2.A.66 The Multidrug/Oligosaccharidyl-lipid/Polysaccharide (MOP) Flippase Superfamily

The MOP flippase superfamily includes eight distantly related families, five for which functional data are available: 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, one (AgnG) which includes a single functionally characterized member that extrudes the antibiotic, Agrocin 84, 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. Members of this family have been reported to have the MATE fold (Ferrada and Superti-Furga 2022). MATEs have been described as transporting primary and secondary metabolites, such as terpenoids, phenols, flavonoids, nicotine, alkaloids, phytohormones, proanthocyanidin, and anthocyanins (Saad et al. 2023).

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. A conserved binding site in the N-lobe of prokaryotic MATE transporters suggests a role for Na+ in ion-coupled drug efflux (Castellano et al. 2021).

Human MATE1 (hMATE1) is an electroneutral H+/organic cation (OC) exchanger responsible for the final excretion step of structurally unrelated toxic organic cations in kidney and liver. Glu273, Glu278, Glu300 and Glu389 are conserved in the transmembrane regions. Substitution with alanine or aspartate reduced export of tetraethylammonium (TEA) and cimetidine, and several had altered substrate affinities (Matsumoto et al., 2008). Thus, all of these glutamate residues are involved in binding and/or transport of TEA and cimetidine, but their roles are different.

There are 59 MATE transporters in grapes (Vitis vinifera) (Watanabe et al. 2022). Group 1 may transport toxic compounds and alkaloids; Group 2 may transport polyphenolic compounds; Group 3 may transport organic acids, and Group 4 may transport plant hormones related to signal transduction. In addition to the known anthocyanin transporters, VvMATE37 and VvMATE39, a novel anthocyanin transporter, VvMATE38 in Group 2, was suggested as a key transporter for anthocyanin accumulation in grape berry skin. VvMATE46, VvMATE47, and VvMATE49 in Group 3 may contribute to Al3+ detoxification and Fe2+/Fe3+ translocation via organic acid transport (Watanabe et al. 2022).

The family includes hundreds of functionally uncharacterized but sequenced homologues from bacteria, archaea, and all eukaryotic kingdoms (Kuroda and Tsuchiya, 2009). 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). A whole-body physiologically based pharmacokinetic study has characterized the interplay of OCTs (TC# 2.A.1.19) and MATEs in intestine, liver and kidney, predicting drug-drug interactions of metformin with perpetrators (Yang et al. 2021).

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).

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 α-helical spanners twelve times. Analyses conducted in 1997 showed that they formed two major clusters. One is concerned with lipopolysaccharide O-antigen (undecaprenol pyrophosphate-linked O-antigen repeat unit) export (flipping from the cytoplasmic side to the periplasmic side of the inner membranes) in Gram-negative bacteria. On the periplasmic side, polymerization occurs catalyzed by Wzy. The other 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.  A review of Wzx undecaprenyl pyrophosphate (UndPP)-linked polysaccharide repeat units occurs by a substrate:product antiport mechanism (Islam and Lam 2012). These transporters may function together with auxiliary proteins that allow passage across just the cytoplasmic membrane or both membranes of the Gram-negative bacterial envelope.  They 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 (Islam and Lam 2012). 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).

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.

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.

2.A.66.5 The Agrocin 84 Antibiotic Exporter (AgnG) Family

Agrocin 84 is a disubstituted adenine nucleotide antibiotic made by and specific for Agrobacteria. It is encoded by the pAgK84 plasmid of A. tumefaciens (Kim et al., 2006) and targets a tRNA synthetase (Reader et al., 2005). The agnG gene encodes a protein of 496 aas with 12-13 putative TMSs and a short hydrophilic N-terminal domain of 80 residues. AgnG is distantly related to members of the Mop superfamily, but is so distant, that it does not retrieve any such members in a TC BLAST search. Nevertheless, an NCBI BLAST search retrieves proteins of the PST and MVI families without iterations. agnG null mutants accumulate agrocin 84 intracellularly and do not export it (Kim et al., 2006).

The reaction catalyzed by AgnG is:

agrocin (in) agrocin (out)

2.A.66.6 The Putative Exopolysaccharide Exporter (EPS-E) Family

2.A.66.7 Putative O-Unit Flippase (OUF) Family

2.A.66.8 Unknown MOP-1 (U-MOP1) Family

2.A.66.9 The Progressive Ankylosis (Ank) Family

Craniometaphyseal dysplasia (CMD) is a bone dysplasia characterized by overgrowth and sclerosis of the craniofacial bones and abnormal modeling of the metaphyses of the tubular bones. Hyperostosis and sclerosis of the skull may lead to cranial nerve compressions resulting in hearing loss and facial palsy. An autosomal dominant form of the disorder has been linked to chromosome 5p15.2-p14.1 within a region harboring the human homolog (ANKH) of the mouse progressive ankylosis (ank) gene. The ANK protein spans the cell membrane and shuttles inorganic pyrophosphate (PPi), a major inhibitor of physiologic and pathologic calcification, bone mineralization and bone resorption (Nurnberg et al., 2001).

The ANK protein has 12 membrane-spanning helices with a central channel permitting the passage of PPi. Mutations occur at highly conserved amino acid residues presumed to be located in the cytosolic portion of the protein. The PPi channel ANK is concerned with bone formation and remodeling (Nurnberg et al., 2001).

2.A.66.10 LPS Precursor Flippase (LPS-F) Family

2.A.66.11 Uncharacterized MOP-11 (U-MOP11) Family

2.A.66.12 Uncharacterized MOP-12 (U-MOP12) Family

This family belongs to the Multidrug/Oligosaccharidyl-lipid/Polysaccharide Flippase (MOP) Superfamily.



AlQumaizi, K.I., S. Kumar, R. Anwer, and S. Mustafa. (2022). Differential Gene Expression of Efflux Pumps and Porins in Clinical Isolates of MDR. Life (Basel) 12:.

Bianco, M.I., M. Jacobs, S.R. Salinas, A.G. Salvay, M.V. Ielmini, and L. Ielpi. (2014). Biophysical characterization of the outer membrane polysaccharide export protein and the polysaccharide co-polymerase protein from Xanthomonas campestris. Protein Expr Purif 101: 42-53.

Brown, D.G., J.K. Swanson, and C. Allen. (2007). Two host-induced Ralstonia solanacearum genes, acrA and dinF, encode multidrug efflux pumps and contribute to bacterial wilt virulence. Appl. Environ. Microbiol. 73: 2777-2786.

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.

Butler EK., Davis RM., Bari V., Nicholson PA. and Ruiz N. (2013). Structure-function analysis of MurJ reveals a solvent-exposed cavity containing residues essential for peptidoglycan biogenesis in Escherichia coli. J Bacteriol. 195(20):4639-49.

Cao, X., Q. Wang, Q. Liu, H. Liu, H. He, and Y. Zhang. (2010). Vibrio alginolyticus MviN is a LuxO-regulated protein and affects cytotoxicity toward EPC cell. J Microbiol Biotechnol 20: 271-280.

Carr, G., S.H. Moochhala, L. Eley, A. Vandewalle, N.L. Simmons, and J.A. Sayer. (2009). The pyrophosphate transporter ANKH is expressed in kidney and bone cells and colocalises to the primary cilium/basal body complex. Cell Physiol Biochem 24: 595-604.

Castellano, S., D.P. Claxton, E. Ficici, T. Kusakizako, R. Stix, W. Zhou, O. Nureki, H.S. Mchaourab, and J.D. Faraldo-Gómez. (2021). Conserved binding site in the N-lobe of prokaryotic MATE transporters suggests a role for Na in ion-coupled drug efflux. J. Biol. Chem. [Epub: Ahead of Print]

Chauhan, N., L. Farine, K. Pandey, A.K. Menon, and P. Bütikofer. (2016). Lipid topogenesis - 35years on. Biochim. Biophys. Acta. [Epub: Ahead of Print]

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.

Chen, L., Y. Liu, H. Liu, L. Kang, J. Geng, Y. Gai, Y. Ding, H. Sun, and Y. Li. (2015). Identification and Expression Analysis of MATE Genes Involved in Flavonoid Transport in Blueberry Plants. PLoS One 10: e0118578.

Claxton, D.P., K.L. Jagessar, P.R. Steed, R.A. Stein, and H.S. Mchaourab. (2018). Sodium and proton coupling in the conformational cycle of a MATE antiporter from. Proc. Natl. Acad. Sci. USA 115: E6182-E6190.

Collins, R.F., V. Kargas, B.R. Clarke, C.A. Siebert, D.K. Clare, P.J. Bond, C. Whitfield, and R.C. Ford. (2017). Full-length, Oligomeric Structure of Wzz Determined by Cryoelectron Microscopy Reveals Insights into Membrane-Bound States. Structure 25: 806-815.e3.

Cunneen, M.M. and P.R. Reeves. (2008). Membrane topology of the Salmonella enterica serovar Typhimurium Group B O-antigen translocase Wzx. FEMS Microbiol. Lett. 287: 76-84.

Damjanovic, M., A.S. Kharat, A. Eberhardt, A. Tomasz, and W. Vollmer. (2007). The essential tacF gene is responsible for the choline-dependent growth phenotype of Streptococcus pneumoniae. J. Bacteriol. 189: 7105-7111.

Debeaujon, I., A.J. Peeters, K.M. Léon-Kloosterziel, and M. Koornneef. (2001). The TRANSPARENT TESTA12 gene of Arabidopsis encodes a multidrug secondary transporter-like protein required for flavonoid sequestration in vacuoles of the seed coat endothelium. Plant Cell 13: 853-871.

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.

Dridi, L., J. Tankovic, and J.C. Petit. (2004). CdeA of Clostridium difficile, a new multidrug efflux transporter of the MATE family. Microb Drug Resist 10: 191-196.

Durães, F., M. Pinto, and E. Sousa. (2018). Medicinal Chemistry Updates on Bacterial Efflux Pump Modulators. Curr. Med. Chem. 25: 6030-6069.

Durrett, T.P., W. Gassmann, and E.E. Rogers. (2007). The FRD3-mediated efflux of citrate into the root vasculature is necessary for efficient iron translocation. Plant Physiol. 144: 197-205.

Eijkelkamp, B.A., K.A. Hassan, I.T. Paulsen, and M.H. Brown. (2011). Development of a high-throughput cloning strategy for characterization of Acinetobacter baumannii drug transporter proteins. J. Mol. Microbiol. Biotechnol. 20: 211-219.

Fay, A. and J. Dworkin. (2009). Bacillus subtilis homologs of MviN (MurJ), the putative Escherichia coli lipid II flippase, are not essential for growth. J. Bacteriol. 191: 6020-6028.

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.

Ferrada, E. and G. Superti-Furga. (2022). A structure and evolutionary-based classification of solute carriers. iScience 25: 105096.

Ficici, E., W. Zhou, S. Castellano, and J.D. Faraldo-Gómez. (2018). Broadly conserved Na-binding site in the N-lobe of prokaryotic multidrug MATE transporters. Proc. Natl. Acad. Sci. USA 115: E6172-E6181.

Franklin, K., E.J. Lingohr, C. Yoshida, M. Anjum, L. Bodrossy, C.G. Clark, A.M. Kropinski, and M.A. Karmali. (2011). Rapid genoserotyping tool for classification of Salmonella serovars. J Clin Microbiol 49: 2954-2965.

Fu, Y., S. Zhao, N. Ma, Y. Zhang, and S. Cai. (2024). Exploring the Transmembrane Behaviors of Dietary Flavonoids under Intestinal Digestive Products of Different Lipids: Insights into the Structure-Activity Relationship. J Agric Food Chem 72: 794-809.

Gao JS., Wu N., Shen ZL., Lv K., Qian SH., Guo N., Sun X., Cai YP. and Lin Y. (2016). Molecular cloning, expression analysis and subcellular localization of a Transparent Testa 12 ortholog in brown cotton (Gossypium hirsutum L.). Gene. 576(2 Pt 2):763-9.

Garcia-Oliveira, A.L., C. Benito, H. Guedes-Pinto, and P. Martins-Lopes. (2018). Molecular cloning of TaMATE2 homoeologues potentially related to aluminium tolerance in bread wheat (Triticum aestivum L.). Plant Biol (Stuttg). [Epub: Ahead of Print]

Garcia-Oliveira, A.L., P. Martins-Lopes, R. Tolrá, C. Poschenrieder, M. Tarquis, H. Guedes-Pinto, and C. Benito. (2014). Molecular characterization of the citrate transporter gene TaMATE1 and expression analysis of upstream genes involved in organic acid transport under Al stress in bread wheat (Triticum aestivum). Physiol Plant 152: 441-452.

Gee, C.L., K.G. Papavinasasundaram, S.R. Blair, C.E. Baer, A.M. Falick, D.S. King, J.E. Griffin, H. Venghatakrishnan, A. Zukauskas, J.R. Wei, R.K. Dhiman, D.C. Crick, E.J. Rubin, C.M. Sassetti, and T. Alber. (2012). A phosphorylated pseudokinase complex controls cell wall synthesis in mycobacteria. Sci Signal 5: ra7.

Green, L.S. and E.E. Rogers. (2004). FRD3 controls iron localization in Arabidopsis. Plant Physiol. 136: 2523-2531.

Hashimoto, K., W. Ogawa, T. Nishioka, T. Tsuchiya, and T. Kuroda. (2013). Functionally cloned pdrM from Streptococcus pneumoniae encodes a Na+ coupled multidrug efflux pump. PLoS One 8: e59525.

Hayashi, M., K. Tabata, M. Yagasaki, and Y. Yonetani. (2010). Effect of multidrug-efflux transporter genes on dipeptide resistance and overproduction in Escherichia coli. FEMS Microbiol. Lett. 304: 12-19.

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.

He, X., P. Szewczyk, A. Karyakin, M. Evin, W.X. Hong, Q. Zhang, and G. Chang. (2010). Structure of a cation-bound multidrug and toxic compound extrusion transporter. Nature 467: 991-994.

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.

Hiasa, M., T. Matsumoto, T. Komatsu, H. Omote, and Y. Moriyama. (2007). Functional characterization of testis-specific rodent multidrug and toxic compound extrusion 2, a class III MATE-type polyspecific H+/organic cation exporter. Am. J. Physiol. Cell Physiol. 293: C1437-1444.

Hong, Y., D. Hu, A.D. Verderosa, J. Qin, M. Totsika, and P.R. Reeves. (2023). Repeat-Unit Elongations To Produce Bacterial Complex Long Polysaccharide Chains, an O-Antigen Perspective. EcoSal Plus eesp00202022. [Epub: Ahead of Print]

Hong, Y., M.M. Cunneen, and P.R. Reeves. (2012). The Wzx translocases for Salmonella enterica O-antigen processing have unexpected serotype specificity. Mol. Microbiol. 84: 620-630.

Huang, J. and M. Schell. (1995). Molecular characterization of the eps gene cluster of Pseudomonas solanacearum and its transcriptional regulation at a single promoter. Mol. Microbiol. 16: 977-989.

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.

Hug, L.A., B.J. Baker, K. Anantharaman, C.T. Brown, A.J. Probst, C.J. Castelle, C.N. Butterfield, A.W. Hernsdorf, Y. Amano, K. Ise, Y. Suzuki, N. Dudek, D.A. Relman, K.M. Finstad, R. Amundson, B.C. Thomas, and J.F. Banfield. (2016). A new view of the tree of life. Nat Microbiol 1: 16048.

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.

Inoue, A., Y. Murata, H. Takahashi, N. Tsuji, S. Fujisaki, and J. Kato. (2008). Involvement of an essential gene, mviN, in murein synthesis in Escherichia coli. J. Bacteriol. 190: 7298-7301.

Islam ST. and Lam JS. (2013). Wzx flippase-mediated membrane translocation of sugar polymer precursors in bacteria. Environ Microbiol. 15(4):1001-15.

Jin, Y., A. Nair, and H.W. van Veen. (2014). Multidrug transport protein norM from vibrio cholerae simultaneously couples to sodium- and proton-motive force. J. Biol. Chem. 289: 14624-14632.

Kaatz, G.W., C.E. DeMarco, and S.M. Seo. (2006). MepR, a repressor of the Staphylococcus aureus MATE family multidrug efflux pump MepA, is a substrate-responsive regulatory protein. Antimicrob. Agents Chemother. 50: 1276-1281.

Kanai, M., T. Kawata, Y. Yoshida, Y. Kita, T. Ogawa, M. Mizunuma, D. Watanabe, H. Shimoi, A. Mizuno, O. Yamada, T. Fujii, and H. Iefuji. (2017). Sake yeast YHR032W/ERC1 haplotype contributes to high S-adenosylmethionine accumulation in sake yeast strains. J Biosci Bioeng 123: 8-14.

Kobara, A., M. Hiasa, T. Matsumoto, M. Otsuka, H. Omote, and Y. Moriyama. (2008). A novel variant of mouse MATE-1 H+/organic cation antiporter with a long hydrophobic tail. Arch Biochem Biophys 469: 195-199.

Kohga, H., T. Mori, Y. Tanaka, K. Yoshikaie, K. Taniguchi, K. Fujimoto, L. Fritz, T. Schneider, and T. Tsukazaki. (2022). Crystal structure of the lipid flippase MurJ in a "squeezed" form distinct from its inward- and outward-facing forms. Structure. [Epub: Ahead of Print]

Kuk, A.C., E.H. Mashalidis, and S.Y. Lee. (2016). Crystal structure of the MOP flippase MurJ in an inward-facing conformation. Nat Struct Mol Biol. [Epub: Ahead of Print]

Kumar, S., F.A. Rubino, A.G. Mendoza, and N. Ruiz. (2019). The bacterial lipid II flippase MurJ functions by an alternating-access mechanism. J. Biol. Chem. 294: 981-990.

Kuroda, T. and T. Tsuchiya. (2009). Multidrug efflux transporters in the MATE family. Biochim. Biophys. Acta. 1794: 763-768.

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.

Lefaucheur, L., J. Le Dividich, J. Mourot, G. Monin, P. Ecolan, and D. Krauss. (1991). Influence of environmental temperature on growth, muscle and adipose tissue metabolism, and meat quality in swine. J Anim Sci 69: 2844-2854.

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.

Li, Y., H. He, and L.F. He. (2018). Genome-wide analysis of the MATE gene family in potato. Mol Biol Rep. [Epub: Ahead of Print]

Liu, Y., X. Wu, C. Sun, W. Chen, M. Zhang, N. Liu, Q. Zhang, L. Xu, and Z. Luo. (2023). Preferential transport activity of DkDTX5/MATE5 affects the formation of different astringency in persimmon. J Integr Plant Biol. [Epub: Ahead of Print]

Long, F., C. Rouquette-Loughlin, W.M. Shafer, and E.W. Yu. (2008). Functional cloning and characterization of the multidrug efflux pumps NorM from Neisseria gonorrhoeae and YdhE from Escherichia coli. Antimicrob. Agents Chemother. 52: 3052-3060.

Lu, M., J. Symersky, M. Radchenko, A. Koide, Y. Guo, R. Nie, and S. Koide. (2013). Structures of a Na+-coupled, substrate-bound MATE multidrug transporter. Proc. Natl. Acad. Sci. USA 110: 2099-2104.

Lu, M., M. Radchenko, J. Symersky, R. Nie, and Y. Guo. (2013). Structural insights into H+-coupled multidrug extrusion by a MATE transporter. Nat Struct Mol Biol 20: 1310-1317.

Ma, Y., D. Li, Y. Zhong, X. Wang, L. Li, A. Osbourn, W.J. Lucas, S. Huang, and Y. Shang. (2023). Vacuolar MATE/DTX protein-mediated cucurbitacin C transport is co-regulated with bitterness biosynthesis in cucumber. New Phytol. [Epub: Ahead of Print]

Marinova, K., L. Pourcel, B. Weder, M. Schwarz, D. Barron, J.M. Routaboul, I. Debeaujon, and M. Klein. (2007). The Arabidopsis MATE transporter TT12 acts as a vacuolar flavonoid/H+ -antiporter active in proanthocyanidin-accumulating cells of the seed coat. Plant Cell 19: 2023-2038.

Marolda, C.L., B. Li, M. Lung, M. Yang, A. Hanuszkiewicz, A.R. Rosales, and M.A. Valvano. (2010). Membrane topology and identification of critical amino acid residues in the Wzx O-antigen translocase from Escherichia coli O157:H4. J. Bacteriol. 192: 6160-6171.

Marolda, C.L., L.D. Tatar, C. Alaimo, M. Aebi, and M.A. Valvano. (2006). Interplay of the Wzx translocase and the corresponding polymerase and chain length regulator proteins in the translocation and periplasmic assembly of lipopolysaccharide o antigen. J. Bacteriol. 188: 5124-5135.

Maron, L.G., C.T. Guimarães, M. Kirst, P.S. Albert, J.A. Birchler, P.J. Bradbury, E.S. Buckler, A.E. Coluccio, T.V. Danilova, D. Kudrna, J.V. Magalhaes, M.A. Piñeros, M.C. Schatz, R.A. Wing, and L.V. Kochian. (2013). Aluminum tolerance in maize is associated with higher MATE1 gene copy number. Proc. Natl. Acad. Sci. USA 110: 5241-5246.

Matsumoto, T., T. Kanamoto, M. Otsuka, H. Omote, and Y. Moriyama. (2008). Role of glutamate residues in substrate recognition by human MATE1 polyspecific H+/organic cation exporter. Am. J. Physiol. Cell Physiol. 294: C1074-1078.

McAleese, F., P. Petersen, A. Ruzin, P.M. Dunman, E. Murphy, S.J. Projan, and P.A. Bradford. (2005). A novel MATE family efflux pump contributes to the reduced susceptibility of laboratory-derived Staphylococcus aureus mutants to tigecycline. Antimicrob. Agents Chemother. 49: 1865-1871.

McAnulty, M.J. and T.K. Wood. (2014). YeeO from Escherichia coli exports flavins. Bioengineered 5: 386-392.

Mitton-Fitzgerald, E., C.M. Gohr, B. Bettendorf, and A.K. Rosenthal. (2016). The Role of ANK in Calcium Pyrophosphate Deposition Disease. Curr Rheumatol Rep 18: 25.

Miyauchi, H., S. Moriyama, T. Kusakizako, K. Kumazaki, T. Nakane, K. Yamashita, K. Hirata, N. Dohmae, T. Nishizawa, K. Ito, T. Miyaji, Y. Moriyama, R. Ishitani, and O. Nureki. (2017). Structural basis for xenobiotic extrusion by eukaryotic MATE transporter. Nat Commun 8: 1633.

Mohamed, Y.F. and M.A. Valvano. (2014). A Burkholderia cenocepacia MurJ (MviN) homolog is essential for cell wall peptidoglycan synthesis and bacterial viability. Glycobiology 24: 564-576.

Morita, M., N. Shitan, K. Sawada, M.C. Van Montagu, D. Inzé, H. Rischer, A. Goossens, K.M. Oksman-Caldentey, Y. Moriyama, and K. Yazaki. (2009). Vacuolar transport of nicotine is mediated by a multidrug and toxic compound extrusion (MATE) transporter in Nicotiana tabacum. Proc. Natl. Acad. Sci. USA 106: 2447-2452.

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.

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.

Mousa, J.J., Y. Yang, S. Tomkovich, A. Shima, R.C. Newsome, P. Tripathi, E. Oswald, S.D. Bruner, and C. Jobin. (2016). MATE transport of the E. coli-derived genotoxin colibactin. Nat Microbiol 1: 15009.

Müller, F., J. König, H. Glaeser, I. Schmidt, O. Zolk, M.F. Fromm, and R. Maas. (2011). Molecular mechanism of renal tubular secretion of the antimalarial drug chloroquine. Antimicrob. Agents Chemother. 55: 3091-3098.

Nigam, S.K. (2015). What do drug transporters really do? Nat Rev Drug Discov 14: 29-44.

Nishino, K. and A. Yamaguchi. (2001). Analysis of a complete library of putative drug transporter genes in Escherichia coli. J. Bacteriol. 183: 5803-5812.

Nürnberg, P., H. Thiele, D. Chandler, W. Höhne, M.L. Cunningham, H. Ritter, G. Leschik, K. Uhlmann, C. Mischung, K. Harrop, J. Goldblatt, Z.U. Borochowitz, D. Kotzot, F. Westermann, S. Mundlos, H.S. Braun, N. Laing, and S. Tinschert. (2001). Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia. Nat. Genet. 28: 37-41.

Ohta, K.Y., K. Inoue, Y. Hayashi, and H. Yuasa. (2006). Molecular identification and functional characterization of rat multidrug and toxin extrusion type transporter 1 as an organic cation/H+ antiporter in the kidney. Drug Metab Dispos 34: 1868-1874.

Ongley, S.E., J.J. Pengelly, and B.A. Neilan. (2016). Elevated Na+ and pH influence the production and transport of saxitoxin in the cyanobacteria Anabaena circinalis AWQC131C and Cylindrospermopsis raciborskii T3. Environ Microbiol 18: 427-438.

Ormazabal, V., F.A. Zuñiga, E. Escobar, C. Aylwin, A. Salas-Burgos, A. Godoy, A.M. Reyes, J.C. Vera, and C.I. Rivas. (2010). Histidine residues in the Na+-coupled ascorbic acid transporter-2 (SVCT2) are central regulators of SVCT2 function, modulating pH sensitivity, transporter kinetics, Na+ cooperativity, conformational stability, and subcellular localization. J. Biol. Chem. 285: 36471-36485.

Otsuka, M., M. Yasuda, Y. Morita, C. Otsuka, T. Tsuchiya, H. Omote, and Y. Moriyama. (2005). Identification of essential amino acid residues of the NorM Na+/multidrug antiporter in Vibrio parahaemolyticus. J. Bacteriol. 187: 1552-1558.

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.

Pérez-Burgos, M., I. García-Romero, J. Jung, E. Schander, M.A. Valvano, and L. Søgaard-Andersen. (2020). Characterization of the Exopolysaccharide Biosynthesis Pathway in Myxococcus xanthus. J. Bacteriol. 202:.

Radchenko, M., J. Symersky, R. Nie, and M. Lu. (2015). Structural basis for the blockade of MATE multidrug efflux pumps. Nat Commun 6: 7995.

Rekhter, D., D. Lüdke, Y. Ding, K. Feussner, K. Zienkiewicz, V. Lipka, M. Wiermer, Y. Zhang, and I. Feussner. (2019). Isochorismate-derived biosynthesis of the plant stress hormone salicylic acid. Science 365: 498-502.

Rodríguez-Beltrán, J., A. Rodríguez-Rojas, J.R. Guelfo, A. Couce, and J. Blázquez. (2012). The Escherichia coli SOS gene dinF protects against oxidative stress and bile salts. PLoS One 7: e34791.

Roschzttardtz, H., M. Séguéla-Arnaud, J.F. Briat, G. Vert, and C. Curie. (2011). The FRD3 citrate effluxer promotes iron nutrition between symplastically disconnected tissues throughout Arabidopsis development. Plant Cell 23: 2725-2737.

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.

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.

Ruiz, N. (2008). Bioinformatics identification of MurJ (MviN) as the peptidoglycan lipid II flippase in Escherichia coli. Proc. Natl. Acad. Sci. USA 105: 15553-15557.

Saad, K.R., G. Kumar, B. Puthusseri, S.M. Srinivasa, P. Giridhar, and N.P. Shetty. (2023). Genome-wide identification of MATE, functional analysis and molecular dynamics of DcMATE21 involved in anthocyanin accumulation in Daucus carota. Phytochemistry 210: 113676.

Sailer, C., A. Babst-Kostecka, M.C. Fischer, S. Zoller, A. Widmer, P. Vollenweider, F. Gugerli, and C. Rellstab. (2018). Transmembrane transport and stress response genes play an important role in adaptation of Arabidopsis halleri to metalliferous soils. Sci Rep 8: 16085.

Schlunk I., Krause K., Wirth S. and Kothe E. (2015). A transporter for abiotic stress and plant metabolite resistance in the ectomycorrhizal fungus Tricholoma vaccinum. Environ Sci Pollut Res Int. 22(24):19384-93.

Seo, P.J., J. Park, M.J. Park, Y.S. Kim, S.G. Kim, J.H. Jung, and C.M. Park. (2012). A Golgi-localized MATE transporter mediates iron homoeostasis under osmotic stress in Arabidopsis. Biochem. J. 442: 551-561.

Sham, L.T., E.K. Butler, M.D. Lebar, D. Kahne, T.G. Bernhardt, and N. Ruiz. (2014). Bacterial cell wall. MurJ is the flippase of lipid-linked precursors for peptidoglycan biogenesis. Science 345: 220-222.

Shitan, N., S. Minami, M. Morita, M. Hayashida, S. Ito, K. Takanashi, H. Omote, Y. Moriyama, A. Sugiyama, A. Goossens, M. Moriyasu, and K. Yazaki. (2014). Involvement of the leaf-specific multidrug and toxic compound extrusion (MATE) transporter Nt-JAT2 in vacuolar sequestration of nicotine in Nicotiana tabacum. PLoS One 9: e108789.

Shoji, T., K. Inai, Y. Yazaki, Y. Sato, H. Takase, N. Shitan, K. Yazaki, Y. Goto, K. Toyooka, K. Matsuoka, and T. Hashimoto. (2009). Multidrug and toxic compound extrusion-type transporters implicated in vacuolar sequestration of nicotine in tobacco roots. Plant Physiol. 149: 708-718.

Soldo, B., V. Lazarevic, M. Pagni, and D. Karamata. (1999). Teichuronic acid operon of Bacillus subtilis 168. Molec. Microbiol. 31: 795-805.

Song, H.X., A.M. Ping, M.X. Sun, X.H. Qi, M.Y. Gao, X.Y. Xu, Z.J. Zhu, M.L. Li, and L.P. Hou. (2017). Identification of genes related to floral organ development in pak choi by expression profiling. Genet Mol Res 16:.

Soto-Liebe, K., M.A. Méndez, L. Fuenzalida, B. Krock, A. Cembella, and M. Vásquez. (2012). PSP toxin release from the cyanobacterium Raphidiopsis brookii D9 (Nostocales) can be induced by sodium and potassium ions. Toxicon 60: 1324-1334.

Soto-Liebe, K., X.A. López-Cortés, J.J. Fuentes-Valdes, K. Stucken, F. Gonzalez-Nilo, and M. Vásquez. (2013). In silico analysis of putative paralytic shellfish poisoning toxins export proteins in cyanobacteria. PLoS One 8: e55664.

Su, X.Z., J. Chen, T. Mizushima, T. Kuroda, and T. Tsuchiya. (2005). AbeM, an H+-coupled Acinetobacter baumannii multidrug efflux pump belonging to the MATE family of transporters. Antimicrob. Agents Chemother. 49: 4362-4364.

Sun, X., E.M. Gilroy, A. Chini, P.L. Nurmberg, I. Hein, C. Lacomme, P.R. Birch, A. Hussain, B.W. Yun, and G.J. Loake. (2011). ADS1 encodes a MATE-transporter that negatively regulates plant disease resistance. New Phytol 192: 471-482.

Szeri, F., F. Niaziorimi, S. Donnelly, N. Fariha, M. Tertyshnaia, D. Patel, S. Lundkvist, and K. van de Wetering. (2022). The Mineralization Regulator ANKH Mediates Cellular Efflux of ATP, Not Pyrophosphate. J Bone Miner Res 37: 1024-1031.

Takanashi, K., K. Yokosho, K. Saeki, A. Sugiyama, S. Sato, S. Tabata, J.F. Ma, and K. Yazaki. (2013). LjMATE1: a citrate transporter responsible for iron supply to the nodule infection zone of Lotus japonicus. Plant Cell Physiol. 54: 585-594.

Tanaka, Y., C.J. Hipolito, A.D. Maturana, K. Ito, T. Kuroda, T. Higuchi, T. Katoh, H.E. Kato, M. Hattori, K. Kumazaki, T. Tsukazaki, R. Ishitani, H. Suga, and O. Nureki. (2013). Structural basis for the drug extrusion mechanism by a MATE multidrug transporter. Nature 496: 247-251.

Tanaka, Y., S. Iwaki, A. Sasaki, and T. Tsukazaki. (2021). Crystal structures of a nicotine MATE transporter provide insight into its mechanism of substrate transport. FEBS Lett. [Epub: Ahead of Print]

Tanaka, Y., S. Iwaki, and T. Tsukazaki. (2017). Crystal Structure of a Plant Multidrug and Toxic Compound Extrusion Family Protein. Structure 25: 1455-1460.e2.

Tanihara, Y., S. Masuda, T. Sato, T. Katsura, O. Ogawa, and K. Inui. (2007). Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H+-organic cation antiporters. Biochem Pharmacol 74: 359-371.

Thompson, E.P., C. Wilkins, V. Demidchik, J.M. Davies, and B.J. Glover. (2010). An Arabidopsis flavonoid transporter is required for anther dehiscence and pollen development. J Exp Bot 61: 439-451.

Tocci, N., F. Iannelli, A. Bidossi, M.L. Ciusa, F. Decorosi, C. Viti, G. Pozzi, S. Ricci, and M.R. Oggioni. (2013). Functional analysis of pneumococcal drug efflux pumps associates the MATE DinF transporter with quinolone susceptibility. Antimicrob. Agents Chemother. 57: 248-253.

Vanni, S., P. Campomanes, M. Marcia, and U. Rothlisberger. (2012). Ion binding and internal hydration in the multidrug resistance secondary active transporter NorM investigated by molecular dynamics simulations. Biochemistry 51: 1281-1287.

Vasseur P., C. Soscia, R. Voulhoux, and A. Filloux. (2007). PelC is a Pseudomonas aeruginosa outer membrane lipoprotein of the OMA family of proteins involved in exopolysaccharide transport. Biochimie. 89(8): 903-915.

Vasudevan, P., J. McElligott, C. Attkisson, M. Betteken, and D.L. Popham. (2009). Homologues of the Bacillus subtilis SpoVB protein are involved in cell wall metabolism. J. Bacteriol. 191: 6012-6019.

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.

Vujica, L., J. Lončar, L. Mišić, B. Lučić, K. Radman, I. Mihaljević, B. Bertoša, J. Mesarić, M. Horvat, and T. Smital. (2023). Environmental contaminants modulate transport activity of zebrafish (Danio rerio) multidrug and toxin extrusion protein 3 (Mate3/Slc47a2.1). Sci Total Environ 901: 165956. [Epub: Ahead of Print]

Wang, R., X. Liu, S. Liang, Q. Ge, Y. Li, J. Shao, Y. Qi, L. An, and F. Yu. (2015). A subgroup of MATE transporter genes regulates hypocotyl cell elongation in Arabidopsis. J Exp Bot 66: 6327-6343.

Watanabe, M., S. Otagaki, S. Matsumoto, and K. Shiratake. (2022). Genome-Wide Analysis of Multidrug and Toxic Compound Extruction Transporters in Grape. Front Plant Sci 13: 892638.

Whitfield, C. and I.S. Roberts. (1999). Structure, assembly and regulation of expression of capsules in Escherichia coli. Mol. Microbiol. 31: 1307-1319.

Yang, S., C.R. Lopez, and E.L. Zechiedrich. (2006). Quorum sensing and multidrug transporters in Escherichia coli. Proc. Natl. Acad. Sci. USA 103: 2386-2391.

Yang, Y., Z. Zhang, P. Li, W. Kong, X. Liu, and L. Liu. (2021). A Whole-Body Physiologically Based Pharmacokinetic Model Characterizing Interplay of OCTs and MATEs in Intestine, Liver and Kidney to Predict Drug-Drug Interactions of Metformin with Perpetrators. Pharmaceutics 13:.

Yonezawa, A., S. Masuda, S. Yokoo, T. Katsura, and K. Inui. (2006). Cisplatin and oxaliplatin, but not carboplatin and nedaplatin, are substrates for human organic cation transporters (SLC22A1-3 and multidrug and toxin extrusion family). J Pharmacol Exp Ther 319: 879-886.

Young, K.D. (2014). Microbiology. A flipping cell wall ferry. Science 345: 139-140.

Yuan, J., Z. Qiu, Y. Long, Y. Liu, J. Huang, J. Liu, and Y. Yu. (2023). Functional identification of PhMATE1 in flower color formation in petunia. Physiol Plant e13949. [Epub: Ahead of Print]

Zakrzewska, S., A.R. Mehdipour, V.N. Malviya, T. Nonaka, J. Koepke, C. Muenke, W. Hausner, G. Hummer, S. Safarian, and H. Michel. (2019). Inward-facing conformation of a multidrug resistance MATE family transporter. Proc. Natl. Acad. Sci. USA. [Epub: Ahead of Print]

Zhang X., He X., Baker J., Tama F., Chang G. and Wright SH. (2012). Twelve transmembrane helices form the functional core of mammalian MATE1 (multidrug and toxin extruder 1) protein. J Biol Chem. 287(33):27971-82.

Zhang, H., F.G. Zhao, R.J. Tang, Y. Yu, J. Song, Y. Wang, L. Li, and S. Luan. (2017). Two tonoplast MATE proteins function as turgor-regulating chloride channels in Arabidopsis. Proc. Natl. Acad. Sci. USA 114: E2036-E2045.

Zhang, H., H. Zhu, Y. Pan, Y. Yu, S. Luan, and L. Li. (2014). A DTX/MATE-type transporter facilitates abscisic acid efflux and modulates ABA sensitivity and drought tolerance in Arabidopsis. Mol Plant 7: 1522-1532.

Zhao, J. and R.A. Dixon. (2009). MATE transporters facilitate vacuolar uptake of epicatechin 3''-O-glucoside for proanthocyanidin biosynthesis in Medicago truncatula and Arabidopsis. Plant Cell 21: 2323-2340.

Zhou, G., E. Delhaize, M. Zhou, and P.R. Ryan. (2013). The barley MATE gene, HvAACT1, increases citrate efflux and Al3+ tolerance when expressed in wheat and barley. Ann Bot 112: 603-612.

2.A.66.1 The Multi Antimicrobial Extrusion (MATE) Family


TC#NameOrganismal TypeExample

Drug:Na+ antiporter (norfloxacin, ethidium, kanamycin, ciprofloxin, streptomycin efflux pump), NorM. Transport is dependent on Na+, and several essential residiues have been identified. Specifically, Asp32, Glu251, and Asp367 are involved in the Na+-dependent drug transport process. (Otsuka et al. 2005).


NorM of Vibrio parahaemolyticus (O82855)


Na -dependent cationic drug (ethidium, acriflavine, 2-N-methyl ellipticinium, berberine, norfloxacin, ciprofloxacin, rhodamine 6G, crystal violet, doxorubicin, novobiocin, enoxacin, and tetraphenylphosphonium chloride) efflux pump, NorM (Long et al. 2008).  3-d structures of the N. gonorrheae NorM transporter (96% identical to the N. miningitidis protein) have been solved complexed with three different substrates in a multidrug cavity and Cs (4HUN; Lu et al. 2013).  Lu et al. an identified an uncommon cation-π interaction in the Na+-binding site located outside the drug-binding cavity and validated the biological relevance of both the substrate- and cation-binding sites by conducting drug resistance and transport assays. Additionally, they observed a potential rearrangement of at least two transmembrane helices upon Na+-induced drug export. They suggested that Na+ triggers multidrug extrusion by inducing protein conformational changes rather than by directly competing for the substrate-binding amino acids.  However, see 2.A.66.1.32 where the opposite was concluded for a homologue that functions by drug:H+ antiport.


NorM of Neisseria meningitidis


The Enhanced Disease Susceptibility Protein (EDS5), also called the Salicylate Induction Deficient (Sid1) protein; a chloroplast isochorismate exporter that exports isochorismate from the plastid to the cytosol (Rekhter et al. 2019).


EDS5 of Arabidopsis thaliana chloroplasts

2.A.66.1.12Drug:H+ antiporter (benzalkonium chloride, fluoroquinolone, ethidium bromide, acriflavin, tetraphenylphosphonium chloride efflux pump), PmpM (He et al., 2004)BacteriaPmpM of Pseudomonas aeruginosa (Q9I3Y3)

Drug (monovalent and divalent biocides; fluoroquinolones including norfloxacin and ciprofloxacin) efflux pump, SvrA (MepA) (Kaatz et al., 2006). Also exports tigecycline (McAleese et al., 2005).


SvrA of Staphylococcus aureus (Q2G140)


Human MATE1 electroneutral organocation:H antiporter (transports tetraethylammonium, TEA, and cimetidine as well as cisplatin and oxaliplatin) (Yonezawa et al., 2006). MATE1 also exports chloroquine across the luminal membrane (Müller et al., 2011). It has an established 13 TMS topology with the "extra" TMS in an extracellular C-terminal region that is not essential for function (Zhang et al., 2012).  Also exports 1-methyl-4-phenylpyridinium (MPP), N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acyclovir, cimetidine, ganciclovir and the zwitterionic cephalosporin, cephalexin and cephradin (Nigam 2015). Seems to also play a role in the uptake of oxaliplatin (a platinum anticancer agent). Able to transport paraquat (PQ or N,N-dimethyl-4-4'-bipiridinium); a widely used herbicid. Responsible for the secretion of cationic drugs across the brush border membranes (Tanihara et al. 2007).


SLC47A1 of Homo sapiens

2.A.66.1.15Electroneutral Multidrug & Toxin Extrusion-1 organic cation:H+ antiporter (MATE-1). Exports tetraethylammonium (TEA) and cimetidine, and probably other organic cations, such as 1-methyl-4-phenylpyridinium, amiloride, imipramine, and quinidine (Ohta et al., 2006).


MATE-1 of Rattus norvegicus (Q5I0E9)

2.A.66.1.16Electroneutral organic cation:H+ antiporter MATE2 (Hiasa et al., 2007). 50% identical to MATE1; 2.A.66.1.15.


MATE2 of Mus musculus (Q3V050)


MATE efflux pump, MatE


MatE of Tetrahymena thermophila

2.A.66.1.18MATE1b (mediates tetraethylammonium (TEA) uptake with properties similar to that of mMATE1; localized in renal brush border membranes (Kobara et al., 2008)).

MATE1b of Mus musculus (Q8K0H1)

2.A.66.1.19JAT1 (transports nicotine and anabasine, and other alkaloids, such as hyoscyamine and berberine, but not flavonoids) (Morita et al., 2009).


JAT1 of Nicotiana tabacum (B7ZGMO)


Drug:Na+ antiporter, VcmA (exports norfloxacin, ciprofloxacin, ofloxacin, daunomycin, doxorubicin, streptomycin, kanamycin, ethidium, 4',6'-diamidino-2-phenylindole, Hoechst 33342 and acriflavin). The 3-d x-ray structure (3.65Å resolution) is available (He et al., 2010). Ion binding and internal hydration have been studied by molecular dynamics simulations (Vanni et al., 2012).  NorM simultaneously couples drug export to the sodium-motive force and the proton-motive force. Residues involved and protein regions that play important roles in Na+ or H+ binding have been identified (Jin et al. 2014). Na+- and H+-driven conformational changes are facilitated by a network of polar residues in the N-terminal domain cavity, whereas conserved carboxylates buried in the C-terminal domain are critical for stabilizing the drug-bound state. These results establish the role of ion-coupled conformational dynamics in the functional cycle and implicate H+ in the doxorubicin release mechanism (Claxton et al. 2018).


VcmA (NorM) of Vibrio cholerae non-01


Multidrug and Toxin Extrusion Protein 2, MATE-2 (catalyzes drug:H+ antiport; broad specificity, low affinity (50-3000 μM) for organic cationic and anionic compounds (Tanihara et al., 2007)).

AnimalsSLC47A2 of Homo sapiens

H+-coupled multidrug efflux pump, AbeM (most like 2.A.66.1.2, NorM of Vibrio cholerae) (Su et al., 2005). Exports norfloxacin, ciprofloxacin, DAPI, acriflavin, Hoechst 33342, daunorubicin, doxorubicin, and ethidium (Su et al., 2005) as well as carbapenem (AlQumaizi et al. 2022).


AbeM of Acinetobacter baumannii (Q5FAM9)


Quinolone:H+ antiporter, EmmdR. Substates include benzalkonium chloride, norfloxacin, ciprofloxacin, levofloxacin, ethidium bromide, acriflavine, rhodamine 6G and trimethoprim.


EmmdR of Enterobacter cloacae (D5CJ69)


MDR efflux pump, YeeO (NorA) (81.8% identical to 2.A.66.1.22). Transports dipeptides (see 2.A.1.2.55) (Hayashi et al., 2010).  Also exports both flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). However, significant amounts of flavins were trapped intracellularly when YeeO was produced. Wild-type E. coli secretes 3 flavins (riboflavin, FMN, and FAD), so it must have additional flavin transporters (McAnulty and Wood 2014).


YeeO of E. coli (P76352)


FRD3 efflux pump for citrate; involved in iron homeostasis. Localized to the pericycle and vascular cylinder of roots; loads citrate into xylem tissues facilitating iron transport from the roots to the shoots; null mutants are sterile (Green and Rogers 2004; Roschzttardtz et al., 2011; Durrett et al., 2007).


FRD3 of Arabidopsis thaliana (Q9SFB0)


Probable multidrug resistance protein YoeA


YoeA of Bacillus subtilis

2.A.66.1.26Uncharacterized transporter MJ0709ArchaeaMJ0709 of Methanocaldococcus jannaschii
2.A.66.1.27Probable multidrug resistance protein NorM (Multidrug-efflux transporter)Bacteria

NorM of Caulobacter crescentus

2.A.66.1.28Probable multidrug resistance protein NorM (Multidrug-efflux transporter)Bacteria

NorM of Thermotoga maritima


MATE exporter protein


MATE exporter protein of Myxococcus xanthus


Multidrug-resistance efflux pump, NorM (MdtK, NorE or YdhE) (Nishino and Yamaguchi 2001). Exports chloramphenicol, norfloxacin, enoxacin, phosphomycin, doxorubicin, trimethoprim, ethidium, deoxycholate, etc (Long et al., 2008). May also export signals for cell-cell communication (Yang et al., 2006).


NorM (YdhE) of E. coli


Ciprofloxacin export permease, AbeM2


AbeM2 of Acinetobacter baumannii


Ciprofloxacin efflux pump, AbeM4 (Eijkelkamp et al. 2011).


AbeM4 of Acinetobacter baumannii


Multidrug:proton antiporter of the DinF subfamily.  The structure has been solved to 3.2 Å resolution with and without the substrate, Rhodamine 6 G.  The 12 TMSs show asymmetry with a membrane-embedded substrate-binding chamber.  Direct competition between the H+ and the substrate during transport was suggested (Lu et al. 2013).  However, the opposite was suggested for a sodium antiporter (see TC# 2.A.66.1.10).


DinF-like MDR pump of Bacillus halodurans


MDR efflux pump for quinolones (moxifloxacin, ciprofloxacin and levofloxacin) of 456 aas, DinF (Tocci et al. 2013).


DinF of Streptococcus pneumoniae


MATE MDR exporter of 411 aas, SP2065 (Tocci et al. 2013).  Exports novobiocin.


SP2065 of Streptococcus pneumoniae


Citrate-specific transporter of 538 aas, MATE1.  Necessary for iron supply to the nodule infection zone (Takanashi et al. 2013).


MATE1 of Lotus japonicus


Multidrug exporter, DinF, of 457 aas.  Exports various toxic compounds, including antibiotics, phytoalexins, and detergents. Mutants are less virulent on the tomato plant than the wild-type strain (Brown et al. 2007).


DinF of Ralstonia solanacearum (Pseudomonas solanacearum)


Multidrug resistance protein, CdeA of 441 aas.  Exports ethidium bromide, fluoroquinolone and acriflavin but had no effect on susceptibility to the following antibiotics: norfloxacin, ciprofloxacin, gentamicin, erythromycin, tetracyclin, and chloramphenicol (Dridi et al. 2004).  May be a Na+ antiporter.

CdeA of Clostridium difficile

CdeA of Clostridium difficile


Homologue of Mte1 of Tricholomp vaccinum of 588 aas which mediates detoxification of xenobiotics and metal ions such as Cu, Li, Al, and Ni, as well as secondary plant metabolites (Schlunk et al. 2015).


Mte1 homologue of Moniliophthora roreri (Cocoa frosty pod rot fungus) (Crinipellis roreri)


Jasmonate-inducible alkaloid transporter-2, JAT2.Transports nicotine and other alkaloids into the tonoplast vacuole for sequestration (Chen et al. 2015; Shitan et al. 2014).


JAT2 of Nicotiana tabacum


DNA damage-inducible protein F, DinF.  Protects against oxidative stress and bile salts, possibly by pumping relevant compounds out of the cytoplasm (Rodríguez-Beltrán et al. 2012).


DinF of E. coli


Putative MDR or polysaccharide exporter of 514 aas and 12 TMSs


Exporter of Treponema succinifaciens


Na+-coupled multidrug efflux pump, PdrM (Hashimoto et al. 2013). Confers resistance to several antibacterial agents including norfloxacin, acriflavine, and 4',6-diamidino-2-phenylindole (DAPI).


PdrM of Streptococcus pneumoniae


Paralytic shellfish toxin (PST; including saxitoxin (STX)) exporter, SxtM, of 464 aas (Soto-Liebe et al. 2013). These toxins, which block Na+ channels, are produced by cyanobacteria and dinoflagellates, and >30 such natural alkaloids are known (Soto-Liebe et al. 2012).


SxtM of Cylindrospermopsis raciborskii


MATE1 of 563 aas and 12 TMSs.  Involved in aluminum resistance (Maron et al. 2013).

MATE1 of Zea mays (Maize)

Transparent Testa 12 (TT12), also called Protein DETOXIFICATION, is a valuolar transporter of proanthocyanidins (PAs).  It transports these compounds from the cytoplasm into the vacuolar lumen (Gao et al. 2015).

TT12 of Gossypium hirsutum (Upland cotton) (Gossypium mexicanum)


Damage inducible multidrug resistance protein F, DinF of 455 aas and 12 TMSs. An x-ray structure is available (Radchenko et al. 2015).

DinF of Pyrococcus furiosus


Saxitoxin, STX, exporter, SxtF; also exports fluoroquinolone, suggesting it is an MDR pump (Ongley et al. 2016).

SxtF of Cylindrospermopsis raciborskii


Saxitoxin, STX, exporter, SxtM; also exports fluoroquinolone, suggesting it is an MDR pump (Ongley et al. 2016).

SxtM of Aphanizomenon sp. NH-5 (Anabaena circinalis)


MATE transporter. ClbM, of 479 aas and 12 TMSs, ClbM.  Exports precolibactin, a genotoxin made by a polyketide complex in E. coli, that generates double strand breaks in the DNA (Mousa et al. 2016). The 3-d structure is available (PDB# 4Z3N).

ClbM of E. coli


MATE family transporter of 475 aas and 12 TMSs in a 6 + 6 TMS pseudosymmetic arrangement.  The 3-d structure has been determined at 2.9 Å resolution (Tanaka et al. 2017). The protein possesses a negatively charged internal pocket with an outward-facing shape. This structure was determined for the C. sativa orthologue of the C. rubella protein, the sequence of which is 94% identical to the one provided here.

CasMATE of Capsella rubella


Ethionine resistance protein, ERC1, of 581 aas and 11 TMSs in a 6 + 5 TMS arrangement. It catalyzes S-adenosyl methionine (SAM) accumulation in Sake yeast (Kanai et al. 2017).


ERC1 (YHR032w) of Saccharomyces cerevisiae


Detoxification protein, DTX35, of 614 aas and 12 TMSs, also called FLOWER FLAVONOID TRANSPORTER (FFT), encodes a MATE family transporter in Arabidopsis thaliana. FFT (AtDTX35) is highly transcribed in floral tissues, the transcript being localized to epidermal guard cells, including those of the anthers, stigma, siliques and nectaries (Thompson et al. 2010). The absence of FFT affects flavonoid levels in the plant. Moreover, root growth, seed development and germination, and pollen development, release and viability are all affected (Thompson et al. 2010). Also functions as a chloride channel, which, together with DTX33, is essential for turgor regulation (Zhang et al. 2017). Involved in floral development (Song et al. 2017). Dietary ilavonoid absorption facilitates the development and utilization of functional foods or dietary supplements (Fu et al. 2024).

DTX35 of Arabidopsis thaliana


Multidrug resistance efflux pump, Detoxification 48, DTX48. Functions as a multidrug and toxin extrusion transporter. Contributes to iron homeostasis during stress responses and senescence (Seo et al. 2012). Overexpression of DTX48 alters shoot developmental programs leading to a loss of apical dominance phenotype (Wang et al. 2015).

DTX48 of Arabidopsis thaliana (Mouse-ear cress)


Detoxification protein 14, DTX14, of 485 aas and 12 TMSs.  This MATE family (MOP superfamily) proter extrduces xenobiotics from the cell.  It's 3-d structure is known to 2.6 Å resolution (Miyauchi et al. 2017). Its carboxy-terminal lobe (C-lobe) contains an extensive hydrogen-bonding network with well-conserved acidic residues, as demonstrated by structure-based mutational analyses. The analyses suggest that the transport mechanism involves a structural change of transmembrane helix 7, induced by the formation of a hydrogen-bonding network upon the protonation of the conserved acidic residue in the C-lobe (Miyauchi et al. 2017).

DTX14 of Arabidopsis thaliana


Citrate exporter, MATE1 or DETOXIFICATION, of 553 aas and 12 probable TMSs.  It's activity gives rise to aluminum (Al3+) tolerance (Garcia-Oliveira et al. 2014). 98% identical to the rye and barley orthologs (Zhou et al. 2013).

MATE1 of Tritium aestivum (Wheat)


MATE2 or Detoxification 47 (DTX47) of 543 aas and 12 TMSs.  The orthologs from several plants have been sequenced and characterized (i.e., wheat; potato) (Li et al. 2018).  This protein may be a citrate and salicylate exporter and promote resistance to aluminum (Al3+) (Garcia-Oliveira et al. 2018). It may also transport cyanidine-3-glucoside (anthocyanin) (Saad et al. 2023).

MATE2 of Arabidopsis thaliana


MATE drug:sodium symporter of 461 aas and 12 TMSs.  Several crystal structures are known (3VVO, 3VVP, 3VVR, 3VVS, 6FHZ, 6GWH) in several distinct apo-form conformations, and in complexes with a derivative of the antibacterial drug norfloxacin and three in vitro selected thioether-macrocyclic peptides, at 1.8 - 3.0 Å resolutions. The structures, combined with functional analyses, show that the protonation of Asp 41 on the N-terminal lobe induces the bending of TMS1, which in turn collapses the N-lobe cavity, thereby extruding the substrate drug to the extracellular space. Moreover, the macrocyclic peptides bind the central cleft in distinct manners, which correlate with their inhibitory activities (Tanaka et al. 2013). The  Na+-binding site, in the N-lobe of this transporter, is selective against K+, weakly specific against H+, and broadly conserved among prokaryotic MATEs (Ficici et al. 2018). The inward-facing state was obtained after crystallization in the presence of native lipids (Zakrzewska et al. 2019). The transition from the outward-facing state to the inward-facing state involves rigid body movements of TMSs 2-6 and 8-12 to form an inverted V, facilitated by a loose binding of TMS1 and TMS7 to their respective bundles and their conformational flexibility. The inward-facing structure of PfMATE in combination with the outward-facing one supports an alternating access mechanism for MATE family transporters ()Zakrzewska et al. 2019.

MOP superfamily transporter of Pyrococcus furiosus


MATE transporter,DETOXIFICATION 4, DTX4 or At2g04070, of 476 aas and 12 TMSs. May transport alkaloids, heavy metals, bile salts, organic acids amd organic amines (Li et al. 2018).

DTX4 of Arabidopsis thaliana (Mouse-ear cress)


DETOXIFICATION 41, DTX41, TDS3, TT12 of 507 aas and 12 TMSs. Acts as a flavonoid/H+-antiporter that controls the vacuolar sequestration of flavonoids in the seed coat endothelium (Debeaujon et al. 2001; Marinova et al. 2007).  May also transport the anthocyanin cyanidin-3-O-glucoside (Marinova et al. 2007) and epicatechin 3'-O-glucoside (Zhao and Dixon 2009). These results have been confirmed in Daucus carota and other plants (Saad et al. 2023). A similar protein in Petunia hybrida, PhMATE1 transports antocyanins (flavanoids involved in flower color) and has 11 TMSs (Yuan et al. 2023).  Soybean oil may facilitate interactions with flavonoids to form more stable and compact fatty acid-flavonoid complexes (Fu et al. 2024).

DTX41 of Arabidopsis thaliana (Mouse-ear cress)


Detoxification-50, DTX50, of 505 aas and 12 TMSs. It catalyzes abscisic acid efflux and modulates ABA sensitivity as well as drought tolerance (Zhang et al. 2014). It may also function in heavy metal ion and drug export (Sailer et al. 2018; Li et al. 2002).  Its ortholog in cucumber, the vacuolar MATE/DTX protein, exports cucurbitacin C, and its gene is co-regulated with bitterness biosynthesis in cucumber (Ma et al. 2023).

DTX50 of Arabidopsis thaliana


The Activated Disease Susceptibility 1, ADS1 (DTX51, ABS3, ADP1, NIC4), putative exporter of 532 aas and 12 TMSs.  ADS1 negatively regulates the accumulation of the plant immune activator salicylic acid as well as cognate Pathogenesis-Related 1 (PR1) gene expression which influences microbial pathogenesis (Sun et al. 2011). It may be a salicylate exporter.

ADS1 of Arabidopsis thaliana


Drug (norfloxacin, ciprofoxacin, ethidium, tetramethylammonium, pyrrolidinone, polyvinylpyrrolidone) resistance pump, Alf5 or DTOXIFICATION 19, DTX19, of 427 aas and 12 TMSs.  Note:  A. thaliana has 56 MATE transporters (Takanashi et al. 2013).


Alf5 of Arabidopsis thaliana


Probable multidrug resistence efflux pump of 452 aas and 12 TMSs in a 6 + 6 TMS arrangement.

MDR pump of Candidatus Prometheoarchaeum syntrophicum


Vacuolar nicotine exporter (from the cytoplasm into the vacuole), the NtMATE2 transporter, also designated the DETOXIFICATION 40-like protein, of 500 aas and 12 TMSs in a 6 + 6 TMS arrangement. NtMATE2 is located in the vacuole membrane of the tobacco plant root and is involved in the transport of nicotine, a secondary or specialized metabolic compound in Solanaceae ((Shoji et al. 2009). The crystal structures of NtMATE2 in its outward-facing forms have been determined (Tanaka et al. 2021). The overall structure has a bilobate V-shape with pseudo-symmetrical assembly of the N- and C-lobes. In one crystal structure, the C-lobe cavity of NtMATE2 interacts with an unidentified molecule that may mimic a substrate. NtMATE2-specific conformational transitions imply that an unprecedented movement of the transmembrane alpha-helix 7 (TMS7) is related to the release of the substrate into the vacuolar lumen (Tanaka et al. 2021).

NtMATE2 of Nicotiana tabacum (common tobacco)


MATE family toxin extrusion protein 3 (Mate3/Slc47a2.1) of 590 aas and 13 TMSs in a 2 + 4 + 2 + 4 + 1 (C-terminal) TMSs.  The 2 + 4 TMSs are repeated twice and comprise the usual 6 TMS repeat unit. its gene is highly expressed in the kidneys, intestine, testes, and brain of males. It interacts with xenobiotic compounds, suggesting a role in the efflux of toxic compounds (Vujica et al. 2023). These autors also showed that this porter interacts with and may export dozens of polutants in an aqueous environment.

MATE family protein of Danio rerio


MATE efflux family protein, DTX5 or MATE5, of 479 aas and 12 TMSs, preferentially transports different astringencies of proanthocyanidins (PAs) in persimmon (Liu et al. 2023).  DkDTX5/MATE5 binds PA precursors via Ser-84, demostrating an association between the transporter and PA variation (Liu et al. 2023).

MATE5 of Triticum urartu


Cationic drug (4',6'-diamidino-2-phenylindole (DAPI), tetraphenylphosphonium (TPP), acriflavin, ethidium):Na+ antiporter, VmrA of 447 aas and 12 TMSs.


VmrA of Vibrio parahaemolyticus


Plasma membrane efflux pump, AtDTX1, for plant alkaloids, drugs (e.g., norfloxacin), antibiotics and Cd2+ (Li et al. 2002). 


AtDTX1 of Arabidopsis thaliana


Drug (norfloxacin, polymyxin B) resistance efflux pump, NorM, of 462 aas and 12 TMSs.


NorM of Burkholderia vietnamiensis


2.A.66.10 LPS Precursor Flippase (LPS-F) Family


TC#NameOrganismal TypeExample

Wzx isoprenoid-linked O-antigen precursor glycan translocase.  A 12 TMS topology with N- and C-termini in the cytoplasm has been established, and functionally important residues have been identified (Marolda et al. 2010).  A substrate:proton antiport mechanism has been established (Islam et al. 2013). The Wzx/Wzy pathway produces repeat-units of mostly 3-8 sugars on the cytosolic face of the cytoplasmic membrane that is translocated by the Wzx flippase to the periplasmic face and is polymerized by Wzy polymerase to give long-chain polysaccharides (Hong et al. 2023).



Wzx of E. coli O157:H7 str 1125


2.A.66.11 Uncharacterized MOP-11 (U-MOP11) Family



TC#NameOrganismal TypeExample

Uncharacterized protein


Uncharacterized protein of Streptomyces coelicolor


Uncharacterized protein


Uncharacterized protein of Beggiatoa alba


2.A.66.12 Uncharacterized MOP-12 (U-MOP12) Family



TC#NameOrganismal TypeExample

Uncharacterized MOP superfamily member of 506 aas and 14 TMSs. Subfamily 2.A.66.12 may be most closely related to 2.A.66.2, suggesting that these proteins are glycolipid flippases.


U-MOP family 12 member-1 of Myxococcus xanthus


Uncharacterized protein of 452 aas and 12 TMSs.

UP of Parvularcula oceani


Uncharacterized putative flippase of 496 aas and 14 TMSs.

UP of Cyclobacterium lianum


Exopolysaccharide flippase, Wzxeps (MXAN_7416) of 490 aas and 14 TMSs in a 6 + 2 + 6 TMS arrangement. The gene encoding this transporter is adjacent to two genes encoding EpsZ (MXAN_7415; TC# 9.B.18.1.6), a glycosyl transferase that initiates repeat unit synthesis, and an outer membrane exopolysaccharide export protein, Opx or EpsY (MXAN_7417; TC# 1.B.18.3.9)  (Pérez-Burgos et al. 2020).

Wzxeps of Myxococcus xanthus


Uncharacterized MOP superfamily member of 1049 aas and 14 or 15 TMSs


U-MOP family 12 member-2


Uncharacterized MOP superfamily member of 489 aas and 14 TMSs


U-MOP family 12 member-3


Uncharacterized MOP superfamily member of 487 aas and 14 TMSs


U-MOP superfamily protein


Uncharacterized MOP superfamily of 488 aas and 14 TMSs


U-MOP superfamily member


Putative polysaccharide exporter of 449 aas, YghQ.


YghQ of E. coli


The succinoglycan biosynthesis transporter homologue, Mth342


Mth342 of Methanobacterium thermoautotrophicum (O26442)


Putative Wzx flippase of 499 aas and 14 TMSs (Hug et al. 2016).

Wzx of Candidatus Peribacter riflensis


Uncharacterized flippase of 516 aas and 14 TMSs

UP of Cuniculiplasma divulgatum


2.A.66.2 The Polysaccharide Transport (PST) Family


TC#NameOrganismal TypeExample
2.A.66.2.1Lipopolysaccharide (possibly the O-antigen side chain intermediate) exporterGram-negative bacteriaRfbX1 of E. coli
2.A.66.2.10The O-antigent transporter homologue, Mth347ArchaeaMth347 of Methanobacterium thermoautotrophicum(O26447)
2.A.66.2.11Exopolysaccharide exporter, EpsE (Huang and Schell, 1995)BacteriaEpsE of Ralstonia solanacearum (Q45411)

Isoprenoid lipid sugar glycan flippase, Wzx (note: Wzx forms a complex with Wzy and Wzz for assembly of periplasmic O-antigen) (Marolda et al., 2006). Wzx has a 12 TMS topology (Cunneen and Reeves, 2008). WzyE (450aas; 12 TMSs; TC#9.B.128.1.1; B614D1) is called the enterobacterial common antigen (ECA) polysaccharide chain elongation polymerase (Marolda et al., 2006). The structure of Wzz has been determined by cryoEM (Collins et al. 2017).


Wzx of E. coli (Q1L811)

2.A.66.2.13Unknown PST proteinBacteriaUnknown PST protein of Alteromonadales bacterium (A0XZ57)

The 14 TMS SpoVB protein (possibly catalyzes lipid-linked oligosaccharide transport across the cytoplasmic membrane; required for proper cell wall biosynthesis) (Vasudevan et al., 2009).


The SpoVB protein of Bacillus subtilis (Q00758)


Anionic O-antigen (undecaprenyl pyrophosphate-linked anionic O-Ag) subunit flippase, Wzx. Translocates from the inner to the outer leaflets of the inner membrane.  The topology has been studied (Ormazabal et al. 2010).


Wzx of Pseudomonas aeruginosa (G3XD19)


Capsular polysaccharide exporter, CpsU (428aas; 12 TMSs).


CpsU of Streptococcus thermophilus (Q8KUK6)


Sporulation protein YkvU


YkvU of Bacillus subtilis


O-antigen transmembrane translocase, Wzx (Franklin et al. 2011). In S. enterica groups B, D2 and E, Wzx translocation exhibits specificity for the repeat-unit structure, as variants with single sugar differences are translocated with lower efficiency, and little long-chain O antigen is produced. It appears that Wzx translocases are specific for their O antigen for normal levels of translocation (Hong et al. 2012).


Wzx of Salmonella enterica subsp. enterica


O-antigen transmembrane translocase, Wzx (Franklin et al. 2011).  For S. enterica groups B, D2 and E, Wzx translocation exhibits specificity for the repeat-unit structure, as variants with single sugar differences are translocated with lower efficiency, and little long-chain O antigen is produced. It appears that Wzx translocases are specific for their O antigen for normal levels of translocation (Hong et al. 2012).


Wzx of Salmonella typhimurium subsp. houtenae

2.A.66.2.2Probable succinoglycan exporterGram-negative bacteriaExoT of Rhizobium meliloti

PST family homologue of 14 TMSs


Hypothetical protein of Parachlamydia acanthamoebae


Putative polysaccharide transporter


Putative polysaccharide transporter of Leptospira interrogans


Choline-derivatized teichoic acid exporter (flippase), TacF of495 aas.  TacF is responsible for the choline dependent growth phenotype (Damjanovic et al. 2007).


TacF of Streptococcus pneumoniae


Xanthan precursor exporter of 499 aas and 14 TMSs, GumJ (Bianco et al. 2014).


GumJ of Xanthomonas campestris


Putative polysaccharide exporter of 471 aas and 14 TMSs

UP of E. coli


Polysaccharide export protein of 572 aas and 12 TMSs.

PS exporter of Candidatus Beckwithbacteria bacterium


Uncharacterized MOP superfamily member of 456 aas and 12 TMSs.

UP of Parvularcula oceani


Putative flippase of 416 aas and 12 TMSs.

Flippase of Candidatus Marithrix sp. Canyon 246


Uncharacterized protein of 435 aas and 13 TMSs.

UP of Bacillus wiedmannii


Uncharacterized polysaccharide precursor flippase of 476 aas and 14 TMSs.

UP of Clostridium botulinum


Undecaprenol-pyrophosphate O-antigen flippase WzxE

Gram-negative bacteria

WzxE of E. coli (P0AAA7)


Uncharacterized putative carbohydrate-lipid flippase of 486 aas and 14 TMSs in a 6 + 2 + 6 arrangement.

UP of Bacteroides timonensis


Uncharacterized protein of 455 aas and 14 TMSs.

UP of Exiguobacterium sp. KRL4


Probable polysaccharide biosynthesis transport proteinof 433 aas and 12 TMSs [Candidatus Amesbacteria bacterium

PS transporter of Candidatus Amesbacteria bacterium

2.A.66.2.4Probable acetan exporterGram-negative bacteriaAceE of Acetobacter xylinus
2.A.66.2.5Capsular polysaccharide exporterGram-positive bacteriaCapF of Staphylococcus aureus
2.A.66.2.6Teichuronic acid exporter, TuaB (YvhB)Gram-positive bacteriaTuaB of Bacillus subtilis
2.A.66.2.7Lipopolysaccharide (colanic acid) exporter, WzxCGram-negative bacteriaWzxC of E. coli

Exopolysaccharide (Amylovoran) exporter, AmsL

Gram-negative bacteria

AmsL of Erwinia amylovora


2.A.66.3 The Oligosaccharidyl-lipid Flippase (OLF) Family


TC#NameOrganismal TypeExample

The OLF (Rft1 protein) of Saccharomyces cerevisiae.  May play a role in phospholipid flipping from the inner leaflet of the plasma membrane to the outer leaflet (Chauhan et al. 2016).


Rft1 of Saccharomyces cerevisiae

2.A.66.3.2Endoplasmic reticular RFT1 homologueAnimalsRFT1 homologue of Homo sapiens (Q96AA3)
2.A.66.3.3Nuclear division RFT1 homologuePlantsRFT1 homologue of Arabidopsis arenosa (Q6V5B3)

Uncharacterized protein, RFT1 homologue, of 469 aas and 14 TMSs.


RFT1 homologue of Paramecium tetraurelia (A0D5K0)


2.A.66.4 The Mouse Virulence Factor (MVF) Family


TC#NameOrganismal TypeExample

The mouse virulence factor, MviN. (May flip the Lipid II peptidoglycan precursor from the cytoplasmic side of the inner membrane to the periplasmic surface) (Vasudevan et al., 2009). MviN, a putative lipid flippase (Fay and Dworkin, 2009).  In E. coli, MviN is an essential protein which when defective results in the accumulation of polyprenyl diphosphate-N-acetylmuramic acid-(pentapeptide)-N-acetyl-glucosamine.  This may be the peptidoglycan intermediated exported via MviN (Inoue et al. 2008).  It is essential for the growth of several bacteria.


MviN of Salmonella typhimurium (P37169)

2.A.66.4.2Putative virulence factor, MviN (21% identity with 2.A.66.4.1)BacteriaMviN of Borrelia garinii (Q65ZW3)

Peptidoglycan biosynthesis protein MurJ (Ruiz 2008). A 3-d structural model showed a solvent-exposed cavity within the plane of the membrane (Butler et al. 2013). MurJ has 14 TMSs, and specific charged residues localized in the central cavity are essential for function. This structural homology model suggests that MurJ functions as an essential transporter in PG biosynthesis (Butler et al. 2013). Based on an in vivo assay, MurJ is a flippase for the lipid-linked cell wall precursors, polyisoprenoid-linked disaccharide-peptapeptides (Sham et al. 2014).  There is controversy about the role of this porter and FtsW/RodA which on the basis of an in vitro assay, were thought to be flippases for the same intermediate (Young 2014). MurJ, the bacterial lipid II flippase, functions by an alternating-access mechanism (Kumar et al. 2019). The crystal structure of MurJ in a "squeezed" form, distinct from its inward- and outward-facing forms, has been published (Kohga et al. 2022). These authors reported two crystal structures of inward-facing forms from Arsenophonus endosymbiont MurJ and a crystal structure of E. coli MurJ in a "squeezed" form, which lacks a cavity to accommodate the substrate, mainly because of the increased proximity of transmembrane helices 2 and 8. Molecular dynamics simulations support the hypothesis that the squeezed form is an intermediate conformation (Kohga et al. 2022).


MurJ of Escherichia coli


MviN.  Essential for peptidoglycan biosynthesis (Gee et al. 2012).


MviN of Mycobacterium tuberculosis


MviN; LuxO regulated for induction during the early logarithmic and stationary phase of growth (Cao et al. 2010).


MviN of Vibrio alginolyticus


Uncharacterized protein


UP of E. coli


Probable peptidoglycan-lipid II flippase, MurJ or MviN; essential for cell wall synthesis and viability (Mohamed and Valvano 2014).


MurJ of Burkholderia cenocepacia


MurJ (MviV) of 475 aas and 14 TMSs. Kuk et al. 2016 presented a crystal structure of MurJ from Thermosipho africanus in an inward-facing conformation at 2.0-A resolution. A hydrophobic groove is formed by two C-terminal transmembrane helices, which leads into a large central cavity that is mostly cationic. Their results suggest that alternating access is important for MurJ function, which may be applicable to other MOP superfamily transporters (Kuk et al. 2016).

MurJ of Thermosipho africanus


2.A.66.5 The Agrocin 84 Antibiotic Exporter (AgnG) Family


TC#NameOrganismal TypeExample
2.A.66.5.1The agrocin 84 exporter, AgnGBacteriaAgnG of Agrobacterium tumefaciens (Q676G9)
2.A.66.5.2AgnG homologue 1 (433aas; 12TMSs; (2)6 )BacteriaAgnG homologue 1 of Nitrococcus mobilis (A4BUA1)

AgnG homologue 2 (448aas; 12TMSs; (2)6.  Probable polysaccharide exporter.


AgnG homologue 2 of Lyngbya sp. PCC8106 (A0YL48)


2.A.66.6 The Putative Exopolysaccharide Exporter (EPS-E) Family


TC#NameOrganismal TypeExample

Putative exopolysaccharide transporter with two subunits, PelFG (PelF has 507 aas and 1 N-terminal TMS, while PelG has 456 aas and 12 TMSs) (Vasseur et al., 2007)


PelFG of Pseudomonas aeruginosa (Q02PM3)

2.A.66.6.2Fusion protein (986 aas): Glycosyl transferase group 1 (residues 1-550); putative transporter (flippase) (residue 551-986; 12(6+6) TMSs)BacteriaFusion protein of Ralstonia solanacearum (EAP70965)

2.A.66.7 Putative O-Unit Flippase (OUF) Family


TC#NameOrganismal TypeExample
2.A.66.7.1Putative O-unit flippase (OUF1)BacteriaOUF1 of Pseudomonas fluorescens (Q4K6F5)

2.A.66.8 Unknown MOP-1 (U-MOP1) Family (Most closely related to the OLF Family (2.A.66.3))


TC#NameOrganismal TypeExample

Hypothetical protein (598aas with 12-14TMSs; probably 14 with the central 2 being of low hydrokphobicity) The topologies and sequence similarities of subfamily 8 is like that of subfamily 3.


Hypothetical protein of Trypanosoma brucei (Q383B3)

2.A.66.8.2Hypothetical protein (729aas; 14TMSs ?)ProtozoaHypothetical protein of Leishmania infantum (A4I3X2)

2.A.66.9 The Progressive Ankylosis (Ank) Family


TC#NameOrganismal TypeExample

The progressive ankylosis (ANK) protein (AnkH; SLC62A1) gives rise to craniometaphyseal bone dysplasia in man. This 12 TMS protein was reported to transport pyrophosphate, but a more recent report suggests it transports ATP instead of pyrophosphate (Szeri et al. 2022). It is expressed in the primary ciliary/basal body complex of kidney and bone tissues (Nürnberg et al., 2001; Carr et al. 2009). It is critical for the regulation of pyrophosphate, and gain of function ANK mutations are associated with calcium pyrophosphate deposition disease (Mitton-Fitzgerald et al. 2016).



AnkH of Homo sapiens (Q9HCJ1)


Hypothetical protein, Pcar_0400


Pcar_0400 of Pelobacter carbinolicus (Q3A7I4)

2.A.66.9.3Ank family memberBacteriaAnk protein of Desulfuromonas acetoxidans (Q1K211)