TCDB is operated by the Saier Lab Bioinformatics Group
TCIDNameDomainKingdom/PhylumProtein(s)
2.A.6.1:  The Heavy Metal Efflux (HME) Family
*2.A.6.1.1









Heavy metal (Ni2+ and Co2+) efflux pump, CnrA.  Functions with CnrB (TC# 8.A.1.2.1) and CnrC (TC# 1.B.17.2.1) (Grass et al. 2000; Tibazarwa et al. 2000).

Bacteria
Proteobacteria
CnrA of Cupriavidus (Ralstonia; Alcaligenes) metallidurans (eutrophus or eutropha) (P37972)
*2.A.6.1.2









Heavy metal (Co2+, Zn2+, Cd2+) efflux pump, CzcAB.  Functions with CzcC (P13509; 1.B.17.2.2).

Bacteria
Proteobacteria
CzcA/CzcB of Cupriavidus (Ralstonia; Alcaligenes) metallidurans (eutriphus or eutropha)
CzcA (P13511)
CzcB (P13510) 
*2.A.6.1.3









Silver ion (Ag+)-specific efflux pump
Bacteria
Proteobacteria
SilA of Salmonella typhimurium
*2.A.6.1.4









Cu+ /Ag+ efflux pump, CusABCF (may pump ions from the periplasm to the external medium); CusF is a periplasmic Cu+ /Ag+ binding receptor essential for full resistance (Franke et al., 2003). Bagai et al. (2007) reported that CusB (MFP) binds one molecule of Ag+ or Cu+ via four conserved methionines and induces a substrate-linked conformational change (Bagai et al., 2007). The crystal structures of CusB are available (Su et al., 2009). The crystal structure of the CusAB complex has been solved (PDB# 3K07) (Su et al., 2011a). CusC is listed under TC# 1.B.17.3.5. The metal-binding methionines play a role in restricting the substrates to monovalent heavy metals (Conroy et al., 2010). It has been reported to export L-cysteine (Yamada et al., 2006). Crystal structures of the CusA efflux pump suggested that methionine residues in a 3-methionine cluster, bind the metal as a transport intermediate (Long et al., 2010). Four methionine pairs in the transmembrane region, and one in the periplasmic domain may comprise the channel. Cu+ is exported from the cytoplasm to the periplasmic chaparone, CusF in the extracellular space (Padilla-Benavides et al. 2014). The Cus efflux system removes Cu+ and Ag+ from both the cell cytoplasm and the periplasm (Su et al., 2011b; Delmar et al. 2014). Metal-bound CusB is required for activation of Cu+ transfer from CusF directly to a site in the CusA antiporter (Chacón et al. 2014). Metal transfer occurs between CusF and apo-CusB, and when metal-loaded, CusB plays a role in the regulation of metal ion transfer from CusF to CusA in the periplasm.  The ratio of CusA (RND):CusB (MFP):CusC (OMF) is 3:6:3 (Delmar et al. 2013). 

Bacteria
Proteobacteria
CusCFBA of E. coli:
CusA (RND)
CusB (MFP)
CusC (OMF) (see 1.B.17.3.5)
CusF (BP)
*2.A.6.1.5









The Zn2+, Cd2+, Pb2+ exporter, CzcCBA1 (induced by Zn2+, Cd2+, Pb2+, Ni2+, Co2+ and Hg2+ (Leedjarv et al., 2007))
Bacteria
Proteobacteria
CzcCBA1 of Pseudomonas putida
CzcA1 (RND) (Q88RT6)
CzcB1 (MFP) (Q88RT5)
CzcC1 (OMF) (Q88RT4)
*2.A.6.1.6









The Zn2+-specific exporter, ZneABC. The ZneB MFP plays an active role in substrate efflux through metal binding and release. Its 2.8 Å structure is available (De Angelis et al., 2010).  3.0 Å  intermediate conformational structures of ZneA have been determined, revealing two Zn2+ binding sites separated by a channel, and the protein has been shown to catalyze electrogenic Zn2+:H+ antiport (Pak et al. 2013).

Bacteria
Proteobacteria
ZneABC of Cupriavidus (Ralstonia) metallidurans (eutrophus or eutropha)
ZneC (DMF) (Q1LCD9)
ZneA (RND) (Q1LCD8)
ZneB (MFP) (Q1LCD7)
*2.A.6.1.7









Putative Zn2+ exporter, Cus1ABC (induced by Zn2+; Moraleda-Muñoz et al., 2010)

Bacteria
Proteobacteria
Cus1ABC of Myxococcus xanthus 
Cus1A (RND) (Q1DDM9)
Cus1B (MFP) (Q1DDM8) 
Cus1C (OMF) (Q1DDM7) 
*2.A.6.1.8









Putative Cu2+ exporter, Cus2ABC (induced by Cu2+; Moraleda-Muñoz et al., 2010)

Bacteria
Proteobacteria
Cus2ABC of Myxococcus xanthus 
Cus2A (RND) (Q1DDM4)
Cus2B (MFP) (Q1DDM3) 
Cus2C (OMF) (Q1DDM2) 
*2.A.6.1.9









Putative heavy metal (Me2+) exporter, Czc1ABC (induced by heavy metals, but not Cu2+; Moraleda-Muñoz et al., 2010)

Bacteria
Proteobacteria
Czc1ABC of Myxococcus xanthus
Czc1A (RND) (Q1D6S7)
Czc1B (MFP) (Q1D6S8)
Czc1C (OMF) (Q1D6S9)
 
*2.A.6.1.10









Putative Cu2+ exporter, Czc2ABC. (induced by Cu2+ and other heavy metal ions; Moraleda-Muñoz et al., 2010)

Bacteria
Proteobacteria
Czc2AB of Myxococcus xanthus
Czc2A (RND) (Q1D665)
Czc2B (MFP) (Q1D664) 
*2.A.6.1.11









Putative metal ion exporter (induced by starvation; Moraleda-Muñoz et al., 2010)

Bacteria
Proteobacteria
Czc3ABC of Myxococcus xanthus 
Czc3A (RND) (Q1CVN2)
Czc3B (MFP) (Q1CVN1)
Czc3C (OMF) (Q1CVN0) 
*2.A.6.1.12









NccABC Ni2+, Co2+, Cd2+ resistance efflux pump (Schmidt and Schlegel, 1994).

Bacteria
Proteobacteria
NccABC of Alcaligenes xylosoxidans
NccA (RND) (Q44586)
NccB (MFP) (Q44585)
NccC (OMF) (Q44584) 
*2.A.6.1.13









CzrABC Cd2+, Zn2+ resistance efflux pump (Hassan et al., 1999).

Bacteria
Proteobacteria
CzrABC of Pseudomonas aeruginosa
CzrA (RND) (Q9RLI8)
CzrB (MFP) (Q9RLI9)
CzrC (OMF) (Q9RLJ0) 
*2.A.6.1.14









CznABC Cd2+, Zn2+, Ni2+ resistance efflux pump. Required for urea modulation and gastric colonization (Stähler et al., 2006).

Bacteria
Proteobacteria
CznABC of Helicobacter pylori
CznA (RND) (O25622)
CznB (MFP) (O25623)
CznC (OMF) (O25624) 
*2.A.6.1.15









The CzrCBA operon is induced by Cd2+ and Zn2+. CzrCBA transports Cd2+, Zn2+, and Co2+ but not Ni2+ (Valencia et al., 2013, in press).

Bacteria
Proteobacteria
CzrCBA of Caulobacter crescentus NA1000
CzrA (RND) (B8H146)
CzrB (MFP) (B8H144)
CzrC (OMF) (B8H143) 
*2.A.6.1.16









The nczCBA operon (also called the czc operon) is induced maximally by Ni2+ and Co2+, moderately by Zn2+ but not by Cd2+. NczCBA transports Ni2+ Co2+and probably Zn2+ and Cd2+(Valencia et al. 2013).

Bacteria
Proteobacteria
NczCBA of Caulobacter crescentus NA1000
NczA (RND) (B8GZE9)
NczB (MFP) (B8GZE8)
NczC (OMF) (B8GZE7) 
*2.A.6.1.17









Zn2 exporter, ZniA.  Functions with an MFP and an OMF (Nies,2013, in Microbial Efflux Pumps, EW Yu, Q Zhang and MH Brown, editors, Caister Acadmic Press, 2013).

Bacteria
Proteobacteria
ZniA of Cupriavidus metallidurans
*2.A.6.1.18









Ni2 , Co2 exporter, NimA.  Functions with an MFP and an OMF (Nies, 2013, in Microbial Efflux Pumps, EW Yu, Q Zhang and MH Brown, editors, Caister Acadmic Press, 2013).

Bacteria
Proteobacteria
NimA of Cupriavidus metallidurans
2.A.6.2:  The (Largely Gram-negative Bacterial) Hydrophobe/Amphiphile Efflux-1 (HAE1) Family
*2.A.6.2.1









Multidrug (acriflavin, doxorubicin, ethidium, rhodamine 6G, SDS, deoxycholate) resistance pump [required for normal chromosomal condensation and segregation as well as cell division] (Lau and Zgurskaya, 2005). Exports L-cysteine (Yamada et al., 2006).

Bacteria
Proteobacteria
AcrEF (EnvCD) of E. coli
AcrE (MFP) (P24180)
AcrF (EnvD) (RND) (P24181)
*2.A.6.2.2









Multidrug/dye/detergent/bile salt/organic solvent resistance pump (substrates include: chloramphenicol, tetracycline, erythromycin, nalidixic acid, fusidic acid, fluoroquinolones, lipophilic β-lactams, norfloxacin, doxorubicin, novobiocin, rifampin, trimethoprim, acriflavin, crystal violet, ethidium, disinfectants, rhodamine-6G, TPP, benzalkonium, SDS, Triton X-100, deoxycholate/bile salts/organic solvents (alkanes), growth inhibitory steroid hormones (estradiola and progesterone), and phospholipids) (Elkins and Mullis, 2006). Lateral entry of substrates from the lipid bilayer into AcrB and its homologues has been proposed (Yu et al., 2003a; 2003b). [An asymmetric trimeric structure is established with AcrA having a hexameric structure, and TolC having a trimeric structure (Seeger et al., 2006]. A structure of a complex with YajC is also known (Törnroth-Horsefield et al., 2007). A covalently linked trimer of AcrB provides evidence for a peristaltic pump, alternative access, rotation mechanism (Takatsuka and Nikaido, 2009;Nikaido and Takatsuka, 2009; Pos, 2009) Further evidence for a rotatory mechanisms stems from kinetic analyses for cephalosporin efflux which can exhibit positive cooperativity (Nagano and Nikaido, 2009). May also export signaling molecules for cell-cell communication (Yang et al., 2006). The substrates may be captured in the lower cleft region of AcrB, then transported through the binding pocket, the gate, and finally to the AcrA funnel that connects AcrB to TolC (Husain & Nikaido et al., 2010).  AcrB has been converted into a light-driven proton pump using delta-rhodopsin (dR) linked to AcrB via a glycophorin A transmembrane domain. This created a solar powered protein capable of selectively capturing antibiotics from bulk solutions (Kapoor and Wendell 2013).  The trimeric structure is essential for activity (Ye et al. 2014).  Association with AcrZ (TC# 8.A.50), a small 1 TMS protein (49 aas) that modifies the substrate specificity of AcrAB, has been demonstrated (Hobbs et al. 2012).  In a similar way, the binding of YajC to AcrB stimulates the export of ampicillin (Törnroth-Horsefield et al. 2007). AcrZ binds to AcrB in a concave surface of the transmembrane domain (Du et al. 2015).  Substrate binding accelerates conformational transitions and substrate dissociation, demonstrating cooperativity (Wang et al. 2015). The overall structure of AcrAB-TolC exemplifies the adaptor bridging model, wherein the funnel-like AcrA hexamer forms an intermeshing cogwheel interaction with the alpha-barrel tip region of TolC. Direct interaction between AcrB and TolC is not allowed (Kim et al. 2015).  TMS2 in AcrB is required for lipophilic carboxylate binding. A groove shaped by the interface between TMS1 and TMS2 specifically binds fusidic acid and other lipophilic carboxylated drugs (Oswald et al. 2016). After ligand binding, a proton may bind to an acidic residue(s) in the transmembrane domain, i.e., Asp407 or Asp408, within the putative network of electrostatically interacting residues, which also include Lys940 and Thr978, and this may initiate a series of conformational changes that result in drug expulsion (Su et al. 2006). His978 is probably on the H+ pathway (Takatsuka and Nikaido 2006). AcrAB-TolC segregates to the old pole following cell division, causing the two daughter cells to exhibit different drug resistances (Bergmiller et al. 2017).

Bacteria
Proteobacteria
AcrABZ of E. coli
AcrA (MFP) (P31223)
AcrB (RND) (P31224)
AcrZ of 49 aas (P0AAW9)
*2.A.6.2.3









Isoflavonoid efflux pump, IfeB

Bacteria
Proteobacteria
IfeB of Agrobacterium tumefaciens
*2.A.6.2.4









The multidrug resistance pump, AdeDE (exports amikacin, ceftazidime, chloramphenicol, ciprofloxacin, erythromycin, ethidium bromide, meropenem, rifampin, and tetracycline) (Chau et al., 2004).
Bacteria
Proteobacteria
AdeDE of Acinetobacter  sp. 4356 AdeD (Q67GM1)
AdeE (Q8GKU1)
*2.A.6.2.5









Fatty acid, bile salt, gonadal steroid, antibacterial peptide efflux pump, MtrCDE (Kamal et al., 2007). Opening of the outer membrane protein channel, MtrE, in the tripartite efflux pump, MtrCDE, is induced by interaction with the membrane fusion partner, MtrC (Janganan et al., 2011).  The crystal structure of the trimeric MtrE forms a vertical tunnel extending down contiguously from the outer membrane surface to the periplasmic end in the open conformational state of this channel (Lei et al. 2014).

Bacteria
Proteobacteria
MtrCDE of Neisseria gonorrhoeae:
MtrC (MFP) (P43505)
MtrD (RND) (Q51073)
MtrE (OMF) (Q51006)
*2.A.6.2.6









Multiple drug; N-(3-oxododecanoyl)- L-homoserine lactone autoinducer efflux pump, MexB (functions with MexA (an MFP, 8.A.1) and OprM (an OMF, 1.B.17; see 2.A.6.2.21). All three interact with each other. MexA promotes assembly and stability of the complex (Nehme and Poole, 2007)). Exports β-lactams, fluoroquinolones, tetracycline, macrolides, chloramphenicol, biocides, and a toxic indole compound, CBR-4830, that targets the MreB actin (Robertson et al., 2007). Confers tolerance to tea tree oil and its monoterpene components Terpinen-4-ol, 1,8-cineole and α-terpineol (Papadopoulos et al., 2008) as well as the antimicrobial peptide, colistin (Pamp et al., 2008) (Mao et al., 2002; Poole, 2008). The crystal structure has been solved at 3.0Å resolution (Sennhauser et al., 2009). The MexA-OprM complex has an elongated cylindrical appearance (Trépout et al., 2010).  Mutations affecting export of antibiotics with cytoplasmic targets have been identified (Ohene-Agyei et al. 2012).

Bacteria
Proteobacteria
MexAB of Pseudomonas aeruginosa
MexA (P52477)
MexB (P52002)
*2.A.6.2.7









Multidrug efflux pump, AcrD (exports aminoglycosides (amikacin, gentamycin, neomycin, kanamycin and tobramycin) as well as anionic detergents (SDS and deoxycholate) and growth inhibitory steroid hormones (estradiol and progesterone)(Elkins and Mullis, 2006)) (exports aminoglycosides from the periplasm as well as the cytoplasm) (Aires and Nikaido, 2005). (Also contributes to copper and zinc resistance; regulation is mediated by BaeSR, and indole, Cu2+ and Zn2+ induce (Nishino et al., 2007)). Exports L-cysteine (Yamada et al., 2006).

Bacteria
Proteobacteria
AcrD of E. coli (P24177)
*2.A.6.2.8









Multidrug efflux pump, ArpB (exports tetracycline, chloramphenicol, carbenicillin, streptomycin, erythromycin, novobiocin, etc.)

Bacteria
Proteobacteria
ArpB of Pseudomonas putida
*2.A.6.2.9









Solvent efflux pump, TtgABC (extrudes toluene, styrene, m-xylene, ethylbenzene, acetate, α-pinene and propylbenzene) (Teran et al., 2007; Dunlop et al. 2011Dunlop et al. 2011).

Bacteria
Proteobacteria
TtgABC of Pseudomonas putida:
TtgA (Q9WWZ9)
TtgB (O52248)
TtgC (Q9WWZ8)
*2.A.6.2.10









Solvent efflux pump, TtgDEF (extrudes only toluene and styrene) (Teran et al., 2007).
Bacteria
Proteobacteria
TtgDEF of Pseudomonas putida:
TtgD (Q9KWV5)
TtgE (Q9KWV4)
TtgF (Q9KWV3)
*2.A.6.2.11









Solvent and antibiotic efflux pump, TtgGHI (SrpABC) (Kieboom et al. 1998; Terán et al., 2007) (solvents extruded include toluene, styrene, m-xylene, ethylbenzene and propylbenzene) (Teran et al., 2007). TtgGHI is the same as SrpABC (Kieboom et al., 1998)
Bacteria
Proteobacteria
TtgGHI of Pseudomonas putida
TtgG (Q93PU5)
TtgH (Q93PU4)
TtgI (Q93PU3)
*2.A.6.2.12









Heteromeric multidrug/detergent resistance protein YegM/YegN/YegO (MdtA/MdtB/MdtC) (Nishino and Yamaguchi 2001). Exports nalidixic acid, norfloxacin, cloxicillin, enoxacin, kanamycin, benzalkonium, bile salts, SDS and deoxycholate. It forms a complex with MdtA (YegM) (an MFP, TC# 8.A.1.6.2). Drug resistance depends on the simultaneous presence of all three proteins (Baranova and Nikaido, 2002). (Also contributes to copper and zinc resistance; regulation is mediated by BaeSR, and indole, Cu2+ and Zn2+ induce (Nishino et al., 2007)). MdtB:C stoichiometry = 2:1; MdtB and MdtC may play different roles (Kim et al., 2010), MdtB transporting the proton and MdtC transporting the drug (Kim and Nikaido 2012).  MdtBC is reported to export bile salts without MdtA (Nagakubo et al. 2002), but this conclusion seems questionable.

Bacteria
Proteobacteria
MdtB/MdtC of E. coli
MdtB (YegN) (P76398)
MdtC (YegO) (P76399) 
*2.A.6.2.13









Multidrug/dye/detergent resistance protein, YhiU/YhiV or MdtE/MdtF (Nishino and Yamaguchi 2001) MdtE (YhiU) is listed under TC# 8.A.1.6.3.  The system exports erythromycin, doxorubicin, crystal violet, ethidium, rhodamine 6G, TPP, benzalkonium, SDS, deoxycholate and growth inhibitory steroid hormones (estradiol and progesterone) (Elkins and Mullis, 2006).

Bacteria
Proteobacteria
YhiUV or MdtEF of E. coli
*2.A.6.2.14









SmeVWX MDR efflux pump. Drugs include chloramphenicol, quinolones, tetracyclines and aminoglycosides, but not β-lactams and erythromycin (Chen et al., 2011).

Bacteria
Proteobacteria
SmeVWX of Stenotrophomonas maltophilia
SmeV (MFP) (B2FLY3)
SmeW (RND) (B2FLY4)
SmeX (OMF) (B2FLY6) 
*2.A.6.2.15









Multidrug efflux pump, MexD (exports β-lactams, fluoroquinolones, tetracycline, macrolides, chloramphenicol, biocides, including levofloxacin, carbenicillin, aztreonam, ceftazidime, cefepime, cefoperazone, piperacillin, erythromycin, azithromycin, chloramphenicol, etc.; Mao et al., 2002). Functions with MexC (MFP) and OprJ (OMF) (Mao et al., 2002; Poole, 2008).

Bacteria
Proteobacteria
MexD of Pseudomonas aeruginosa
*2.A.6.2.16









Multidrug efflux pump, MexF (exports fluoroquinolones, chloramphenicol, biocides, xenobiotics and chloramphenicol; functions with MexE (MFP) and OprN (OMF)) (Kohler et al., 1997; Poole, 2008).  The P. putida orthologue also exports solvents such as farnesyl hexanoate (Dunlop et al. 2011).

Bacteria
Proteobacteria
MexF of Pseudomonas aeruginosa (AAG05882)
*2.A.6.2.17









Multidrug efflux pump, MexK (exports fluoroquinolones, macrolides, chloramphenicol; biocides, and triclosan [with MexJ but without OprM] as well as tetracycline, erythromycin [requiring both MexJ and OprM]; Chuanchuen et al., 2002). Can function with OpmH (BAC24099) instead of OprM (Poole, 2008).

Bacteria
Proteobacteria
MexK of Pseudomonas aeruginosa
*2.A.6.2.18









The polycyclic aromatic hydrocarbon (phenanthrene; anthacene; fluoranthene)/drug (chloramphenicol; nalidixic acid) exporter, EmhABC (Hearn et al., 2003; 2006)

Bacteria
Proteobacteria
EmhABC of Pseudomonas fluorescens
EmhA (Q6V6X9)
EmhB (Q6V6X8)
EmhC (Q6V6X7)
*2.A.6.2.19









The multidrug efflux pump, EefABC (exports chloramphenicol, ciprofloxacin, erythromycin, tetracycline and doxycycline) (Masi et al., 2005). EefC exhibits low ionic selectivity (Masi et al., 2007).
Bacteria
Proteobacteria
EefABC of Enterobacter aerogenes
EefA (MFP) (Q8GC84)
EefB (RND) (Q8GC83)
EefC (OMF) (Q8GC82)
*2.A.6.2.20









The toxoflavin (a phytotoxin) exporter, ToxGHI (Kim et al., 2004)
Bacteria
Proteobacteria
ToxGHI of Burkholderia glumae
ToxG (MFP) (AAV52812)
ToxH (RND) (AAV52813)
ToxI (OMF) (AAV52814)
*2.A.6.2.21









The multidrug (aminoglycosides, β-lactams, fluoroquinolones, macrolides, chloramphenicol, tetracycline, erythromycin, ofloxacin, etc.) efflux pump, MexXY-OprM (Jeannot et al., 2005).  The 3-d structurre of OprM (also called OprK) is known (1WP1).

Bacteria
Proteobacteria
MexXY-OprM of Pseudomonas aeruginosa
MexX, BAA34299
MexY, BAA34300
OprM, Q51487
*2.A.6.2.22









The conjugated and unconjugated bile (bile-inducible)/multidrug (ethidium, ciprofloxacin, norfloxacin, tetracycline, cefotaxime, rifampicin, erythromycin, chloramphenicol, salicylate; drug-noninducible) efflux pump, CmeABC (Lin et al., 2005).  The 3-d structure of the OMF, CmeC, has been determined (Su et al. 2014). The system is involved in biofilm production (Teh et al. 2017).

Bacteria
Proteobacteria
CmeABC of Campylobacter jejuni
CmeA (MFP) (AAL74244)
CmeB (RND) (AAL74245)
CmeC (OMF) (AAL74246)
*2.A.6.2.23









The multidrug (β-lactams, aminoglycerides (gentamycin and streptomycin) macrolides (erythromycin) and dye (acriflavin)) efflux pump, BpeAB-OprB (Chan et al., 2004; Chan and Chua, 2005). It also exports acyl homoserine lactones including N-octanoyl-homoserine lactone, N-decanoyl-homoserine lactone, N-(3-hydroxy)-octanoyl-homoserine lactone, N-(3-hydroxy)-decanoyl-homoserine lactone, N-(3-oxo)-decanoyl-homoserine lactone, and N-(3-oxo)-tetradecanoyl-homoserine lactone (Chan et al., 2007). Q9HWH6 is a DoxX family member (see 9.B.214.2).

Bacteria
Proteobacteria
BpeAB-OprB of Burkholderia pseudomallei
BpeA (MFP) (AAQ94109)
BpeB (RND) (AAQ94110)
OprB (OMF) (AAQ94111)
*2.A.6.2.24









The multidrug (aminoglycosides (e.g., streptomycin, gentamycin, neomycin, tobramycin, kanamycin and spectinomycin) and macrolides (e.g., erythromycin and clarithromycin, but not lincosamide and clindamycin)) efflux pump, AmrAB-OprA (Moore et al., 1999)
Bacteria
Proteobacteria
AmrAB-OprA of Burkholderia pseudomallei
AmrA (MFP) AAC27753
AmrB (RND) AAC27754
OprA (OMF)
*2.A.6.2.25









The gold (Au2+) resistance efflux pump, GesABC (induced by GolS in the presence of Au2+; also mediates drug resistance when induced by Au2+ (Pontel et al., 2007). Also exports a variety of organic chemicals including chloramphenicol (Conroy et al., 2010).

Bacteria
Proteobacteria
GesABC of Salmonella enterica
GesA (MFP) (Q8ZRG8)
GesB (RND) (Q8ZRG9)
GesC (OMF) (Q8ZRH0)
*2.A.6.2.26









The multidrug efflux pump, VmeAB-VpoC (Matsuo et al., 2007).  There are 11 RND-type efflux transporters in Vibrio parahaemolyticus, and several (VmeCD, VmeEF and VmeYZ) contribute not only to intrinsic drug resistance but also to virulence (Matsuo et al. 2013).

Bacteria
Proteobacteria
VmeAB-VpoC of Vibrio parahaemolyticus:
VmeA (MFP) (Q2AAU4)
VmeB (RND) (Q2AAU3)
VpoC (OMF) (Q87SJ8)
*2.A.6.2.27









The Triclosan resistance efflux pump TriABC-OpmH (the only known RND pump requiring two MFPs) (Mima et al., 2007)
Bacteria
Proteobacteria
TriABC-OpmH of Pseudomonas aeruginosa
TriA (MFP) (Q9I6X6)
TriB (MFP) (Q9I6X5)
TriC (RND) (Q9I6X4)
OpmH (OMF) (Q9HUJ1)
*2.A.6.2.28









Multidrug efflux pump, AcrAB (Bina et al. 2008).

Bacteria
Proteobacteria
AcrAB of Francisella tularensis

*2.A.6.2.29









The AdeIJK MDR pump (contributes to resistance to β-lactams, chloramphenicol, tetracycline, erythromycin, lincosamides, fluoroquinolines, fusidic acid, tigecycline, novobiocin, rifampin, trimethoprim, acridine, safranin, pyronine, triclosan and sodium dodecyl sulfate) (Damier-Piolle et al., 2008; Fernando et al. 2014Fernando et al. 2014)

Bacteria
Proteobacteria
AdeIJK of Acinetobacter baumannii
AdeI (MFP) (Q2FD95)
AdeJ (RND) (Q24LT7)
AdeK (OMF) (Q24LT6)
*2.A.6.2.30









VexEF-TolC mediates resistance to various antimicrobials; ethidium efflux is Na+-dependent (Rahman et al., 2007)
Bacteria
Proteobacteria
VexEF / TolC of Vibrio cholerae
VexE (MFP) (A6P7H2)
VexF (RND) (A6P7H3)
TolC (OMF) (Q9K2Y1)
*2.A.6.2.31









Multidrug efflux pump, SdeAB-HasF (mediates fluoroquinolone efflux) (Begic and Worobec, 2008) (HasF is > 60% identical to TolC of E. coli (1.B.17.1.1))
Bacteria
Proteobacteria
SdeAB-HasF of Serratia marcescens
SdeA (MFP) (Q79MP5)
SdeB (RND) (Q84GI9)
HasF (OMF) (Q6GW09)
*2.A.6.2.32









Multidrug efflux pump, MexHI OpmD (exports fluoroquinolones; Poole, 2008).  The encoding genes are part of the SoxR regulon (Naseer et al. 2014). These genes are preceded by a gene encoding PA4205, a 148 aas 4 TMS protein, MexG, a member of the DoxX family (TC# 9.B.214) of unknown function, but possibly a component of this ABC transporter (Naseer et al. 2014).

Bacteria
Proteobacteria
MexHI OpmD of Pseudomonas aeruginosa
MexH (MFP) (Q9HWH5)
MexI (RND) (Q9HWH4)
OpmD (OMF) (Q9HWH3)
MexG (4 TMS protein (Q9HWH6)
*2.A.6.2.33









Multidrug efflux pump, MexVW OmpM (exports fluoroquinolones, macrolides, chloramphenicol, and tetracycline) (Poole, 2008).

Bacteria
Proteobacteria
MexW of Pseudomonas aeruginosa
MexW (RND) (Q9HW27)
*2.A.6.2.34









Multidrug efflux pump, MexPQ-OpmE; export fluoroquinolones, tetracycline, macrolides and chloramphenicol (Poole, 2008)
Bacteria
Proteobacteria
MexPQ-OpmE of Pseudomonas aeruginosa
MexP (MFP) (Q9HY86)
MexQ (RND) (Q4LDT6)
OpmE (OMF) (Q9HY88)
*2.A.6.2.35









Multidrug efflux pump, MexMN-OprM; exports chloramphenicol (Poole, 2008)
Bacteria
Proteobacteria
MexMN-OprM of Pseudomonas aeruginosa
MexM (MFP) (Q9I3R2)
MexN (RND) (Q4LDT8)
*2.A.6.2.36









Multidrug/detergent exporter.  VexB (Bina et al., 2008b).
Bacteria
Proteobacteria
VexB of Vibrio cholerae (Q9KVI2)
*2.A.6.2.37









Detergent exporter, VexD (Bina et al., 2008b).
Bacteria
Proteobacteria
VexD of Vibrio cholerae (A6P7H1)
*2.A.6.2.38









Detergent exporter, VexK (Bina et al., 2008b).
Bacteria
Proteobacteria
VexK of Vibrio cholerae (Q9KRG9)
*2.A.6.2.39









THe MuxABC-OpmB multidrug (aztreonam, macrolides, novobiocin and tetracycline) resistance efflux pump complex (with two RND-type proteins (MuxB and MuxC)), both required for activity (Mima et al., 2009).

Bacteria
Proteobacteria
MuxABC-OpmB complex of Pseudomonas aeruginosa
MuxA (MFP) (PA2528) (Q9I0V5)
MuxB (RND) (PA2527) (Q9I0V6)
MuxC (RND) (PA2526) (Q9I0V7)
OpmB (OMF) (Q9I0V8)
*2.A.6.2.40









MDR pump, AdeABC. Exports chloramphenicol and tetracycline (Hassan et al., 2011). Also confers resistance to meropenem, tigecycline and ceftazidime (Peleg et al. 2007; Provasi Cardoso et al. 2016).

Bacteria
Proteobacteria
AdeABC of Acinetobacter baumannii
AdeA (MFP) (Q2FD71)
AdeB (RND) (Q2FD70)
AdeC (OMF) (Q2FD69)
*2.A.6.2.41









SmeABC MDR efflux pump. Drugs include ciprofloxacin (Cho et al., 2012).

Bacteria
Proteobacteria
SmeABC of Stenotrophomonas maltophilia
SmeA (MFP) (Q9RBY9)
SmeB (RND) (Q9RBY8)
SmeC (OMF) (Q9RBY7) 
*2.A.6.2.42









SmeDEF MDR efflux pump. Mediates resistance to a wide range of drugs including ethidium bromide and norfloxacin (Alonso and Martínez, 2000). Regulated by SmeT and activated by insertion of the transposon, IS1246 (Gould and Avison, 2006).

Bacteria
Proteobacteria
SmeDEF of Stenotrophomonas maltophilia 
SmeD (MFP) (Q9F241)
SmeE (RND) (Q9F240)
SmeF (OMF) (Q9F239) 
*2.A.6.2.43









Multidrug resistance pump, SmeJK. Shown to export teracycline, minocycline, ciprofloxacin and levofloxacin (Gould et al., 2012).

Bacteria
Proteobacteria
SmeJK of Stenotrophomonas maltophilia D457
SmeJ (I0KTJ0)
SmeK (I0KTJ1) 
*2.A.6.2.44









Multidrug efflux pump, AdeFGH.  Mediates high level resistance to chloramphenicol, clindamycin, fluoroquinolones, and trimethoprim and decreased susceptibility to tetracycline-tigecycline and sulfonamides; susceptibility to β-lactams, erythromycin, aminoglycosides and rifampin was not affected. It also mediates increased resistance to ethidium bromide, safranin O, acridine orange, trimethoprim and sulfamethoxazole (Coyne et al. 2010).

Bacteria
Proteobacteria
AdeFGH of Acinetobacter baumannii
AdeF (MFP) (Q2FD82)
AdeG (RND) (Q2FD81)
AdeH (OMF) (Q2FD80) 

*2.A.6.2.45









The AcrA/AcrB multidrug resistance pump.  Exports various toxic compounds, including antibiotics, phytoalexins, and detergents. Mutants are less virulent on tomato plants than the wild-type strain (Brown et al. 2007).

Bacteria
Proteobacteria
AcrAB of Ralstonia solanacearum (Pseudomonas solanacearum)
*2.A.6.2.46









Solvent (such as limonene) efflux pump, TtgABC (Dunlop et al. 2011).

Bacteria
Proteobacteria
TtgABC of Alcanivorax borkumensis
TtgA (MFP)
TtgB (RND)
TtgC (OMF)
*2.A.6.2.47









Multidrug resistance exporter, OqxA (BepF)-OqxB (BepE) (Taherpour and Hashemi 2013).

Bacteria
Proteobacteria
OqxAB of Klebsiella pneumoniae
OqxA, MFP
OqxB, RND  
*2.A.6.2.48









Multidrug resistance (MDR) pump, AcrD, AcrF, Env.  Catalyzes efflux of various hydrophilic and amphipathic drugs including clotrimazole and luteolin, but not aminoglycosides.  Induction of acrD expression occurs in infected apple tissue but not in pear tissues.  Regulated by the two component BaeSR sensor kinase/response regulator (Pletzer and Weingart 2014).

Bacteria
Proteobacteria
ArcD of Erwinia amylovora, the causal agent of fire blight disease.
*2.A.6.2.49









Multidrug resistance exporter, AcrABZ.  Exports tigecycline and many other drugs (Nielsen et al. 2014; Li et al. 2016; Yuhan et al. 2016; He et al. 2015; Bialek-Davenet et al. 2015).  AcrA-AcrB-AcrZ-TolC is a drug efflux protein complex with a broad substrate specificity. AcrZ (YbhT) binds to AcrB and is required for efflux of some but not all substrates, suggesting it may influence the specificity of drug export (Hobbs et al. 2012; Du et al. 2015).

Bacteria
Proteobacteria
AcrABZ of Klebsiella pneumoniae
AcrA (MFP)
AcrB (RND)
AcrZ (YbhT) (RND auxiliary protein; see 8.A.50)
2.A.6.3:  The Putative Nodulation Factor Exporter (NFE) Family
*2.A.6.3.1









Putative lipooligosaccharide nodulation factor exporter, NolG (1065 aas; previously thought to be 3 ORFs, NolGHI, an artifact due to sequencing errors and consequent frameshifting (Baev et al. 1991; Ardourel et al. 1994).

Bacteria
Proteobacteria
NolG of Rhizobium meliloti (P25197)
*2.A.6.3.2









NolG homologue, Atu4636

Bacteria
Proteobacteria
NolG of Agrobacterium tumefaciens (A9CGX6)
*2.A.6.3.3









NolG homologue 

Bacteria
Proteobacteria
NolG of Acinetobacter baumanii (E8PBU7)
*2.A.6.3.4









NolG homologue

Bacteria
Proteobacteria
NolG of Myxococcus xanthus (Q1DEX6)
*2.A.6.3.5









NolG homologue 

Bacteria
Cyanobacteria
NolG of Synechococcus sp. PCC7335 (B4WH09)
*2.A.6.3.6









NolG homologue 

Bacteria
Firmicutes
NolG of Oceanobacillus iheyensis (Q8CX78)
*2.A.6.3.7









Putative Cu2+ exporter, Cus3ABC.  Induced by Cu2+; Moraleda-Muñoz et al., 2010)

Bacteria
Proteobacteria
Cus3ABC of Myxococcus xanthus
Cus3A (RND) (Q1CZ65)
Cus3B (MFP) (Q1CZ64)
Cus3C (OMF) (Q1CZ66) 
*2.A.6.3.8









Efflux pump for antifungal and antibacterial syringopeptin and syringmycin lipodepsipeptides (see 1.D.35) as well as acriflavin, erythromycin and tetracycline, PseABC (Kang and Gross 2005).

Bacteria
Proteobacteria
PseABC of Pseudomonas syringae
PseA (OMF) (L8NE56)
PseB (MFP) (L8NGR5)
PseC (RND) (L8NFZ8)
*2.A.6.3.9









Primary surfactin exporter of 1056 aas and 12 TMSs, YerP (Li et al. 2015).

Bacteria
Firmicutes
YerP of Bacillus subtilis
*2.A.6.3.10









Multidrug resistance pump, CmeDEF.  The substrates of CmeDEF include ampicillin, ethidium bromide, acridine, sodium dodecyl sulfate (SDS), deoxycholate, triclosan, and cetrimide, but not ciprofloxacin or erythromycin (Pumbwe et al. 2005). This system is similar to the Helicobacter pylori MDR pump, HefABC (Huang et al. 2015).

Bacteria
Proteobacteria
CmeDEF of Campylobacter jejuni
CmeD (OMF, 424 aas)
CmeE (MFP, 246 aas)
CmeF (RND. 1005 aas
*2.A.6.3.11









RND family protein involved in virulence and resistance to antimicrobial agents, BesABC.  BesC forms channels in lipid bilayers (Bunikis et al. 2008).

Bacteria
Spirochaetes
BesABC of Borrelia burgdorferi
BesA, 317 aas
BesB, 1070 aas
BesC, 428 aas
*2.A.6.3.12









The multidrug efflux porter, HefABC; HefA is an OMF (TC#1.b.17) of 477 aas and 1 N-terminal TMS; HefB is an MFP (TC# 8.A.1) of 234 aas and 1 N-terminal TMS. HefC is the RND pump of 1028 aas and 12 TMSs (Mehrabadi et al. 2011; Liu et al. 2008).

Bacteria
Proteobacteria
HefABC of Helicobacter pylori
2.A.6.4:  The SecDF (SecDF) Family
*2.A.6.4.1









The secretory accessory proteins, SecDF. The first periplasmic domain of SecDF has been crystallized (Echizen et al., 2011) as has the intact SecDF complex (Tsukazaki and Nureki 2011). SecDF appears to function as a pmf-driven H+ transporter that functions as a chaperone to achieve ATP-dependent protein translocation (Tsukazaki et al. 2011).  SecDF is believed to assume at least two conformations differing by a 120 degrees rotation during polypeptide translocation (Mio et al. 2014).

Bacteria
Proteobacteria
SecDF of E. coli; SecD; SecF
*2.A.6.4.2









Protein translocase subunit SecDF
Bacteria
Firmicutes
SecDF of Bacillus subtilis
*2.A.6.4.3









Protein translocase subunit SecDF.  The 3-dimensional structure is known at 3.3 Å resolution (Tsukazaki et al. 2011).  SecDF serves several functions, such as stabilizing other Sec translocon components within the membrane, maintaining the transmembrane (TM) potential, and facilitating the ATP-independent stage of the translocation mechanism. SecDF also undergoes functionally important conformational changes that involve mainly its P1-head domain, and these changes are coupled with the proton motive force (Δpmf). Using all-atom molecular dynamics simulations combined with umbrella sampling, Ficici et al. 2017 studied the P1-head conformational change and how it is coupled to the pmf. They reported potentials of mean force along a root-mean-square-distance-based reaction coordinate obtained in the presence and absence of the TM electrical potential. Their results showed that the interaction of the P1 domain dipole moment with the TM electrical field lowers the free-energy barrier in the direction of the F-form to I-form transition, two conformations that vary by the relative positioning of the P1-head subdomain—the large periplasmic domain of TtSecDF—which is suggested to undergo a hinge motion (Ficici et al. 2017).

Bacteria
Deinococcus-Thermus
SecDF of Thermus thermophilus
2.A.6.5:  The (Gram-positive Bacterial Putative) Hydrophobe/Amphiphile Efflux-2 (HAE2) Family
*2.A.6.5.1









The antibiotic actinorhodin transport-associated protein, ActII3
Bacteria
Actinobacteria
ActII3 of Streptomyces coelicolor
*2.A.6.5.2









The phthiocerol dimycocerosate (PDIM) lipid exporter, MmpL7. Also confers high level isoniazid efflux and resistance (Pasca et al., 2005).

Bacteria
Actinobacteria
MmpL7 of Mycobacterium tuberculosis ( P65370)
*2.A.6.5.3









The putative glycopeptidolipid exporter, TmtpC (most similar to MmpL of M. leprae; implicated in sliding motility). May function with the MmpS4 protein of Mucobacterium smegmatis (A0QPN7) to form a scaffold for coupled biosynthesis and transport (Deshayes et al., 2010).

Bacteria
Actinobacteria
TmtpC of Mycobacterium smegmatis
*2.A.6.5.4









sulfolipid, 2,3-diacyl-α, α'-D-trehalose-2'-sulfate (sulfatide precursor) exporter, MmpL8 (Domenech et al., 2004; Seeliger et al. 2012Seeliger et al. 2012).

Bacteria
Actinobacteria
MmpL8 of Mycobacterium tuberculosis (CAB10022)
*2.A.6.5.5









Mycobacterial heme acquisition system, Rv0202c - Rv0207c. Takes up free heme and heme from hemoglobin as an iron source together with the secreted protein, Rv0203 (O53654) (Owens et al. 2013). May function with Rv0206c (MmpL3; TC#2.A.6.5.6) and Rv0202c (Tullius et al., 2011). However, see description of MmpL3 (2.A.6.5.6).  These two proteins are targets of drug action (Owens et al. 2013).

Bacteria
Actinobacteria
Heme uptake system of Mycobacterium tuberculosis
MmpL11 (P65374)

 
*2.A.6.5.6









MmpL3 (Rv0206; 944 aas) May function with MmpL11 (TC# 2.A.6.5.5) (Tullius et al., 2011). MmpL3 exports trehalose monomycolate, involved in mycolic acid donation to the cell wall core (Tahlan et al., 2012). SQ109, a 1,2,-diamine related to ethambutol  is an inhibitor of MmpL3 (Tahlan et al., 2012).  May also transport heme.  Inhibitors have been identified (Rayasam 2013; Li et al. 2014).  MmpL3 has been shown to be a homotrimer of three 12 TMS subunits, confirming its RND-type structure (Belardinelli et al. 2016).  MmpL3 is a flipppase for mycolic acids, transporting them from the cytoplasmic side of the inner membrane to the external side. A 1.5-diarylpyrrole compound, BM212, is a potent inibitor (Xu Z, Poce G, and Chng SS, manuscript in press, 2017). Inactivation of the mmpL3 gene in M. neoaurum increased the permeability of the outer membrae and allowed increased uptake of sterols for coversion to other sterols for industrial purposes. One such product is 22-hydroxy-23,24-bisnorchol-4-ene-3-one (4-HBC), used for the synthesis of various steroids in the industry (Xiong et al. 2017).

Bacteria
Actinobacteria
MmpL3 of Mycobacterium tuberculosis (O53657)
*2.A.6.5.7









Siderophore export transporter, MmpL4 (Wells et al. 2013).  Functions with MmpS4 (TC#8.A.35.1.1) which is essential for transport activity.  MmpL4/MmpS4 and MmpL5/MmpS5 (TC# 2.A.6.5.8 and TC# 8.A.35.1.2, respectively) are two siderophore exporters that overlap in function (Wells et al. 2013).  The M. abscessus, subspecies bolletii orthologue (TC# 2.A.6.5.12), of 959 aas, is 65% identical to M. tuberculosis MmpL4 and affects the rough vs smooth phenotype of the cell envelope (Bernut et al. 2016).

Bacteria
Actinobacteria
MmpL4 of Mycobacterium tuberculosis
*2.A.6.5.8









Siderophore exporter, MmpL5.  Functions with MmpS5, and both proteins are essential for transport activitiy (Wells et al. 2013).

Bacteria
Actinobacteria
MmpL5 of Mycobacterium tuberculosis
*2.A.6.5.9









The MmpL-like protein of 1138 aas (sequence similarity is observed only in the hydrophilic extracytoplasmic regions of both proteins (residues 452-665 in PIP)
Bacteria
Firmicutes
MmpL-like protein of Bacillus weihenstephanensis (A9VJD5)
*2.A.6.5.10









Multidrug resistance protein, CmpL1, of 772 aas and 12 TMSs. Mutants are hypersusceptible to multiple antibiotics, have growth deficiencies in minimal medium and accumulate intracellular trehalose monocorynomycolates, free corynomycolates, and a previously uncharacterized corynomycolate-containing lipid.  It is inferred that this transporter exports one or more of these lipids.  Evidence for a pmf-dependent mechanism was obtained (Yang et al. 2014).

Bacteria
Actinobacteria
CmpL1 of Corynebacterium glutamicum
*2.A.6.5.11









CmpL4 of 801 aas and 12 TMSs.  Multidrug resistance protein of 801 aas and 12 TMSs. Mutants are hypersusceptible to multiple antibiotics, have growth deficiencies in minimal medium and accumulate intracellular trehalose monocorynomycolates, free corynomycolates, and a previously uncharacterized corynomycolate-containing lipid.  It is inferred that this transporter exports one or more of these lipids.  Evidence for a pmf-dependent mechanism was obtained (Yang et al. 2014).

Bacteria
Actinobacteria
CmpL4 of Corynebacterium glutamicum
*2.A.6.5.12









MmpL4a of 959 aas and 12 TMSs.  A rough morphotype has a Y842H mutation that causes a deficiency in glycopeptidolipid production and a gain in the capacity to produce cords in vitro. In zebrafish, increased virulence of the M. bolletii R variant over the parental S strain was noted, involving massive production of serpentine cords, abscess formation and rapid larval death. Tyr842 is conserved in several MmpL proteins (Bernut et al. 2016).

Bacteria
Actinobacteria
MmpL4a of Mycobacterium abscessus subsp. bolletii
*2.A.6.5.13









Lipid (acyl and diacyl trehalose) exporter of 1002 aas and 12 TMSs, MmpL10 (Bailo et al. 2015).

Bacteria
Actinobacteria
MmpL10 of Mycobacterium tuberculosis
2.A.6.6:  The Eukaryotic (Putative) Sterol Transporter (EST) Family
*2.A.6.6.1









Niemann-Pick C1 and C2 disease proteins, NPC1 and NPC2, together may form a lipid/cholesterol exporter from lysosomes to other cellular sites including the plasma membrane (Sleat et al., 2004; Kennedy et al. 2014). NPC1 or NPC2 deficiency causes lysosomal retention of cholesterol, sphingolipids, phospholipids, and glycolipids as well as neuronal dysfunction and neurodegeneration (Infante et al. 2008a).  Increased mitochondrial cholesterol, observed in NPC1 or NPC2 deficiency, causes oxidative stress and increased rates of glycolysis and lactate release (Kennedy et al. 2014).  NPC1 binds cholesterol, 25-hydroxycholesterol and various oxysterols (Infante et al. 2008b; Liu et al., 2009 ). Soluble NPC2 binds cholesterol, and then passes it to the N-terminal domain of membranous NPC1 (Abi-Mosleh et al., 2009). Cholesterol trafficking in Niemann-Pick C-deficient cells was reviewed by Peake and Vance (2010). NPC1 is a late-endosomal membrane protein involved in trafficking of LDL- derived cholesterol, Niemann-Pick disease type C, and Ebola virus infection.  It is the Ebola virus receptor. It contains 13 TMSs, five of which are thought to represent a "sterol-sensing domain", also present in other key regulatory proteins of cholesterol biosynthesis, uptake, and signaling. A crystal structure of a large fragment of human NPC1 at 3.6 Å resolution revealed internal twofold pseudosymmetry along TMSs 2-13 and two structurally homologous domains that protrude 60 Å into the endosomal lumen (Li et al. 2016). NPC1's sterol sensing domain forms a cavity that is accessible from both the luminal bilayer leaflet and the endosomal lumen; this cavity is large enough to accommodate one cholesterol molecule. A model was proposed for  cholesterol sensing and transport (Li et al. 2016).  Lysosomal cholesterol activates TORC1 via an SLC38A9-Niemann-Pick C1 signaling complex (Castellano et al. 2017).  Gong et al. 2016 presented a 4.4 Å structure of the full-length human NPC1 and a low-resolution reconstruction of NPC1 in complex with the cleaved glycoprotein (GPcl) of EBOV, both determined by single-particle electron cryomicroscopy. NPC1 contains three distinct lumenal domains A (also designated NTD), C, and I. TMSs 2-13 exhibit a typical RND fold, among which TMSs 3-7 constitute the sterol-sensing domain conserved in several proteins involved in cholesterol metabolism and signaling. A trimeric EBOV-GPcl binds to one NPC1 monomer through domain C (Gong et al. 2016).

Eukaryota
Metazoa
NPC1 and NPC2 of Homo sapiens
NPC1 (AAH63302)
NPC2 (AAH02532)
*2.A.6.6.2









Patched (Ptc) segmentation polarity protein
Eukaryota
Metazoa
"Patched" of Drosophila melanogaster
*2.A.6.6.3









Yeast membrane protein YPL006w
Eukaryota
Fungi
YPL006w of Saccharomyces cerevisiae
*2.A.6.6.4









SREBP cleavage-activating protein, Scap of 1279 aas.  Cholesterol homeostasis is mediated by Scap, a polytopic ER protein that transports SREBPs from ER to Golgi where SREBPs are processed to forms that activate cholesterol synthesis. Scap has eight transmembrane helices and two large luminal loops, designated Loop1 and Loop7. Evidence suggests that Loop1 binds to Loop7, allowing Scap to bind COPII proteins for transport in coated vesicles (Zhang et al. 2016). When ER cholesterol rises, it binds to Loop1 causeing dissociation from Loop7, abrogating COPII binding. Direct binding of the two loops causes dissociation from the membrane, allowing the soluble complex to be secreted.  Point mutations that disrupt the Loop1-Loop7 interaction prevented secretion.

Eukaryota
Metazoa
SCAP of Cricetulus griseus
*2.A.6.6.5









3-hydroxy-3-methylglutaryl (HMG)-CoA reductase
Eukaryota
Metazoa
HMG-CoA reductase of Homo sapiens
*2.A.6.6.6









Liver/intestinal enterocyte brush border Niemann-Pick C1 like 1 (NPC1L1) protein; responsible for ezetimibe-sensitive absorption of luminal lipids and cholesterol via a transport mechanism (Altmann et al., 2004; Davies et al., 2005; Liscum, 2007, Dixit et al. 2007). NPC1L1-dependent sterol uptake seems to be a clathrin-mediated endocytic process and is regulated by cellular cholesterol content (Betters and Yu, 2010; Jia et al., 2011).  Dietary cholesterol induces trafficking of the intestinal NPC1L1 from the brush boarder to endosomes (Skov et al. 2011).  It distributes on the brush border membranes of enterocytes and the canalicular membranes of hepatocytes. It is the target of ezetimibe, a hypocholesterolemic drug which blocks internalization of NPC1L1 and cholesterol in the mouse small intestine (Wang and Song 2012; Xie et al. 2012). Human NPC1L1 is a 1,332-amino acid protein with a putative sterol-sensing domain (SSD) that shows sequence homology to HMG-CoA reductase (HMGCR), Niemann-Pick C1 (NPC1), and SREBP cleavage-activating protein (SCAP). NPC1L1 may have evolved at two sites (apical membrane of enterocytes and canalicular membrane of hepatocytes) to mediate cholesterol uptake through a clathrin-mediated endocytic process, protecting the body against fecal and biliary loss of cholesterol (Yu 2008).

Eukaryota
Metazoa
NPC1L1 of Homo sapiens (NP_037521)
*2.A.6.6.7









Niemann-Pick C-type protein (NPC) (1342 aas; 16 putative TMSs in a 1+3+1+5+1+5 arrangement)

Eukaryota
Dictyosteliida
NPC of Dictyostelium discoideum (Q9TVK6) 
*2.A.6.6.8









Niemann-Pick C1 protein homologue-1, Ncr1; contains a sterol sensing domain. Catalyzes intracellular cholesterol release from endocytic organelles.

Eukaryota
Metazoa
Ncr-1 of Caenorhabditis elegans (Q19127)
*2.A.6.6.9









Niemann-Pick C1 protein homologue-2, Ncr2; contains a sterol sensing domain. Catalyzes intracellular cholesterol release from endocytic organelles.

Eukaryota
Metazoa
Ncr-2 of Caenorhabditis elegans (P34389)
*2.A.6.6.10









Pacific oyster protein of unknown function

Eukaryota
Metazoa
Uncharacterized protein of Crassostrea angulata
*2.A.6.6.11









3-hydroxy-3-methylglutaryl-coenzyme A reductase of 438 aas and 1 or 0 TMSs.

Bacteria
Proteobacteria
3-hydroxy-3-methylglutaryl-coenzyme A reductase of Bdellovibrio bacteriovorus
*2.A.6.6.12









Niemann-Pick C1 protein, NPC1 of 1339 aas and 16 TMSs in a 1 + 3 + 1 +5 + 1 +5 arrangement. Trafficking of EhNPC1 and EhNPC2 during cholesterol uptake and phagocytosis as well as their association with molecules involved in endocytosis clearly suggest that these proteins play a key role in cholesterol uptake (Bolaños et al. 2016).

Eukaryota
Entamoebidae
NPC1 of Entamoeba histolytica
2.A.6.7:  The (Largely Archaeal Putative) Hydrophobe/Amphiphile Efflux-3 (HAE3) Family
*2.A.6.7.1









Gene AF1229
Archaea
Euryarchaeota
ORF in Archaeoglobus fulgidus
*2.A.6.7.2









Gene MJ1562
Archaea
Euryarchaeota
ORF in Methanococcus jannaschii
*2.A.6.7.3









Bacterial HAE3 family member

Bacteria
Proteobacteria
HAE3 family member of Myxococcus xanthus
*2.A.6.7.4









Bacterial HAE3 family member

Bacteria
Proteobacteria
HAE3 family member of Myxococcus xanthus
*2.A.6.7.5









Bacteria
Proteobacteria
Putative hopanoid transporter, HpnN, of Rhodopseudomonas palustris
*2.A.6.7.6









Putative RND lipid exporter

Bacteria
Planctomycetes
RND exporter of Rhodopirellula baltica
*2.A.6.7.7









Putative lipid exporter of 797 aas and 12 TMSs.

Bacteria
Spirochaetes
Putative exporter of Treponema brennaborense
2.A.6.8:  The Brominated, Aryl Polyene Pigment Exporter (APPE) Family
*2.A.6.8.1









Xanthomonadin (brominated, aryl polyene pigment) exporter (to its outer membrane site), ORF4
Bacteria
Proteobacteria
ORF4 in the pig (pigment) gene locus of Xanthomonas oryzae pv. oryzae
*2.A.6.8.2









RND transporter.  Encoded in a 17 cistron operon that appears in pathogenic proteobacteria including pathogenic E. coli strains, but not non-pathogenic E. coli strains like K12.  May be involved in host associations (EE Allen, personal communication)

Bacteria
Proteobacteria
RND transporter of E. coli
2.A.6.9:  The Dispatched (Dispatched) Family
*2.A.6.9.1









Dispatched, putative exporter of the cholesterol-modified peptide, hedgehog; sterol sensor protein (Ma et al., 2002). Loss prevents hedgehog signaling. (Nakano et al., 2004; Higgins, 2007).

Eukaryota
Metazoa
Dispatched of Drosophila melanogaster (AAF_23397)
*2.A.6.9.2









Protein dispatched homologue 1 (MdispA)

Eukaryota
Metazoa
Disp1 of Mus musculus
*2.A.6.10.1









Uncharacterized protein

Bacteria
Actinobacteria
Uncharacterized protein of Streptomyces coelicolor (Q9K3K9)  
*2.A.6.10.2









Uncharacterized protein of 316 aas and 6 TMSs.

Bacteria
Actinobacteria
UP of Hoyosella subflava (Amycolicicoccus subflavus)
*2.A.6.10.3









Uncharacterized protein of 353 aas and 5 or 6 TMSs.

Bacteria
Actinobacteria
UP of Gordonia alkanivorans