2.A.7 The Drug/Metabolite Transporter (DMT) Superfamily

The DMT Superfamily consists of 24 recognized families, each, in general, with a characteristic function, size and topology. These phylogenetic families will be presented and described below; references, when available, will be provided, and representative well-characterized proteins, when available, will be tabulated. Lolkema et al. (2008) have presented bioinformatic analysis of prokaryotic members of the DMT (DUF606) superfamily concerning evolution of the antiparallel arrangements of the two homologous 5TMS domains.

2.A.7.1 The 4 TMS Small Multidrug Resistance (SMR) Family

SMR family pumps are prokaryotic transport systems consisting of homodimeric or heterodimeric structures (Chung and Saier, 2001; Bay et al., 2007). The subunits of these systems are of 100-120 amino acid residues in length and span the membrane as α-helices four times. Functionally characterized members of the SMR family catalyze multidrug efflux driven drug:H⁺ antiport where the proton motive force provides the driving force for drug efflux. The drugs transported are generally cationic, and a simple cation antiport mechanism involving the conserved Glu-14 has been proposed (Yerushalmi and Schuldiner, 2000). This mechanism suggests a requisite, mutually exclusive occupancy of Glu-14, providing a simple explanation for coupling the movement of two positively charged molecules. One system (YdgEF of E. coli; TC# 2.A.7.1.8) is reported to confer resistance to anionic detergents (Nishino and Yamaguchi, 2001).

The 3-D structure of the dimeric EmrE shows opposite orientation of the two subunits in the membrane (Chen et al., 2007). The first three transmembrane helices from each monomer surround the substrate binding chamber, whereas the fourth helices participate only in dimer formation. Selenomethionine markers clearly indicate an antiparallel orientation for the monomers, supporting a 'dual topology' model. On the basis of available structural data, a model for the proton-dependent drug efflux mechanism of EmrE was proposed.

2.A.7.2 The 5 TMS Bacterial/Archaeal Transporter (BAT) Family

The BAT family consists of 5 TMS proteins from bacteria and archaea. None of these proteins is functionally characterized.

2.A.7.3 The 10 TMS Drug/Metabolite Exporter (DME) Family

The DME family is a large family of integral membrane proteins with sizes ranging from 287 to 310 amino acyl residues and exhibiting 10 putative α-helical transmembrane spanners (TMSs). These proteins are derived from phylogenetically divergent bacteria and archaea, and B. subtilis, E. coli, S. coelicolor and A. fulgidus have multiple paralogues. Distant eukaryotic homologues are more closely related to DME family members than to other DM superfamily members can be found (i.e., the Riken gene product of the mouse (BAC31006)).

Proteins of the DME family evidently arose by an internal gene duplication event as the first halves of these proteins are homologous to the second halves. One of these prokaryotic proteins, YdeD, is functionally characterized and exports cysteine metabolites in E. coli. Another, RhtA of E. coli, exports threonine and homoserine. A third, Sam of Rickettsia prowazekii, takes up S-adenosylmethionine (TC #3.A.7.3.7; Tucker et al., 2003). In addition, several members of the DME family have been implicated in solute transport. Thus, the MttP protein of the archaeon, Methanosarcina barkeri, may transport methylamine (Ferguson and Krzycki, 1997); MadN is encoded within the malonate utilization operon of Malonomonas rubra and may be an acetate efflux pump, and PecM is encoded within a locus of Erwinia chrysanthemi controlling pectinase, cellulase and blue pigment production and might export the pigment indigoidine, produced by gene products encoded in the pecM operon. The PecM protein has been shown experimentally to exhibit a 10 TMS topology (Rouanet and Nasser, 2001).

2.A.7.4 The Plant Drug/Metabolite Exporter (P-DME) Family

The P-DME family is a large subset of the DME family. All of these proteins are derived from plants, and they cluster loosely together on a phylogenetic tree that includes all members of the DME and P-DME families. All of these proteins appear to have 10 TMSs. If this suggestion proves to be correct, then the two halves of these proteins will have opposite orientation in the membrane. Hydropathy plots suggest that families 2.A.7.3-2.A.7.14 all exhibit 10 putative TMSs. No member of the P-DME family is functionally characterized, although one of these proteins, Nodulin 21 of M. truncatula, may be involved in bacterial nodulation.

2.A.7.5 The Glucose/Ribose Porter (GRP) Family

The glucose/ribose uptake (GRU) family includes two functionally characterized members, a glucose uptake permease of Staphylococcus xylosus, and a probable ribose uptake permease of Lactobacillus sakei. Both proteins probably function by H⁺ symport.

2.A.7.6 The L-Rhamnose Transporter (RhaT) Family

The RhaT family includes only 2 proteins, the rhamnose:H⁺ symporters of E. coli and Salmonella typhimurium, both of which have been functionally characterized. The RhaT proteins of both species are 344 aas long with 10 putative TMSs.

2.A.7.7 The Chloramphenicol-Sensitivity Protein (RarD) Family

No member of the RarD family is functionally characterized. Members of the family are from Gram-negative bacteria, Gram-positive bacteria and possibly archaea. They vary in size from 250-300 residues. They exhibit 10 TMSs.

2.A.7.8 The Caenorhabditis elegans ORF (CEO) Family

The CEO family is a small family of 6 paralogues encoded within the genome of C. elegans. None of these proteins is functionally characterized.

2.A.7.9 The Triose-phosphate Transporter (TPT) Family

Functionally characterized members of the former TPT family are derived from the inner envelope membranes of chloroplasts and nongreen plastids of plants. However, homologues are also present in yeast. Saccharomyces cerevisiae has three functionally uncharacterized TPT paralogues encoded within its genome. Under normal physiological conditions, chloroplast TPTs mediate a strict antiport of substrates, frequently exchanging an organic three carbon compound phosphate ester for inorganic phosphate (P_i). Normally, a triose-phosphate, 3-phosphoglycerate, or another phosphorylated C₃ compound made in the chloroplast during photosynthesis, exits the organelle into the cytoplasm of the plant cell in exchange for P_i. These transporters are members of a subfamily, the TPT subfamily within the TPT family. Experiments with reconstituted translocators in artificial membranes indicate that transport can also occur by a channel-like uniport mechanism with up to 10-fold higher transport rates. Channel opening may be induced by a membrane potential of large magnitude and/or by high substrate concentrations. Nongreen plastid and chloroplast carriers, such as those from maize endosperm and root membranes, mediate transport of C₃ compounds phosphorylated at carbon atom 2, particularly phosphoenolpyruvate, in exchange for P_i. These are the phosphoenolpyruvate:P_i antiporters (the PPT subfamily). Glucose-6-P has also been shown to be a substrate of some plastid translocators (the GPT subfamily). These three subfamilies of proteins (TPT, PPT and GPT) are divergent in sequence as well as substrate specificity, but their substrate specificities overlap.

Each TPT family protein consists of about 400-450 amino acyl residues with 5-8 putative transmembrane α-helical spanners TMSs). The actual number has been proposed to be 6 for the plant proteins as for mitochondrial carriers (TC# 2.A.29) and members of several other transporter families. However, proteins of the TPT family do not exhibit significant sequence similarity with the latter proteins, and there is no evidence for an internal repeat sequence. TPT proteins may exist as homodimers in the membrane.

The generalized reaction catalyzed by the proteins of the TPT family is:

organic phosphate ester (in) + P_i (out) &8652; organic phosphate ester (out) + P_i (in).

2.A.7.10 The UDP-N-Acetylglucosamine:UMP Antiporter (UAA) Family

Nucleotide-sugar transporters (NSTs) are found in the Golgi apparatus and the endoplasmic reticulum of eukaryotic cells. Members of the family have been sequenced from yeast, protozoans and animals. Animals such as C. elegans possess many of these transporters. Humans have at least two closely related isoforms of the UDP-galactose:UMP exchange transporter.

NSTs generally appear to function by antiport mechanisms, exchanging a nucleotide-sugar for a nucleotide. Thus, CMP-sialic acid is exchanged for CMP; GDP-mannose is preferentially exchanged for GMP, and UDP-galactose and UDP-N-acetylglucosamine are exchanged for UMP (or possibly UDP). Other nucleotide sugars (e.g., GDP-fucose, UDP-xylose, UDP-glucose, UDP-N-acetylgalactosamine, etc.) may also be transported in exchange for various nucleotides, but their transporters have not been molecularly characterized. Each compound appears to be translocated by its own transport protein. Transport allows the compound, synthesized in the cytoplasm, to be exported to the lumen of the Golgi apparatus or the endoplasmic reticulum where it is used for the synthesis of glycoproteins and glycolipids. Comparable transport proteins exist for ATP which phosphorylates proteins, and phosphoadenosine phosphosulfate (PAPS) which is used as a percursor for protein sulfation. It is not known if these transport proteins are members of the DMT superfamily.

The sequenced NSTs are generally of about 320-340 amino acyl residues in length and exhibit 8-12 putative transmembrane α-helical spanners. An 8 TMS model has been presented by Kawakita et al. (1998) for the human UDP galactose transporter 1.

The generalized reaction catalyzed by NSTs is:

nucleotide-sugar (cytoplasm) + nucleotide (lumen) &8652; nucleotide-sugar (lumen) + nucleotide (cytoplasm)

2.A.7.11 The UDP-Galactose:UMP Antiporter (UGA) Family

The generalized reaction catalyzed by NSTs is:

nucleotide-sugar (cytoplasm) + nucleotide (lumen) &8652; nucleotide-sugar (lumen) + nucleotide (cytoplasm)

2.A.7.12 The CMP-Sialate:CMP Antiporter (CSA) Family

The generalized reaction catalyzed by NSTs is:

nucleotide-sugar (cytoplasm) + nucleotide (lumen) &8652; nucleotide-sugar (lumen) + nucleotide (cytoplasm)

2.A.7.13 The GDP-Mannose:GMP Antiporter (GMA) Family

The yeast VRG4 protein, also called 'vanidate resistance protein', is a GDP-mannose transporter with the same size and topology as the other NSTs, but it shows very little sequence similarity with them. Only with the PSI-BLAST program with one iteration do these proteins exhibit apparent similarity. VRG4 is most similar to proteins in C. elegans, Leishmania donovani, Arabidopsis thaliana, and another S. cerevisiae protein reported to be of 249 aas (spP40027).

2.A.7.14 The Plant Organocation Permease (POP) Family

A single member of the POP family (AtPUP1) has been functionally characterized. It has been shown to transport adenine and cytosine with high affinity. Evidence concerning energy coupling suggested an H⁺ symport mechanism. Purine derivatives (e.g., hypoxanthine), phytohormones (e.g., zeatin and kinetin) and alkaloids (e.g., caffeine) proved to be competitive inhibitors suggesting that they may be transport substrates. In fact trans-zeatin (a cytokinin) has been shown to be taken up, probably by at least two systems (Cedzich et al. 2008). The order of inhibition of adenine uptake by a variety of purine derivatives, phytohormones and alkaloids was reported to be: adenine, kinetin, caffeine, cytosine, zeatin, hypoxanthine, cytidine, nicotine, kinetin riboside, adenosine, zeatin riboside and thymine (Williams and Miller, 2001). At least 15 members of this family have been sequenced from A. thaliana (Gillissen et al., 2000). Thus, AtPUP1 may be a broad specificity organocation transporter. Other family members have been reported to exhibit different affinities for nucleobases.

The generalized transport reaction probably catalyzed by AtPUP1 is:

Organocation (out) + H⁺ (out) → Organocation (in) + H⁺ (in)

2.A.7.15 The UDP-glucuronate/UDP-N-acetylgalactosamine Transporter (UGnT) Family

2.A.7.16 The GDP-fucose Transporter (GFT) Family

2.A.7.17 The Aromatic Amino Acid/Paraquat Exporter (ArAA/P-E) Family

The ArAA/PE family is a small family of proteobacterial proteins with 10 putative TMSs and sizes and sequences that most resemble the proteins of the DME family (2.A.7.3) within the DMT superfamily. One member of this family, YddG of E. coli and Salmonella typhimurium (<95% identical), have been functionally characterized (Santiviago et al., 2002; Doroshenko et al., 2007). They are efflux pumps for paraquat (methyl viologen) which is a hydrophilic, doubly charged, quaternary ammonium compound that can participate in a redox cycle that generates oxygen free radicals in the bacterial cell under aerobic conditions. YddG cannot pump out acriflavin, showing that it is fairly specific. It also exports aromatic amino acids. Therefore, it may not be a multidrug resistance pump. Paraquat resistance is also dependent on the major Salmonella porin, OmpD. Thus, YddG and OmpD are believed to function together in exporting paraquat to the external medium, but it is not known if this occurs in one or two steps (Santiviago et al., 2002).

The overall reaction catalyzed by YddG is:

Paraquat (in) → Paraquat (out).

2.A.7.18 The Choline Uptake Transporter (LicB-T) Family

A single functionally characterized secondary transporter, LicB of Haemophilus influenzae defines the LicB-T family (Fan et al., 2003). It has 292 aas and 10 putative TMSs.

LicB is a high-affinity choline permease that takes up choline under choline-limiting conditions. It is required for the use of exogenous choline for the synthesis of phosphorylcholine which is incorporated into the bacterium's lipopolysaccharide (LPS). It does not play a role in osmoprotection. Phosphorylcholine derivatized LPS contributes to H. influenzae's pathogenesis by mimicry of host cell molecules (Fan et al., 2003).

The overall reaction catalyzed by LicB is probably:

choline (out) + H⁺ (out) → choline (in) + H⁺ (in).

2.A.7.19 The Nucleobase Uptake Transporter (NBUT) Family

The allantoin permeases of Phaseolus vulgaris (French bean) and Arabidopsis thaliana have been shown to transport uracil and fluorouracil as well as allantoin (Schmidt et al., 2004). Arabidopsis has several paralogues. Distant homologues are present in Bacteroides thetaiotamicron (AAO77915) and Entamoeba histolyticia (EAL46705). These proteins have 10 putative TMSs and comprise a distinct family in the DMT superfamily.

2.A.7.20 The Chloroquine Resistance Transporter (PfCRT) Family

The Plasmodium falciparum chloroquine resistance protein (PfCRT) is a transporter as are its homologues in various species. In Plasmodium species it is localized to the intra-erythrocytic digestive vacuole. Mutations in this protein confer Verapamil-reversible chloroquine resistance to P. falciparum. The mutations in PfCRT give rise to increased compartment acidification. PfCRT-related changes in chloroquine response involve altered drug flux across the parasite degestive vacuole membrane. It has been concluded that PfCRT directly mediates efflux of chloroquine from the digrestive vacuole (Bray et al., 2005).

PfCRT is a 423 amino acyl protein with 10 putative TMSs, it probably catalyzes chloroquine quinine flux with H⁺ across the digestive vacuole membrane (Wellems, 2002). It is a member of the drug metabolite transporter (DMT) superfamily (TC #2.A.7) (Tran and Saier, 2004). In frog oocytes it has been reported to activate various endogenous transporters (Nessler et al., 2004). It transports a variety of qunoline drugs including quinine and quinidine. Mutations in TMSs 1, 4 and 9 alter drug specificity and determine levels of accumulation, suggesting that these TMSs play a role in substrate binding (Cooper et al., 2007).

2.A.7.21 The 5 TMS Bacterial/Archaeal Transporter-2 (BAT2) Family

The BAT2 family consists of 5 TMS proteins that resemble BAT family (2.A.7.2) proteins in size and topology, but show almost no sequence similarity with them.

2.A.7.22 The 4 TMS Small Multidrug Resistance-2 (SMR2) Family

The SMR2 family consists of 4 TMS proteins, most about 110-130 aas long, but some longer, that resemble the SMR family (2.A.7.1) proteins in size and topology. However, they show almost no sequence similarity. Not all of them have the conserved glutamate in TMS1. All close members of this family are from bacteria, but one distant member from Neurospora crassa has this domain N-terminal, fused to a CysT flavodoxin domain followed by a C-terminal radical SAM domain (Nicolet and Drennan, 2004). This protein (gi85104851) is reported to be 1061 aas long. Because this is the only protein in the database with this combination of fused domains, it could be artifactual. Another homologue from Frankia alni (419 aas; gi111220000) has a putative 9 TMS topology with a C-terminal 300 residue hydrophilic domain. Another protein, the TibA precursor glycoprotein adhesin/invasin of E. coli (336 aas; gi72166756) has 8 or 9 putative TMSs plus a C-terminal hydrophilic domain of nearly 100 residues. It may be distantly related to members of the DME family (2.A.7.3).

2.A.7.23 The Putative Tryptophan Efflux (Trp-E) Family

Expression of the Bacillus subtilis tryptophan biosynthetic genes trpEDCFBA and trpG, as well as a putative tryptophan transport gene (trpP), are regulated in response to tryptophan by the trp RNA-binding attenuation protein (TRAP). TRAP regulates expression of these genes by transcription attenuation and translation control mechanisms. TRAP and tryptophan also regulate translation of ycbK, a gene that encodes a protein of 312 aas and 10 TMSs, distantly related to members of the DMT superfamily (Yakhnin et al., 2006).

2.A.7.24 The Thiamine Pyrophosphate Transporter (TPPT) Family

This family includes a diverse group of proteins from all types of eukaryotes as well as prokaryotes. The only one with an assigned probable function is the Thi74 protein of yeast. These proteins have 10 TMSs in a 2 + 8 arrangement (possibly 2 + 4 + 4). No mechanistic details of the transport process are available.

The reaction believed to be catalyzed by Thi74 is:

TPP (out) → TPP (in).

2.A.7.25 The NIPA Mg2+ Uptake Permease (NIPA) Family

Mutations in the NIPA1(SPG6) gene of man, named for 'nonimprinted in Prader-Willi/Angelman' has been implicated in one form of autosomal dominant hereditary spastic paraplegia (HSP), a neurodegenerative disorder characterized by progressive lower limb spasticity and weakness. HSP comprises more than 30 genetic disorders whose predominant feature is a spastic gait. Mutations in at least six genes have been associated with autosomal dominant HSP including NIPA1(SPG6).

Reduced magnesium concentration enhances expression of NIPA1 suggesting a role in cellular magnesium metabolism. Indeed, NIPA1 mediates Mg2+ uptake that is electrogenic, voltage-dependent, and saturable with a Michaelis constant of 0.69 ± 0.21 mM when expressed in Xenopus oocytes (Goytain et al. 2007). Subcellular localization with immunofluorescence showed that endogenous NIPA1 protein associates with early endosomes and the cell surface in a variety of neuronal and epithelial cells. As expected of a magnesium-responsive gene, altered magnesium concentration leads to a redistribution between the endosomal compartment and the plasma membrane; high magnesium results in diminished cell surface NIPA1 whereas low magnesium leads to accumulation in early endosomes and recruitment to the plasma membrane. The mouse NIPA1 mutants, T39R and G100R, corresponding to the respective human mutants, showed a loss of function when expressed in oocytes and altered trafficking in transfected COS7 cells. NIPA1 seems to encode a Mg2+ transporter, and the loss of function of NIPA1(SPG6) due to abnormal trafficking of the mutated protein provides the basis of the HSP phenotype (Goytain et al. 2007).

NIPA has nine putative TMSs. Its mechanism of action is not known. It could be a channel or a carrier, and its energy dependency has not been studied. Homologues are found in a wide variety of animals, plants, and fungi. However, this family is clearly a member of the DMT superfamily (M. H. Saier, unpublished results).

The transport reaction catalyzed by NIPA is:

Mg2⁺ (out) → Mg2⁺ (in)

Macromolecular structures of proteins in this family:

2.A.7.1.3 - 1S7B

View Proteins

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