| 2.A.66 The Multidrug/Oligosaccharidyl-lipid/Polysaccharide (MOP) Flippase Superfamily
The MOP flippase superfamily includes four distantly related families: One ubiquitous family (MATE) specific for drugs, one (PST) specific for polysaccharides and/or their lipid-linked precursors in prokaryotes, one (OLF) specific for lipid-linked oligosaccharide precursors of glycoproteins in eukaryotes, and one (MVI) of unknown transport function. The OLF family is found in the endoplasmic reticular membranes of eukaryotes. All functionally characterized members of the MOP superfamily catalyze efflux of their substrates, presumably by cation antiport.
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| References: |
Hvorup, R.N., B. Winnen, A. Chang, Y. Jiang, X.-F. Zhou,
and M.H. Saier, Jr. (2002). The multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) flippase superfamily. European J. Biochem. 148: 3760-3762.
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 2.A.66.1 The Multi Antimicrobial Extrusion (MATE) Family |
| Description: 2.A.66.1 The Multi Antimicrobial Extrusion (MATE) Family
The MATE family includes a functionally characterized multidrug efflux system from Vibrio parahaemolyticus NorM, and several homologues from other closely related bacteria that function by a drug:Na+ antiport mechanism, a putative ethionine resistance protein of Saccharomyces cerevisiae, a cationic drug efflux pump in A. thaliana and the functionally uncharacterized DNA damage-inducible protein F (DinF) of E. coli. The bacterial proteins are of about 450 amino acyl residues in length and exhibit 12 putative TMS. They arose by an internal gene duplication event from a primordial 6 TMS encoding genetic element. The yeast proteins are larger (up to about 700 residues) and exhibit about 12 TMSs.
The family includes hundreds of functionally uncharacterized but sequenced homologues from bacteria, archaea, and all eukaryotic kingdoms.
The probable transport reaction catalyzed by NorM, and possibly by other proteins of the MATE family is:
Antimicrobial (in) + nNa+ (out) → Antimicrobial (out) + nNa+ (in).
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References:
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| Brown, M.H., I.T. Paulsen, and R.A. Skurray. (1999). The multidrug efflux protein NorM is a prototype of a new family of transporters. Mol. Microbiol. 31: 394-395. |
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| Chen, J., Y. Morita, M.N. Huda, T. Kuroda, T. Mizushima, and T. Tsuchiya. (2002). VmrA, a member of a novel class of Na+-coupled multidrug efflux pumps from Vibrio parahaemolyticus. J. Bacteriol. 184: 572-576. |
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| Diener, A.C., R.A. Gaxiola, and G.R. Fink. (2001). Arabidopsis ALF5, a multidrug efflux transporter gene family member, confers resistance to toxins. The Plant Cell 13: 1625-1637. |
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| Fehlner-Gardiner, C.C. and M.A. Valvano. (2002). Cloning and characterization of the Burkholderia vietnamiensis norM gene encoding a multi-drug efflux protein. FEMS Microbiol. Lett. 215: 279-283. |
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| He, G.-X., T. Kuroda, T. Mima, Y. Morita, T. Mizushima, and T. Tsuchiya. (2004). An H+-coupled multidrug efflux pump, PmpM, a member of the MATE family of transporters, from Pseudomonas aeruginosa. J. Bacteriol. 186: 262-265. |
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| Huda, M.N., Y. Morita, T. Kurodo, T. Mizushima, and T. Tsuchiya. (2001). Na+-driven multidrug efflux pump VcmA from Vibrio cholera non-01, a non-halophidic bacterium. FEMS Microbiol. Lett. 203: 235-239. |
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| Li, L., Z. He, G.K. Pandey, T. Tsuchiya, and S. Luan. (2002). Functional cloning and characterization of a plant efflux carrier for multidrug and heavy metal detoxification. J. Biol. Chem. 277: 5360-5368. |
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| Morita, Y., A. Kataoka, S. Shiota, T. Mizushima, and T. Tsuchiya. (2000). NorM of Vibrio parahaemolyticus is a Na+-driven multidrug efflux pump. J. Bacteriol. 182: 6694-6697. |
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| Morita, Y., K. Kodama, S. Shiota, T. Mine, A. Kataoka, T. Mizushima, and T. Tsuchiya. (1998). NorM, a putative multidrug efflux protein, of Vibrio parahaemolyticus and its homolog in Escherichia coli. Antimicrob. Agents Chemother. 42: 1778-1782. |
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| Nishino, K. and A. Yamaguchi. (2001). Analysis of a complete library of putative drug transporter genes in Escherichia coli. J. Bacteriol. 183: 5803-5812. |
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| Rouquette-Loughlin, C., S.A. Dunham, M. Kuhn, J.T. Balthazar, and W.M. Shafer. (2003). The NorM efflux pump of Neisseria gonorrhoeae and Neisseria meningitidis recognizes antimicrobial cationic compounds. J. Bacteriol. 185: 1101-1106. |
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| 2.A.66.1.1 | Drug:Na+ antiporter (norfloxacin, ethidium, kanamycin, ciprofloxin, streptomycin efflux pump), NorM | Bacteria | NorM of Vibrio parahaemolyticus
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| 2.A.66.1.2 | Drug:Na+ antiporter, VcmA (exports norfloxacin, ciprofloxacin, ofloxacin, daunomycin, doxorubicin, streptomycin, kanamycin, ethidium, 4',6'-
diamidino-2-phenylindole, hoechst33342 and acriflavin) | Bacteria | VcmA (NorM) of Vibrio cholerae non-01 |
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| 2.A.66.1.3 | Multidrug-resistance efflux pump, YdhE (exports chloramphenicol, norfloxacin, enoxacin, phosphomycin, doxorubicin, trimethoprim, ethidium, deoxycholate, etc.) | Bacteria | NorM (YdhE) of E. coli |
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| 2.A.66.1.4 | DNA damage-inducible protein F, DinF | Bacteria | DinF of E. coli |
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| 2.A.66.1.5 | Ethionine resistance protein, ERC1 | Yeast | ERC1 (YHR032w) of Saccharomyces cerevisiae |
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| 2.A.66.1.6 | Drug (norfloxacin, ciprofoxacin, ethidium, tetramethylammonium, pyrrolidinone, polyvinylpyrrolidone) resistance pump, Alf5 | Plants | Alf5 of Arabidopsis thaliana |
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| 2.A.66.1.7 | Cationic drug (4',6'-diamidino-2-phenylindole (DAPI), tetraphenylphosphonium (TPP), acriflavin, ethidium):Na+ antiporter, VmrA | Bacteria | VmrA of Vibrio parahaemolyticus |
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| 2.A.66.1.8 | Plasma membrane efflux pump, AtDTX1, for plant alkaloids, drugs (e.g., norfloxacin), antibiotics and Cd2+ | Plants | AtDTX1 of Arabidopsis thaliana |
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| 2.A.66.1.9 | Drug (norfloxacin, polymyxin B) resistance efflux pump, NorM | Bacteria | NorM of Burkholderia vietnamiensis |
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| 2.A.66.1.10 | Cationic drug (ethidium, acriflavine, 2-N-methyl ellipticinium, berberine, norfloxacin, ciprofloxacin) efflux pump | Bacteria | NorM of Neisseria meningitidis |
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| 2.A.66.1.11 | The Enhanced Disease Susceptibility Protein (EDS5), also called the Salicylate Induction Deficient (Sid1) protein; a possible chloroplast salicylate transporter (S. Heck, personal communication) | Plants | EDS5 of Arabidopsis thaliana chloroplasts |
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| 2.A.66.1.12 | Drug:H+ antiporter (benzalkonium chloride, fluoroquinolone, ethidium bromide, acriflavin, tetraphenylphosphonium chloride efflux pump), PmpM (He et al., 2004) | Bacteria | PmpM of Pseudomonas aeruginosa (Q9I3Y3) |
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| 2.A.66.2 The Polysaccharide Transport (PST) Family |
| Description: 2.A.66.2 The Polysaccharide Transport (PST) Family
The protein members of the PST family are generally of 400-500 amino acyl residues in size and traverse the membrane as putative a-helical spanners twelve times. Analyses conducted in 1997 showed that they formed two major clusters, one of which is probably concerned with lipopolysaccharide O-antigen export (flipping) in Gram-negative bacteria, the other which is concerned with exopolysaccharide or capsular polysaccharide export in both Gram-negative and Gram-positive bacteria. However, arachaeal and eukaryotic homologues are now recognized. The mechanism of energy coupling is not established, but homology with the MATE family suggests that they are secondary carriers. These transporters may function together with auxiliary proteins that allow passage across both membranes of the Gram-negative bacterial envelope and may also regulate transport. Thus, each Gram-negative bacterial PST system specific for an exo- or capsular polysaccharide functions in conjunction with a cytoplasmic membrane-periplasmic auxiliary (MPA) protein with a cytoplasmic ATP-binding domain (MPA1-C; TC #3.C.3) as well as an outer membrane auxiliary protein (OMA; TC #3.C.5). Each Gram-positive bacterial PST system functions in conjunction with a homologous MPA1 + C pair of proteins equivalent to an MPA1-C proteins of Gram-negative bacteria. The C-domain has been shown to possess tyrosine protein kinase activity, so it may function in a regulatory capacity. The lipopolysaccharide exporters may function specifically in the translocation of the lipid-linked O-antigen side chain precursor from the inner leaflet of the cytoplasmic membrane to the outer leaflet, but this possibility has not been established experimentally. In this respect they correlate in function with the members of the oligosaccharidyl-lipid flippase (OLF) family of the MOP flippase superfamily.
The generalized transport reaction catalyzed by PST family proteins is:
Polysaccharide (in) + energy → Polysaccharide (out).
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References:
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| Paulsen, I.T., A.M. Beness, and M.H. Saier, Jr. (1997). Computer-based analyses of the protein constituents of transport systems catalyzing export of complex carbohydrates in bacteria. Microbiology 143: 2685-2699. |
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| Soldo, B., V. Lazarevic, M. Pagni, and D. Karamata. (1999). Teichuronic acid operon of Bacillus subtilis 168. Molec. Microbiol. 31: 795-805. |
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| Vincent, C., P. Doublet, C. Grangeasse, E. Vaganay, A.J. Cozzone, and B. Duclos. (1999). Cells of Escherichia coli contain a protein-tyrosine kinase, Wzc, and a phosphotyrosine-protein phosphatase, Wzb. J. Bacteriol. 181: 3472-3477. |
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| Whitfield, C. and I.S. Roberts. (1999). Structure, assembly and regulation of expression of capsules in Escherichia coli. Mol. Microbiol. 31: 1307-1319. |
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| 2.A.66.2.1 | Lipopolysaccharide (possibly the O-antigen side chain intermediate) exporter | Gram-negative bacteria | RfbX1 of E. coli |
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| 2.A.66.2.2 | Probable succinoglycan exporter | Gram-negative bacteria | ExoT of Rhizobium meliloti |
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| 2.A.66.2.3 | Probable O-antigen flippase | Gram-negative bacteria | Wzx of E. coli |
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| 2.A.66.2.4 | Probable acetan exporter | Gram-negative bacteria | AceE of Acetobacter xylinus |
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| 2.A.66.2.5 | Capsular polysaccharide exporter | Gram-positive bacteria | CapF of Staphylococcus aureus |
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| 2.A.66.2.6 | Teichuronic acid exporter, TuaB (YvhB) | Gram-positive bacteria | TuaB of Bacillus subtilis |
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| 2.A.66.2.7 | Lipopolysaccharide (colanic acid) exporter, WzxC | Gram-negative bacteria | WzxC of E. coli |
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| 2.A.66.2.8 | Exopolysaccharide (Amylovoran) exporter, AmsL | Gram-negative bacteria | AmsL of Erwinia amylovora |
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| 2.A.66.2.9 | A Succinoglycan Transporter and an O-Antigen Transporter | Archaea | Orf of Methanobacterium themoautotrophicum |
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| 2.A.66.3 The Oligosaccharidyl-lipid Flippase (OLF) Family |
| Description: 2.A.66.3 The Oligosaccharidyl-lipid Flippase (OLF) Family
N-linked glycosylation in eukaryotic cells follows a conserved pathway in which a tetradecasaccharide substrate (Glc3Man9GlcNAc2) is initially assembled in the ER membrane as a dolichylpyrophosphate (Dol-PP)-linked intermediate before being transferred to an asparaginyl residue in a lumenal protein. An intermediate, Man5GlcNAc2-PP-Dol is made on the cytoplasmic side of the membrane and translocated across the membrane so that the oligosaccharide chain faces the ER lumen where biosynthesis continues to completion.
The flippase that catalyzes the translocation step is dependent on the Rft1 protein of S. cerevisiae (Helenius et al., 2002). Homologues are found in plants, animals and fungi including C. elegans, D. melanogaster, H. sapiens, A. thaliana, S. cerevisiae and S. pombe. The yeast protein, called the nuclear division Rft1 protein, is 574 aas with 12 putative TMSs. The homologue in A. thaliana is 401 aas in length with 8 or 9 putative TMSs while that in C. elegans is 522 aas long with 11 putative TMSs. These proteins are distantly related to MATE and PST family members and therefore are probably secondary carriers.
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References:
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| Helenius, J., D.T.W. Ng, C.L. Marolda, P. Walter, M.A. Valvano, and M. Aebi. (2002). Translocation of lipid-linked oligosaccharides across the ER membrane requires Rft1 protein. Nature 415: 447. |
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| 2.A.66.3.1 | The OLF (Rft1 protein) of Saccharomyces cerevisiae | Eukaryotes | Rft1 of Saccharomyces cerevisiae |
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| 2.A.66.4 The Mouse Virulence Factor (MVF) Family |
| Description: 2.A.66.4 The Mouse Virulence Factor (MVF) Family
A single member of the MVF family, MviN of Salmonella typhimurium, has been shown to be an important virulence factor for this organism when infecting the mouse (Kutsukake et al., 1994). In several bacteria, mviN genes occur in operons including glnD genes that encode the uridylyl transferase that participates in the regulation of nitrogen metabolism (Rudnick et al., 2001). Nothing more is known about the function of this protein or any other member of the MVF family. However, these proteins are related to members of the PST and MATE families (>9 S.D.), and the greatest sequence similarity is found with members of the PST family. It is therefore possible that MVF family members are functionally related to PST family members and catalyze efflux by a cation antiport mechanism.
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References:
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| Kutsukake, K., T. Okada, T. Yokoseki, and T. Iino. (1994). Sequence analysis of the flgA gene and its adjacent region in Salmonella typhimurium, and identification of another flagellar gene, flgN. Gene 143: 49-54. |
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| Rudnick, P.A., T. Arcondéguy, C.K. Kennedy, and D. Kahn. (2001). glnD and mviN are genes of an essential operon in Sinorhizobium meliloti. J. Bacteriol. 183: 2682-2685. |
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| 2.A.66.4.1 | The mouse virulence factor, MviN | Bacteria | MviN of Salmonella typhimurium |
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