and occludes a region corresponding to the substrate-binding sites of the vitamin-specific S component. Nickel binds to NikM2 by coordination to four nitrogen atoms in Met1, His2 and His67. These nitrogens form a square-planar geometry, similar to that of the metal ion-binding sites in the amino-terminal Cu2+- and Ni2+-binding (ATCUN) motif (Yu et al. 2013).  Constituents other than NikN2 and NikM2 are not known but may be required for activity (T. Eitinger, personal communication).

Firmicutes

NikM2N2 of Thermoanaerobacter tengcongensis  (Caldanaerobacter subterraneus subsp. tengcongensis)

 
3.A.1.23.5

Putative Ni2+/Co2+ uptake porter, NikMNOQ (Yu et al. 2013).

Firmicutes

NikMNOQ of Thermoanaerobacter tengcongensis

 
3.A.1.23.6

Cobalt (Co2+) porter (Rodionov et al., 2006).  CbiMN is a bipartite S-subunit with 8 TMSs (Siche et al. 2010). Dynamic interactions of CbiN and CbiM trigger activity of the transporter (Finkenwirth et al. 2019). Substrate binding (S) components rotate within the membrane to expose their binding pockets alternately to the exterior and the cytoplasm. In contrast to vitamin transporters, metal-specific systems rely on additional proteins with essential functions. CbiN, with two TMSs tethered by an extracytoplasmic loop of 37 amino-acid residues is the auxiliary component that temporarily interacts with the CbiMQO2 Co2+ transporter. CbiN induces Co2+ transport activity in the absence of CbiQO2 in cells producing the S component CbiM plus CbiN or a Cbi(MN) fusion. Finkenwirth et al. 2019 showed that any deletion in the CbiN loop abolished transport activity. Protein-protein contacts between segments of the CbiN loop and loops in CbiM were demonstrated, and an ordered structure of the CbiN loop was shown. The N-terminal loop of CbiM, containing three of four metal ligands was partially immobilized in wild-type Cbi(MN) but completely immobile in inactive variants with CbiN loop deletions. Thus, CbiM-CbiN loop-loop interactions facilitate metal insertion into the binding pocket (Finkenwirth et al. 2019).

Proteobacteria

CbiMNOQ of Salmonella typhimurium
CbiM (M) (Q05594)
CbiN (Essential auxillary subunit) (Q05595)
CbiO (C) (Q05596)
CbiQ (M) (Q05598)

 
3.A.1.23.7

Ni2+, Co2+ uptake transporter, NikMNOQ (subunit sizes: NikMN, 347 aas, 9 TMSs; NikQ, 284 aas, 4 TMSs; NikO, 254 aas, 0 TMS.  NikMN can take up Ni2+ without NikQ or NikO (Kirsch and Eitinger 2014).

Proteobacteria

NikMNQO of Rhodobacter capsulatus
NikMN (M; 9 TMSs)
NikQ  (M; 5 TMSs)
NikO (C; 0 TMSs)

 
3.A.1.23.8

Ni2+/Co2+ uptake porter, CbiMNOQ (CbiM, 222 aas, 5 TMSs; CbiN, 103 aas, 2 TMSs; CbiO, 280 aas, 0 TMSs; CbiQ, 244 aas, 5 TMSs).  CbiMN can take up Ni2+ without CbiO or CbiQ (Kirsch and Eitinger 2014).

Proteobacteria

CbiMNOQ of Rhodobacter capsulatus
CbiM (M)
CbiN (M)
CbiO (C)
CbiQ (M)

 

 


3.A.1.24 The Methionine Uptake Transporter (MUT) Family (Similar to 3.A.1.3 and 3.A.1.12)


Examples:

TC#NameOrganismal TypeExample
3.A.1.24.1

The L- and D-methionine porter (also transports formyl-L-methionine and other methionine derivatives) (Zhang et al., 2003). The 3.7A structure of MetNI has been solved. An allosteric regulatory mechanism operates at the level of transport activity, so increased intracellular levels of the transported ligand stabilize an inward-facing, ATPase-inactive state of MetNI to inhibit further ligand translocation into the cell (Kadaba et al., 2008).  The structure of an MetQ homologue in Neisseria meningitidis has been solved at 2.25 Å resolution revealing a bound methionine in the cleft between the two domains (Yang et al. 2009). Conformational changes in MetQ provide substrate access through the binding protein to the transmembrane translocation pathway. MetQ likely mediates uptake of methionine derivatives through two mechanisms: in the methionine-bound form, substrate is delivered from the periplasm to the transporter (the canonical mechanism) and in the apo form, it facilitates ligand binding when complexed to the transporter (the noncanonical mechanism). This dual role of substrate-binding proteins was proposed to provide a kinetic strategy for ABC transporters to transport both high- and low-affinity substrates present in a physiological concentration range (Nguyen et al. 2018).

Proteobacteria

MetNIQ (abc-yaeE-yaeC) of E. coli
MetN (C) AAC73310
MetI (M) AAC73309
MetQ (R) AAC73308

 
3.A.1.24.2The L- and D-methionine porter (also transports methionine sulfoxide (Hullo et al., 2004)FirmicutesMetNPQ (YusCBA) of Bacillus subtilis
MetN (C) CAB15264
MetP (M) CAB15263
MetQ (R) CAB15262
 
3.A.1.24.3The methionine porter, AtmBDE (Sperandio et al., 2007)bacteriaAtmBDE of Streptococcus mutans
AtmB (R) (Q8K8K9)
AtmD (C) (Q8K8K8)
AtmE (M) (Q8K8K7)
 
3.A.1.24.4L-Methionine uptake porter, MetQNI

Bacteria

MetQNI of Corynebacterium glutamicum
MetQ (R) (Q8NSN1)
MetN (C) (Q8NSN2)
MetI (M) (Q8NSN3)

 
3.A.1.24.5

L-Histidine uptake porter, MetIQN (Johnson et al. 2008)

Proteobacteria

MetIQN of Pseudomonas aeruginosa
MetI (M) (Q9HT69)
MetQ (R) (Q9HT68)
MetN (C) (Q9HT70)

 
3.A.1.24.6

Putative peptide transporter, PepABC.  The three components of this system are encoded in an operon with a gene encoding a peptidase (Q04MS7), providing the only tentative evidence for the substrate transported.  However the similarity with the methionine transporter of Streptococcus mutans (TC# 3.A.1.24.3) suggests that this porter may also be a methionine uptake porter.

Firmicutes

PepABC of Streptococcus pneumoniae
PepA (R; 284 aas)
PepB (C; 353 aas)
PepC (M; 230 aas)

 


3.A.1.25 The Biotin Uptake Transporter (BioMNY) Family

This and other ECF ABC families (3.A.1.18, 23, 25, 26, 28, 31 and 32) have been reviewed (Rempel et al. 2018).


Examples:

TC#NameOrganismal TypeExample
3.A.1.25.1

The biotin uptake porter (binding receptor lacking) (see also the VUT or ECF family; BioY; 2.A.88.1.1) (Rodionov et al., 2006; Hebbeln et al., 2007). BioN (the EcfT component of the biotin transporter) appears to be required for intramolecular signaling and subunit assembly (Neubauer et al., 2009). The Ala-Arg-Ser and Ala-Arg-Gly signatures in BioN are coupling sites to the BioM ATPases (Neubauer et al., 2011).  Subunit stoicheometries have been estimated with the prediction that there are oligomeric forms of BioM and BioY in the BioMNY complex (Finkenwirth et al. 2010).

Bacteria

BioMNY of Rhizobium etli
BioM (C) (226 aas; 0 TMSs; Q6GUB2)
BioN (M) (202 aas; 5 TMSs; Q6GUB1)
BioY (M) (189 aas; 6 TMSs; Q6GUB0)

 
3.A.1.25.2

Putative biotin Ecf transporter, EcfSAA'T (function assigned based on genome context analyses). 

Archaea

Putative Ecf transporter, EcfSAA'T, of Methanospirillum hungatei 
EcfS (M) (Q2FUL6)
EcfA (C) (Q2FUL5)
EcfA' (C) (Q2FUM0)
EcfT (M) (Q2FNH6) 

 
3.A.1.25.3

Putative biotin Ecf transporter, EcfSAA'T (function assigned based on genome context analyses).

Archaea

The putative EcfSAA'T transporter of Methanocorpusculum labreanum
EcfS (A2SPQ3)
EcfA (A2SPQ4)
EcfA' (A2SPQ5)
EcfT (A2SPQ6) 

 
3.A.1.25.4

The biotin uptake system, BioMNY. The 3-d structure of the EcfS subunit, BioY, at 2.1Å resolution is known (Berntsson et al., 2012). BioY and ThiT from L. lactis show similar N-terminal structures for interaction with the ECF module but divergent C-terminal structures for substrate binding. BioY alone binds biotin but doesn''t transport it (Berntsson et al., 2012).  Ala-Arg-Ser and Ala-Arg-Gly signatures in BioN are probably coupling sites to the two BioM ATPase subunits (Neubauer et al., 2011).

Bacteria

BioMNY of Lactococcus lactis 
BioM (A) (A2RI01)
BioN (T) (A2RI03)
BioY (S) (A2RMJ9) 

 
3.A.1.25.5

Biotin/Riboflavin ECF transport system, EcfAA'T/RibU/BioY (Karpowich and Wang 2013). RibU binds riboflavin with high affinity, and the protein-substrate complex is exceptionally stable in solution. The crystal structure of riboflavin-bound RibU reveals an electronegative binding pocket at the extracellular surface in which the substrate is completely buried (Karpowich et al. 2016).

Bacteria

EcfAA''T/RibU/BioY of Thermatoga martima
EcfA (C) (Q9WY65)
EcfA'' (C) (Q9X1Z1)
EcfT (M) (Q9X2I1)
BioY (M) (Q9X1G6)
RibU (M) (Q9WZQ6)

 
3.A.1.25.6

Riboflavin ECF transport system, EcfAA'T/RibU (Karpowich and Wang 2013).

Bacteria

EcfAA'T/RibU of Streptococcus thermophilus 
EcfA (C) (Q5M244)
EcfA' (C) (Q5M243)
EcfT (M) (Q5M245)
RibU (M) (Q5M614)

 
3.A.1.25.7

The riboflavin uptake system, BioMNY.  BioM, EtcA, ATPase, 234 aas;  BioN, EtcT, 190 aas, 5 TMSs; BioY, EtcS, 210 aas, 5 TMSs BioY can also function as a secondary carrier and is therefore listed separately under TC# 2.A.88.1.3.  ATP-dependent conformational changes drive substrate capture and release when BioMNY are together in a complex (Finkenwirth et al. 2015).

Proteobacteria

RibMNY of Rhodobacter capsulatus

 
3.A.1.25.8

An ECF ABC transporter with 4 subunits, EcfS/EcfT/EcfA/EcfA'.  EcfS is also called RibU; EcfT is also called CbiQ, EcfA is also called Cbi01, and EcfA' is also called Cbi02.  This system can take up riboflavin and possibly other vitamins (Karpowich et al. 2015). ATP binding to the EcfAA' ATPases drives a conformational change that dissociates the S subunit from the EcfAA'T ECF module. Upon release from the ECF module, the RibU S subunit then binds the riboflavin transport substrate.  S subunits for distinct substrates compete for the ATP-bound state of the ECF module (Karpowich et al. 2015). RibU appears to be capable of exporting riboflavin, FMN and FAD (Light et al. 2018).

EcfSTAA' complex of LIsteria monocytogenes
EcfS, RibU, 203 aas and 5 TMSs
EcfT, CbiQ, 265 aas and 6 TMSs
EcfA, Cbi01, 279 aas
EcfA', Cbi02, 288 aas

 


3.A.1.26 The Putative Thiamine Uptake Transporter (ThiW) Family

This and other ECF ABC families (3.A.1.18, 23, 25, 26, 28, 31 and 32) have been reviewed (Rempel et al. 2018).


Examples:

TC#NameOrganismal TypeExample
3.A.1.26.1

The putative thiazole ABC porter (COG4732), ThiW; 718 aas; 5 TMSs; domain order: M-C-C; plus the putative ATPase binding subunit, CbiQ homologue (binding receptor unknown) (Rodionov et al., 2009)

Bacteria

ThiW/CbiQ of Chloroflexus aurantiacus
ThiW MCC (SAA) (A9WGB0)
CbiQ M (T) (A9WGA9)

 
3.A.1.26.10

ATP-dependent folic acid uptake porter, FolT/EcfT/EcfA1/EcfA2.  The crystal structure of FolT has been solved to 3.2 Å resolution in substrate-bound and free conformations, revealing a potential gating mechanism (Zhao et al. 2015).

FolT/EcfT/EcfA1/EcfA2 of Enterococcus faecalis
FolT, 182 aas, 5 TMSs
EcfT, 264 aas, 6 TMSs
EcfA1, 279 aas
EcfA2, 289 aas

 
3.A.1.26.11

Putative pantothenate uptake porter, PanT/EcfA/EcfA'/EcfT (Rodionova et al. 2015).

Putative ABC (Ecf) pantothenate transporter of Ktedonobacter racemifer
PanT, (M, substrate binding subunit)
EcfA, (C)
EcfA', (C)
EcfT, (M, transducer subunit)

 
3.A.1.26.2

ThiW homologue/CbiQ homologue (ThiW: 647 aas; M-C-C; 5-6TMSs) (Rodionov et al., 2009)

Archaea

ThiW/ChiQ of Methanocorpusculum labreanum
ThiW MCC (SAA) (A2SPE8)
CbiQ M (T) (A2SPE9)

 
3.A.1.26.3

ThiW homologue (711 aas; M-C-C) (No known binding receptor) plus a CbiQ homologue (Rodionov et al., 2009)

Bacteria

ThiW/CbiQ homologues of Actinomyces odontolyticus
ThiW MCC (SAA) (A7BAX2)
CbiQ M (T) (A7BAX3)

 
3.A.1.26.4

ThiW/CbiQ homologues (ThiW: 697 aas; M-C-C) (No known binding receptor) (Rodionov et al., 2009)

Bacteria

ThiW/CbiQ homologues of Mycobacterium tuberculosis
ThiW MCC (SAA) (P63399)
CbiQ M (T) (P64997)

 
3.A.1.26.5

ThiW/CbiQ/CbiO homologues (ThiW: 174 aas; 5 putative TMSs).  Possible thiamin uptake porter (Rodionov et al., 2009).

Bacteria

ThiW/CbiQ/CbiO homologues of Roseiflexus castenholzii
ThiW (M) (S) (A7NRF9)
CbiQ (M) (T) (A7NRG1)
CbiO C-C (A-A) (A7NRG0)

 
3.A.1.26.6

The ThiW/CbiQ/CbiO1/CbiO2 homologues (ThiW: 184 aas; 1-6 TMSs) (Rodionov et al., 2009)

Archaea

ThiW/CbiQ/CbiO1/CbiO2 homologues of Aeropyrum pernix
ThiW M (S) (Q9Y974)
CbiQ M (T) (Q9Y982)
CbiO1 C (A) (Q9Y979)
CbiO2 C (A) (Q9Y977)

 
3.A.1.26.7

The putative hydroxyethyl thiazole (biosynthetic precursor of thiamine) porter, ThiW-EcfA1-A2-EcfT (this is a group II ECF transporter which uses a universal energy-coupling module (EcfA1-EcfA2-EcfT) in many firmicutes; Rodionov et al., 2002).

Bacteria

ThiW-EcfA1-EcfA2-EcfT of Enterococcus faecalis
ThiW (M) (Q830K3)
EcfA1 (C) (Q839D5)
EcfA2 (C) (Q839D4)
EcfT (M) (Q839D3)

 
3.A.1.26.8

Putative biotin Ecf transporter, EcfSAT

Archaea

Putative Ecf transpoter, EcfSAT, of Archaeoglobus fulgidus 
S-subunit (M) (O29098) 
A-subunit (C) (O29097) 
T-subunit (M) (O29096) 

 
3.A.1.26.9

The folate transporter, FolT/EcfAA''T (The 3-d structure is known to 3.0Å resolution (Xu et al. 2013; 4HUQ).  This transporter uses the same ECF energy coupling complex (AA''T) as 3.A.1.28.2.

Firmicutes

FolT/EcfAA'T of Lactobacillus brevis
FolT (M; EcfS subunit) (Q03S56)
EcfA (C) (Q03PY6)
EcfA' (C) (Q03PY7)
EcfT (M) (Q03PY5)

 
Examples:

TC#NameOrganismal TypeExample


3.A.1.27 The γ-Hexachlorocyclohexane (HCH) Family (Similar to 3.A.1.12 and 3.A.1.24)


Examples:

TC#NameOrganismal TypeExample
3.A.1.27.1The γ-hexachlorocyclohexane (γHCH) uptake permease, LinKLMN (most similar to 3.A.1.12.4, the QAT family) (Endo et al., 2007)BacteriaLinKLMN of Sphingobium japonicum
LinK (M) (BAF51698)
LinL (C) (BAF51699)
LinM (R) (BAF51700)
LinN (lipoprotein) (BAF51701)
 
3.A.1.27.2

The chloroplast lipid (trigalactosyl diacyl glycerol (TDG)) transporter, Tdg1,2,3 (Lu et al., 2007). Lipids such as mono- and digalactolipids are synthesized in the endoplasmic reticulum (ER) of plant cells and transferred to the thylakoid membranes of chloroplasts. Mutations in an outer chloroplastic envelope protein with 350 aas and 7 putative TMSs in the last 250 residues may catalyze translocation as part of a lipid transfer complex (Xu et al., 2003; Roston et al. 2012).

Plant Chloroplast

Tdg 1,2,3 of Arabidopsis thaliana:
Tdg1 (M) (Q8L4R0)
Tdg2 (R) (Q3EB35)
Tdg3 (C) (Q9AT00)

 
3.A.1.27.3

ABC transporter maintaining outer membrane (OM) lipid asymmetry, MlaABCDEF (YrbABCDEF) (Malinverni and Silhavy, 2009). MlaA (VacJ) is a "spreading" protein, essential for Shigella pathogenicity (Suzuki et al., 1994).  The ABC transporter, MlaEFBD, provides energy for maintaining OM lipid asymmetry via the transport of aberrantly localized phospholipids (PLs) from the OM to the inner membrane (IM) (Thong et al. 2016). MlaD forms stable hexamers within the complex, functions in substrate binding with strong affinity for PLs, and modulates ATP hydrolytic activity. MlaB plays critical roles in both the assembly and activity of the transporter.  MlaA forms a complex with OmpC and OmpF in the outer membrane to extract PLs from the outer leaflet of the OM (Chong et al. 2015). MlaA is a monomeric α-helical OM protein that functions as a phospholipid translocation channel, forming a ~20-Å-thick doughnut embedded in the inner leaflet of the OM with a central, amphipathic pore (Abellón-Ruiz et al. 2017). This architecture prevents access of inner leaflet phospholipids to the pore, but allows outer leaflet phospholipids to bind to a pronounced ridge surrounding the channel.

Proteobacteria

MlaABCDEF of E. coli
MlaA, YrbA, OM lipoprotein component (251aas) (P76506)
MlaB, YrbB cytoplasmic STAS component (97aas) (P64602)
MlaC, YrbC periplasmic binding receptor (R) (211aas) (P0ADV7)
MlaD, YrbD anchored periplasmic binding receptor (R) (183aas) (P64604)
MlaE, YrbE inner membrane permease component (M) (260aas) (P64606)
MlaF, YrbF ATP binding protein (C) (269aas) (P63386)

 
3.A.1.27.4

The cholesterol uptake porter (Mohn et al., 2008). Takes up cholesterol, 5-α-cholestanol, 5-α-cholestanone, β-sitosterol, etc. (It is not established that all of these proteins comprise the system or that other gene products are not involved.)

Actinobacteria

Cholesterol uptake porter of Rhodococcus jostii
YrbE4A (ro04696; 254aas; 5-6 TMSs) (M) (Q0S7K4)
YrbE4B (ro04697; 283aas; 5 TMSs) (M) (Q0S7K3)
MceE4A (ro04698; 391aas; 1 N-terminal TMS) (R) (Q0S7K2)
MceE4B (ro04699; 338aas; 1 N-terminal TMS) (R) (Q0S7K1)
MlkA (ro01974; 363aas; 0 TMSs) (C) (Q0SFA1)
MlkB (ro01744; 346aas; 0 TMSs) (C) (Q0SD37)

 

 
3.A.1.27.5

The Mce/Yrb/Mlk (Mammalian cell entry) ABC-type putative steroid uptake transporter (involved in several aspects of mycobacterial pathogenesis) (Mohn et al., 2008; Joshi et al., 2006).

Bacteria

The Mce transporter of Mycobacterium tuberculosis H37Rv
YrbE4A (M) (254aas; 6 TMSs) (O53546)
YrbE4B (M) (280aas; 5 TMSs) (O53545)
MceA (R) (242aas; 1 TMS) (O06356)
MceB (R) (244aas; 1 TMS) (O07422)
Mlk (C) (Mkl; MceG; 359aas; 0 TMSs) (P63357)

 


3.A.1.28 The Queuosine (Queuosine) Family

This and other ECF ABC families (3.A.1.18, 23, 25, 26, 28, 31 and 32) have been reviewed (Rempel et al. 2018).


Examples:

TC#NameOrganismal TypeExample
3.A.1.28.1The putative queuosine uptake transporter, QrtTUVW (Rodionov et al., 2009) (most similar to 2.A.88.2.1)

Bacteria

QrtTUVW of Salmonella enterica su. typh.
QrtT (M) (Q8XGV9)
QrtU (M) (Q8Z3V9)
QrtV (C) (Q8Z3V8)
QrtW (C) (Q8Z3V7)

 
3.A.1.28.2

The folate transporter, FolT/EcfAA''T (The 3-d structure is known to 3.0Å resolution (Xu et al. 2013; 4HUQ).  Thiamine and riboflavin may also be substrates.

Firmicutes

EcfAA'ST of Lactobacillus brevis
EcfA (C) (Q03PY5)
EcfA' (C) (Q03PY6)
EcfS (M) (Q03NM0)
EcfT (M) (Q03PY7)

 


3.A.1.29 The Methionine Precursor (Met-P) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.29.1

The putative methionine precursor/uptake transporter, MtsTUV (T is most similar to 3.A.1.23.2; U is most similar to 2.A.36.7.1 and 3.A.1.14.2; V is most similar to 3.A.1.23.2 and 3.A.1.25.1) (Rodionov et al., 2009)

Bacteria

MtsTUV of Lactobacillus johnsoni
MtsT (M) (Q74I63)
MtsU (C) (Q74I62)
MtsV (M) (Q74I61)

 


3.A.1.3 The Polar Amino Acid Uptake Transporter (PAAT) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.3.1

Histidine/arginine/lysine/ornithine porter (Heuveling et al. 2014). In contrast to some homologous homodimeric systems, the heterodimeric histidine transporter of Salmonella enterica Typhimurium  ligands only one substrate molecule in between its two transmembrane subunits, HisM and HisQ (Heuveling et al. 2019).

Proteobacteria

HisJ (histidine receptor)-ArgT (arg/lys/orn receptor)-HisMPQ of Salmonella typhimurium
HisJ (R)
ArgT (R)
HisM (M)
HisQ (M)
HisP (C)

 
3.A.1.3.10

Cystine/diaminopimelate transporter, CysXYZ; these proteins are also designated FliY/YecS/YecC.  Note, another transporter is designated CysZ in E. coli (TC# 2.A.121.1.1).  CysXYZ also transports the toxic amino acid analogues, L-selenaproline (SCA; L-selenazolidine-4-carboxylic acid) and L-selenocystine (SeCys) (Deutch et al. 2014).

Proteobacteria

Cys/Dap porter of E. coli
CysX or FliY (R)
CysY or YecS (M)
CysZ or YecC (C)

 
3.A.1.3.11Arginine/ornithine (but not lysine) porterProteobacteriaAotJQMP of Pseudomonas aeruginosa
AotJ (R)
AotQ (M)
AotM (M)
AotP (C)
 
3.A.1.3.12Arginine/lysine/histidine/glutamine porterCyanobacteriaBgtAB of Synechocystis PCC6803
BgtA (C)
BgtB (R-M)
 
3.A.1.3.13

Uptake system for L-cystine (Km=2.5 μM), L-cystathionine, L-djenkolate ( 2-amino-3-[(2-amino-3-hydroxy-3-oxopropyl)sulfanylmethylsulfanyl] propanoic acid), and S-methyl-L-cysteine (Burguière et al., 2004, Burguière et al., 2005)

Firmicutes

TcyJKLMN (YtmJKLMN) of Bacillus subtilis
TcyJ (R) (NP_390816)
TcyK (R) (O34852)
TcyL (M) (O34315)
TcyM (M) (O34931)
TcyN (C) (O34900)

 
3.A.1.3.14

Uptake system for L-cystine (Burguière et al., 2004)

Firmicutes

TcyABC (YckKJI) of Bacillus subtilis
TcyA (R) (P42199)
TcyB (M) (P42200)
TcyC (C) (P39456)

 
3.A.1.3.15

Putative uptake system for arginine, YqiXYZ (Sekowska et al., 2001)

Bacteria

YqiXYZ of Bacillus subtilis
YqiX (R) (P54535)
YqiY (M) (P54536)
YqiZ (C) (P54537)

 
3.A.1.3.16Uptake system for glutamate and aspartate (Leon-Kempis et al., 2006)ProteobacteriaPEB1 transport system Campylobacter jejuni
PEB1a (R) (Q0P9X8)
PED1b (M) (A1VZQ3)
PEB1c (C) (A3ZI83)
 
3.A.1.3.17Basic amino acid uptake transporter, BgtAB (BgtA is shared with NatFGH/BgtA; 3.A.1.3.18; Pernil et al., 2008)CyanobacteriaBgtAB of Anabaena sp. PCC7120
BgtA (C) (Q8YPM6)
BgtB (R-M) (Q8YSA2)
 
3.A.1.3.18Acidic and neutral amino acid uptake transporter NatFGH/BgtA. BgtA is shared with BgtAB (3.A.1.3.17; Pernil et al., 2008)CyanobacteriaNatFGH-BgtA of Anabaena sp. PCC7120
BgtA (C) (Q8YPM6)
NatF (R) (Q8YPM9)
NatG (M) (Q8YPM8)
NatH (M) (Q8YPM7)
 
3.A.1.3.19

Acidic amino acid uptake porter, AatJMQP (Singh and Röhm, 2008).  It is the sole system that  transports glutamate and glutamine, but it can also transport aspartate and asparagine (Singh and Röhm 2008).

Bacteria

AatJMQP of Pseudomonas putida
AatJ (R) Q88NY2
AatM (M) Q88NY3
AatQ (M) Q88NY4
AatP (C) Q88NY5

 
3.A.1.3.2

Three component ABC L-glutamine porter. The basal ATPase activity (ATP hydrolysis in the absence of substrate) is mainly caused by the docking of the closed-unliganded state of GlnH onto the transporter domain of GlnPQ. Unlike glutamine, arginine binds both GlnH domains, but does not trigger their closing. Comparison of the ATPase activity in nanodiscs with glutamine transport in proteoliposomes suggested that the stoichiometry of ATP per substrate is close to two (Lycklama A Nijeholt et al. 2018).

Proteobacteria

GlnHPQ of E. coli
GlnH (R)
GlnP (M)
GlnQ (C)

 
3.A.1.3.20

The putative lysine uptake system, LysXY

Bacteria

LysXY of Streptococcus pyogenes
LysX (R-M) (Q9A1H0)
LysY (C) (Q9A1H1)

 
3.A.1.3.21

Hydroxy L-proline uptake porter, HprABC (Johnson et al. 2008).

Proteobacteria

HprABC of Pseudomonas aeruginosa
HprA (C) (Q9I488)
HprB (M) (Q9I487)
HprC (R) (Q9I484)

 
3.A.1.3.22

Amino acid transporter, AatJMQP. Probably transports L-glutamic acid, D-glutamine acid, L-glutamine and N-acetyl L-glutamic acid (Johnson et al. 2008). Very similar to 3.A.1.3.19 of P. putida

Proteobacteria

AatJMQP of Pseudomonas aeruginosa
AatJ (R) (Q9I402)
AatM (M) (Q9I403)
AatQ (M) (Q9I404)
AatP (C) (Q9I405)

 
3.A.1.3.23

Amino acid transporter, PA5152-PA5155. Probably transports numerous amino acids including lysine, arginine, histidine, D-alanine and D-valine (Johnson et al. 2008). Regulated by ArgR.

Proteobacteria

PA5152-PA5144 of Pseudomonas aeruginosa
PA5152 (C) (Q9HU32)
PA5153 (R) (Q9HU31)
PA5154 (M) (Q9HU30)
PA5155 (M) (Q9HU29)

 
3.A.1.3.24

Putative methionine uptake porter, Sco_5260, 5259, 5258. Defects cause impaired sporulation, reduced growth and reduced production of actinorhodin and undecylprodigiosin. Induced by S-adenosylmethionine (Shin et al. 2007).

Actinobacteria

Sco_5260, 5259, 5258 of Streptomyces coelicolor
Sco5260 (R) 320aas (Q9F3K5)
Sco5259 (M) 316aas (Q9F3K6)
Sco5258 (C) 253aas (Q9F3K7) 

 
3.A.1.3.25

Glutamine transporter, GlnQP. Takes up glutamine, asparagine and glutamate which compete for each other for binding both substrate and the transmembrane protein constituent of the system (Fulyani et al. 2015). Tandem substrate binding domains (SBDs) differ in substrate specificity and affinity, allowing cells to efficiently accumulate different amino acids via a single ABC transporter. Analysis revealed the roles of individual residues in determining the substrate affinity (Fulyani et al. 2013).

Firmicutes

GlnPQ of Lactococcus lactis subsp. cremoris (Streptococcus cremoris)

 
3.A.1.3.26

The putative polar amino acid uptake porter, YhdWXYZ.  Probably under NtrBC transcriptional control (Jiang et al. 2006).

Proteobacterial

YhdWXYZ of E. coli
YhdW (R)
YhdX (M)
YhdY (M)
YhdZ (C)

 
3.A.1.3.27

Basic amino acid uptake porter, ArtIQ2N2. Transports Arginine, lysine and histidine.  Several 3-d structures have been solved (4YMS, 4YMT, 4YMU, etc., Yu et al. 2015).  These revealed one binding site for substrate per ArtQ monomer.  Heuveling et al. 2018 then showed that in the close homologue, ArtMP of Geobacillus stearothermophilus, that just one of these two sites needed to bind substrate to get transport.

Firmicutes

ArtIQ2N2 of Caldanaerobacter subterraneus subsp. tengcongensis (Thermoanaerobacter tengcongensis)
ArtI (R)
ArtQ (M)
ArtN (C)

 
3.A.1.3.28

Putative amino acid uptake porter, YckIJK; deletion of YckK (substrate binding protein) increases sensitivity to the antimicrobial peptide, cecropin (Chen et al. 2015). 

YckIJK of Haemophilus psarasuis
YckI (C)
YckJ (M)
YckK (R)

 
3.A.1.3.29

Histidine/Arginine/Lysine (basic amino acid) uptake porter, HisJ/ArgT/HisP/HisM/HisQ [R, R, C, M, M, respectively] (Gilson et al. 1982). HisJ binds L-His (preferred), but 1-methyl-L-His and 3-methyl-L-His also bind, while the dipeptide carnosine binds weakly; D-histidine and the histidine degradation products, histamine, urocanic acid and imidazole do not bind. L-Arg, homo-L-Arg, and post-translationally modified methylated Arg-analogs also bind with the exception of symmetric dimethylated-L-Arg. L-Lys and L-Orn show weaker interactions with HisJ and methylated and acetylated Lys variants show poor binding.The carboxylate groups of these amino acids and their variants are essential (Paul et al. 2016).

Basic amino acid transporter of E. coli

 
3.A.1.3.3Arginine porterProteobacteriaArtI (arginine receptor #1)/ArtJ (arginine receptor #2)-ArtMQP of E. coli
ArtP (C)
ArtQ (M)
ArtM (M)
ArtJ (R)
ArtI (R)
 
3.A.1.3.30

Putative ABC amino acid uptake porter with 3 constituents. The membrane protein is different from other members of this subfamily in having 10 TMSs in a 3 + 2 + 3 + 2 TMS arrangement with a probable 5 TMS duplication), and the receptor has two TMSs at the N- and C-termini.

Putative amino acid uptake porter of Candidatus Heimdallarchaeota archaeon LC_3 (marine sediment metagenome)
OLS25600, R, 372 aas, 2 TMSs, N- and C-terminal
OLS25601, M, 472 aas, 10 TMSs
OLS25602, C, 251 aas, 0 TM

 
3.A.1.3.4

Glutamate/aspartate porter.  Similar in sequence to 3.A.1.3.19 which is specific for Glu, Asp, Gln and Asn (Singh and Röhm 2008).

Proteobacteria

GltIJKL of E. coli
GltI (R)
GltJ (M)
GltK (M)
GltL (C)

 
3.A.1.3.5Octopine porterProteobacteriaOccQMPT of Agrobacterium tumefaciens
OccT (R)
OccQ (M)
OccM (M)
OccP (C)
 
3.A.1.3.6Nopaline porterProteobacteriaNocQMPT of Agrobacterium tumefaciens
NocT (R)
NocQ (M)
NocM (M)
NocP (C)
 
3.A.1.3.7Glutamate/glutamine/aspartate/asparagine porterProteobacteriaBztABCD of Rhodobacter capsulatus
BztA (R)
BztB (M)
BztC (M)
BztD (CC)
 
3.A.1.3.8

General L-amino acid porter; transports basic and acidic amino acids preferentially, but also transports aliphatic amino acids (catalyzes both uptake and efflux) (Prell et al. 2009; Hosie et al. 2002).

Proteobacteria

AapJQMP of Rhizobium leguminosarum
AapJ (R)
AapQ (M)
AapM (M)
AapP (C)

 
3.A.1.3.9Glutamate porterActinobacteriaGluABCD of Corynebacterium glutamicum
GluA (C)
GluB (R)
GluC (M)
GluD (M)
 


3.A.1.30 The Thiamin Precursor (Thi-P) Family


Examples:

TC#NameOrganismal TypeExample
3.A.1.30.1

The putative thiamin precursor uptake transporter, YkoEDC (Rodionov et al., 2009) (E is most similar to 3.A.1.4.3; D is most similar to 3.A.1.26.2; C is most similar to 3.A.1.23.2).

Bacteria

YkoEDC of Bacillus subtilis
YkoE (M) (O34738)
YkoD (C-C) (O34362)
YkoC (M) (O34572)

 
3.A.1.30.2

Putative thiamin transporter

Firmicutes

Potential thiamin transporter of Streptococcus pneumoniae 
Membrane Protein 1 (Q97RJ2) 
ABC ATPase (Q97RS3)
Membrane Protein 2 (Q97RS4) 

 
Examples:

TC#NameOrganismal TypeExample


3.A.1.31 The Unknown-ABC1 (U-ABC1) Family

This and other ECF ABC families (3.A.1.18, 23, 25, 26, 28, 31 and 32) have been reviewed (Rempel et al. 2018).


Examples: