2.A.2 The Glycoside-Pentoside-Hexuronide (GPH):Cation Symporter Family

GPH:cation symporters catalyze uptake of sugars (mostly, but not exclusively, glycosides) in symport with a monovalent cation (H+ or Na+). Mutants of two groups of these symporters (the melibiose permeases of enteric bacteria and the lactose permease of Streptococcus thermophilus) have been isolated and in which altered cation specificity is observed or in which sugar transport is uncoupled from cation symport (i.e., uniport is catalyzed). The various members of the family can use Na+, H+ or Li, Na+ or Li+, H+ or Li+, or only H+ as the symported cation. Most functionally characterized and sequenced members of the family are from bacteria except the distantly related sucrose:H+ symporters of plants and a yeast maltose/sucrose:H+ symporter of S. pombe. This yeast protein is about 24% identical to the plant sucrose:H+ symporters and is more distantly related to the bacterial members of the GPH family (Reinders and Ward, 2001). Homologues are found in archaea and all eukaryotic kingdoms.

Proteins of the GHP family are generally about 500 amino acids in length, although the Gram-positive bacterial lactose permeases are larger, due to a C-terminal hydrophilic domain that is involved in regulation by the phosphotransferase system (TC #4.A.1). All of these proteins possess twelve The GPH family is a member of the MFS. One member of the GPH family, LacS of Streptococcus thermophilus, appears to be a cooperative dimer with one sugar translocation pathway per monomer (Veenhoff et al., 2001).

X-ray crystal structures of MelBSt have revealed the molecular recognition mechanism for sugar binding. Markham et al. 2021 generated a complete single-Cys library containing 476 unique mutants by placing a Cys at each position on a functional Cys-less background. 105 mutants (21%) exhibited poor transport activities, although the expression levels of most mutants were comparable to that of the control. The affected positions are distributed throughout the protein. TMSs I and X and transmembrane residues, Asp and Tyr, are most affected by cysteine replacement, while helix IX, the cytoplasmic middle-loop, and C-terminal tail are least affected. Single-Cys replacements at the major sugar-binding positions (K18, D19, D124, W128, R149, and W342) or at positions important for cation binding (D55, N58, D59, and T121) abolished the Na+-coupled active transport (Markham et al. 2021).

The generalized transport reaction catalyzed by the GPH:cation symporter family is:

Sugar (out) + [H+ or Na+] (out) → Sugar (in) + [H+ or Na+] (in).



This family belongs to the Major Facilitator (MFS) Superfamily.



Adelmann, C.H., A.K. Traunbauer, B. Chen, K.J. Condon, S.H. Chan, T. Kunchok, C.A. Lewis, and D.M. Sabatini. (2020). MFSD12 mediates the import of cysteine into melanosomes and lysosomes. Nature 588: 699-704.

Adhikari, K., J. Mendoza-Revilla, A. Sohail, M. Fuentes-Guajardo, J. Lampert, J.C. Chacón-Duque, M. Hurtado, V. Villegas, V. Granja, V. Acuña-Alonzo, C. Jaramillo, W. Arias, R.B. Lozano, P. Everardo, J. Gómez-Valdés, H. Villamil-Ramírez, C.C. Silva de Cerqueira, T. Hunemeier, V. Ramallo, L. Schuler-Faccini, F.M. Salzano, R. Gonzalez-José, M.C. Bortolini, S. Canizales-Quinteros, C. Gallo, G. Poletti, G. Bedoya, F. Rothhammer, D.J. Tobin, M. Fumagalli, D. Balding, and A. Ruiz-Linares. (2019). A GWAS in Latin Americans highlights the convergent evolution of lighter skin pigmentation in Eurasia. Nat Commun 10: 358.

Andersen, J.M., R. Barrangou, M. Abou Hachem, S. Lahtinen, Y.J. Goh, B. Svensson, and T.R. Klaenhammer. (2011). Transcriptional and functional analysis of galactooligosaccharide uptake by lacS in Lactobacillus acidophilus. Proc. Natl. Acad. Sci. USA 108: 17785-17790.

Anzai, T. and Y. Matsumura. (2019). Topological analysis of TMEM180, a newly identified membrane protein that is highly expressed in colorectal cancer cells. Biochem. Biophys. Res. Commun. [Epub: Ahead of Print]

Anzai, T., S. Saijou, Y. Ohnuki, H. Kurosawa, M. Yasunaga, and Y. Matsumura. (2021). TMEM180 contributes to SW480 human colorectal cancer cell proliferation through intra-cellular metabolic pathways. Transl Oncol 14: 101186.

Bartölke, R., J.J. Heinisch, H. Wieczorek, and O. Vitavska. (2014). Proton-associated sucrose transport of mammalian solute carrier family 45: an analysis in Saccharomyces cerevisiae. Biochem. J. 464: 193-201.

Bassik, M.C. and M. Kampmann. (2011). Knocking out the door to tunicamycin entry. Proc. Natl. Acad. Sci. USA 108: 11731-11732.

Bergman, S., R.J. Cater, A. Plante, F. Mancia, and G. Khelashvili. (2023). Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A. Nat Commun 14: 3391.

Carpaneto, A., D. Geiger, E. Bamberg, N. Sauer, J. Fromm, and R. Hedrich. (2005). Phloem-localized, proton-coupled sucrose carrier ZmSUT1 mediates sucrose efflux under the control of the sucrose gradient and the proton motive force. J. Biol. Chem. 280: 21437-21443.

Carpaneto, A., H. Koepsell, E. Bamberg, R. Hedrich, and D. Geiger. (2010). Sucrose- and H-dependent charge movements associated with the gating of sucrose transporter ZmSUT1. PLoS One 5: e12605.

Cater, R.J., G.L. Chua, S.K. Erramilli, J.E. Keener, B.C. Choy, P. Tokarz, C.F. Chin, D.Q.Y. Quek, B. Kloss, J.G. Pepe, G. Parisi, B.H. Wong, O.B. Clarke, M.T. Marty, A.A. Kossiakoff, G. Khelashvili, D.L. Silver, and F. Mancia. (2021). Structural basis of omega-3 fatty acid transport across the blood-brain barrier. Nature. [Epub: Ahead of Print]

Chaillou, S., P.W. Postma, and P.H. Pouwels. (1998). Functional expression in Lactobacillus plantarum of xylP encoding the isoprimeverose transporter of Lactobacillus pentosus. J. Bacteriol. 180: 4011-4014.

Chen, W., W. Diao, H. Liu, Q. Guo, Q. Song, G. Guo, H. Wan, and Y. Chen. (2022). Molecular characterization of SUT Gene Family in Solanaceae with emphasis on expression analysis of pepper genes during development and stresses. Bioengineered 13: 14780-14798.

Crawford, N.G., D.E. Kelly, M.E.B. Hansen, M.H. Beltrame, S. Fan, S.L. Bowman, E. Jewett, A. Ranciaro, S. Thompson, Y. Lo, S.P. Pfeifer, J.D. Jensen, M.C. Campbell, W. Beggs, F. Hormozdiari, S.W. Mpoloka, G.G. Mokone, T. Nyambo, D.W. Meskel, G. Belay, J. Haut, , H. Rothschild, L. Zon, Y. Zhou, M.A. Kovacs, M. Xu, T. Zhang, K. Bishop, J. Sinclair, C. Rivas, E. Elliot, J. Choi, S.A. Li, B. Hicks, S. Burgess, C. Abnet, D.E. Watkins-Chow, E. Oceana, Y.S. Song, E. Eskin, K.M. Brown, M.S. Marks, S.K. Loftus, W.J. Pavan, M. Yeager, S. Chanock, and S.A. Tishkoff. (2017). Loci associated with skin pigmentation identified in African populations. Science 358:.

Denger, K., M. Weiss, A.K. Felux, A. Schneider, C. Mayer, D. Spiteller, T. Huhn, A.M. Cook, and D. Schleheck. (2014). Sulphoglycolysis in Escherichia coli K-12 closes a gap in the biogeochemical sulphur cycle. Nature 507: 114-117.

Deol KK., Mukherjee S., Gao F., Brule-Babel A., Stasolla C. and Ayele BT. (2013). Identification and characterization of the three homeologues of a new sucrose transporter in hexaploid wheat (Triticum aestivum L.). BMC Plant Biol. 13:181.

Du, J. and D.E. Fisher. (2002). Identification of Aim-1 as the underwhite mouse mutant and its transcriptional regulation by MITF. J. Biol. Chem. 277: 402-406.

Ethayathulla, A.S., M.S. Yousef, A. Amin, G. Leblanc, H.R. Kaback, and L. Guan. (2014). Structure-based mechanism for Na+/melibiose symport by MelB. Nat Commun 5: 3009.

Garg, V., J. Reins, A. Hackel, and C. Kühn. (2022). Elucidation of the interactome of the sucrose transporter StSUT4: sucrose transport is connected to ethylene and calcium signaling. J Exp Bot. [Epub: Ahead of Print]

Granell, M., X. León, G. Leblanc, E. Padrós, and V.A. Lórenz-Fonfría. (2010). Structural insights into the activation mechanism of melibiose permease by sodium binding. Proc. Natl. Acad. Sci. USA 107: 22078-22083.

Grossiord, B.P., E.J. Luesink, E.E. Vaughan, A. Arnaud, and W.M. de Vos. (2003). Characterization, expression, and mutation of the Lactococcus lactis galPMKTE genes, involved in galactose utilization via the Leloir pathway. J. Bacteriol. 185: 870-878.

Hariharan, P. and L. Guan. (2014). Insights into the inhibitory mechanisms of the regulatory protein IIA(Glc) on melibiose permease activity. J. Biol. Chem. 289: 33012-33019.

Hédan, B., E. Cadieu, N. Botherel, C. Dufaure de Citres, A. Letko, M. Rimbault, C. Drögemüller, V. Jagannathan, T. Derrien, S. Schmutz, T. Leeb, and C. André. (2019). Identification of a Missense Variant in Involved in Dilution of Phaeomelanin Leading to White or Cream Coat Color in Dogs. Genes (Basel) 10:.

Heuberger, E.H., E. Smits, and B. Poolman. (2001). Xyloside transport by XylP, a member of the galactoside-pentoside-hexuronide family. J. Biol. Chem. 276: 34465-34472.

Hugouvieux-Cotte-Pattat, N. and S. Reverchon. (2001). Two transporters, TogT and TogMNAB, are responsible for oligogalacturonide uptake in Erwinia chrysanthemi 3937. Molec. Microbiol. 41: 1125-1132.

Inagaki, K., T. Suzuki, S. Ito, N. Suzuki, K. Adachi, T. Okuyama, Y. Nakata, H. Shimizu, H. Matsuura, T. Oono, H. Iwamatsu, M. Kono, and Y. Tomita. (2006). Oculocutaneous albinism type 4: six novel mutations in the membrane-associated transporter protein gene and their phenotypes. Pigment Cell Res 19: 451-453.

Kamaraj, B. and R. Purohit. (2016). Mutational Analysis on Membrane Associated Transporter Protein (MATP) and Their Structural Consequences in Oculocutaeous Albinism Type 4 (OCA4) - A Molecular Dynamics Approach. J. Cell. Biochem. [Epub: Ahead of Print]

Khuller, K., G. Yigit, C.M. Grijalva, J. Altmüller, H. Thiele, P. Nürnberg, N.H. Elcioglu, B. Yeter, U. Hehr, A. Stein, A. Della Marina, A. Köninger, C. Depienne, F.J. Kaiser, B. Wollnik, and A. Kuechler. (2021). MFSD2A-associated primary microcephaly - Expanding the clinical and mutational spectrum of this ultra-rare disease. Eur J Med Genet 104310. [Epub: Ahead of Print]

Laikova, O.N., A.A. Mironov, and M.S. Gelfand. (2001). Computational analysis of the transcriptional regulation of pentose utilization systems in the gamma subdivision of Proteobacteria. FEMS Microbiol. Lett. 205: 315-322.

Lewis, S.S. and K.M. Girisha. (2019). Whole exome sequencing identifies a novel pathogenic variation [p.(Gly194valfs*7)] in SLC45A2 in the homozygous state in multiple members of a family with oculocutaneous albinism in southern India. Clin Exp Dermatol. [Epub: Ahead of Print]

Liang, W.-J., K.J. Wilson, H. Xie, J. Knol, S. Suzuki, N.G. Rutherford, P.J.F. Henderson, and R.A. Jefferson. (2005). The gusBC genes of Escherichia coli encode a glucuronide transport system. J. Bacteriol. 187: 2377-2385.

Liu, Y., Z. Wu, W. Wu, C. Yang, C. Chen, and K. Zhang. (2023). [Functional analysis on sucrose transporters in sweet potato]. Sheng Wu Gong Cheng Xue Bao 39: 2772-2793.

Lohmiller, S., K. Hantke, S.I. Patzer, and V. Braun. (2008). TonB-dependent maltose transport by Caulobacter crescentus. Microbiology 154: 1748-1754.

Markham, K.J., E.B. Tikhonova, A.C. Scarpa, P. Hariharan, S. Katsube, and L. Guan. (2021). Complete cysteine-scanning mutagenesis of the Salmonella typhimurium melibiose permease. J. Biol. Chem. 101090. [Epub: Ahead of Print]

Meyer S., M. Melzer, E. Truernit, C. Hümmer, R. Besenbeck, R. Stadler, N. Sauer. (2000). AtSUC3, a gene encoding a new Arabidopsis sucrose transporter, is expressed in cells adjacent to the vascular tissue and in a carpel cell layer. Plant J. 24: 869-882

Meyer, H., O. Vitavska, and H. Wieczorek. (2011). Identification of an animal sucrose transporter. J Cell Sci 124: 1984-1991.

Moraes, T.F. and R.A. Reithmeier. (2012). Membrane transport metabolons. Biochim. Biophys. Acta. 1818: 2687-2706.

Naderi, S. and M.H. Saier, Jr. (1996). Plant sucrose:H+ symporters are homologous to the melibiose permease of Escherichia coli. Molec. Microbiol. 22: 389-391.

Osanai-Futahashi M., Tatematsu K., Yamamoto K., Narukawa J., Uchino K., Kayukawa T., Shinoda T., Banno Y., Tamura T. and Sezutsu H. (2012). Identification of the Bombyx red egg gene reveals involvement of a novel transporter family gene in late steps of the insect ommochrome biosynthesis pathway. J Biol Chem. 287(21):17706-14.

Pommerrenig B., Popko J., Heilmann M., Schulmeister S., Dietel K., Schmitt B., Stadler R., Feussner I. and Sauer N. (2013). SUCROSE TRANSPORTER 5 supplies Arabidopsis embryos with biotin and affects triacylglycerol accumulation. Plant J. 73(3):392-404.

Poolman, B., J. Knol, C. van der Does, P.J.F. Henderson, W.-J. Liang, G. Leblanc, T. Pourcher, and I. Mus-Veteau. (1996). Cation and sugar selectivity determinants in a novel family of transport proteins. Molec. Microbiol. 19: 911-922.

Quek, D.Q., L.N. Nguyen, H. Fan, and D.L. Silver. (2016). Structural insights into the transport mechanism of the human sodium-dependent lysophosphatidylcholine transporter Mfsd2a. J. Biol. Chem. [Epub: Ahead of Print]

Reiling, J.H., C.B. Clish, J.E. Carette, M. Varadarajan, T.R. Brummelkamp, and D.M. Sabatini. (2011). A haploid genetic screen identifies the major facilitator domain containing 2A (MFSD2A) transporter as a key mediator in the response to tunicamycin. Proc. Natl. Acad. Sci. USA 108: 11756-11765.

Reinders, A. and J.M. Ward. (2001). Functional characterization of the α-glucoside transporter Sut1p from Schizosaccharomyces pombe, the first fungal homologue of plant sucrose transporters. Mol. Microbiol. 39: 445-454.

Reizer, J., A. Reizer, and M.H. Saier, Jr. (1994). A functional superfamily of sodium/solute symporters. Biochim. Biophys. Acta 1197: 133-166.

Rodionov, D.A., C. Yang, X. Li, I.A. Rodionova, Y. Wang, A.Y. Obraztsova, O.P. Zagnitko, R. Overbeek, M.F. Romine, S. Reed, J.K. Fredrickson, K.H. Nealson, and A.L. Osterman. (2010). Genomic encyclopedia of sugar utilization pathways in the Shewanella genus. BMC Genomics 11: 494.

Rodionov, D.A., M.S. Gelfand, and N. Hugouvieux-Cotte-Pattat. (2004). Comparative genomics of the KdgR regulon in Erwinia chrysanthemi 3937 and other γ-proteobacteria. Microbiology 150: 3571-3590.

Rodríguez-Díaz, J., A. Rubio-del-Campo, and M.J. Yebra. (2012). Lactobacillus casei ferments the N-Acetylglucosamine moiety of fucosyl-α-1,3-N-acetylglucosamine and excretes L-fucose. Appl. Environ. Microbiol. 78: 4613-4619.

Saier, M.H., Jr. (1989). Protein phosphorylation and allosteric control of inducer exclusion and catabolite repression by the bacterial phosphoenolpyruvate: sugar phosphotransferase system. Microbiol Rev 53: 109-120.

Santiago, J.P., J.M. Ward, and T.D. Sharkey. (2020). SUT1.1 is a high affinity sucrose-proton co-transporter. Plant Direct 4: e00260.

Schulz, A., D. Beyhl, I. Marten, A. Wormit, E. Neuhaus, G. Poschet, M. Büttner, S. Schneider, N. Sauer, and R. Hedrich. (2011). Proton-driven sucrose symport and antiport are provided by the vacuolar transporters SUC4 and TMT1/2. Plant J. 68: 129-136.

Shimokawa, N., J. Okada, K. Haglund, I. Dikic, N. Koibuchi, and M. Miura. (2002). Past-A, a novel proton-associated sugar transporter, regulates glucose homeostasis in the brain. J. Neurosci. 22: 9160-9165.

Shiraishi, T., K. Ikeda, Y. Tsukada, Y. Nishizawa, T. Sasaki, M. Ito, M. Kojima, G. Ishii, R. Tsumura, S. Saijou, Y. Koga, M. Yasunaga, and Y. Matsumura. (2021). High expression of TMEM180, a novel tumour marker, is associated with poor survival in stage III colorectal cancer. BMC Cancer 21: 302.

Stadler R., E. Truernit, M. Gahrtz, N. Sauer. (1999). The AtSUC1 sucrose carrier may represent the osmotic driving force for anther dehiscence and pollen tube growth in Arabidopsis. Plant J. 19: 269-278.

Sun, Y. and J.M. Ward. (2012). Arg188 in rice sucrose transporter OsSUT1 is crucial for substrate transport. BMC Biochem 13: 26.

Tanaka, J., T. Leeb, J. Rushton, T.R. Famula, M. Mack, V. Jagannathan, C. Flury, I. Bachmann, J. Eberth, S.M. McDonnell, M.C.T. Penedo, and R.R. Bellone. (2019). Frameshift Variant in MFSD12 Explains the Mushroom Coat Color Dilution in Shetland Ponies. Genes (Basel) 10:.

Tóth, L., B. Fábos, K. Farkas, A. Sulák, K. Tripolszki, M. Széll, and N. Nagy. (2017). Identification of two novel mutations in the SLC45A2 gene in a Hungarian pedigree affected by unusual OCA type 4. BMC Med Genet 18: 27.

Veenhoff, L.M., Heuberger, E.H.M.L., and B. Poolman. (2001). The lactose transport protein is a cooperative dimer with two sugar translocation pathways. EMBO J. 20: 3056-3062.

Vitavska, O., R. Bartölke, K. Tabke, J.J. Heinisch, and H. Wieczorek. (2018). Interaction of mammalian and plant H/sucrose transporters with 14-3-3 proteins. Biochem. J. 475: 3239-3254.

Vu, T.M., A.N. Ishizu, J.C. Foo, X.R. Toh, F. Zhang, D.M. Whee, F. Torta, A. Cazenave-Gassiot, T. Matsumura, S. Kim, S.E.S. Toh, T. Suda, D.L. Silver, M.R. Wenk, and L.N. Nguyen. (2017). Mfsd2b is essential for the sphingosine-1-phosphate export in erythrocytes and platelets. Nature 550: 524-528.

Wang, G., Y. Wu, L. Ma, Y. Lin, Y. Hu, M. Li, W. Li, Y. Ding, and L. Chen. (2021). Phloem loading in rice leaves depends strongly on the apoplastic pathway. J Exp Bot. [Epub: Ahead of Print]

Wang, J.Y., X.Y. Li, H.J. Li, J.W. Liu, Y.G. Yao, M. Li, X. Xiao, and X.J. Luo. (2021). Integrative Analyses Followed by Functional Characterization Reveal TMEM180 as a Schizophrenia Risk Gene. Schizophr Bull 47: 1364-1374.

Wang, L.Y., V.M. Ravi, G. Leblanc, E. Padrós, J. Cladera, and A. Perálvarez-Marín. (2016). Helical unwinding and side-chain unlocking unravel the outward open conformation of the melibiose transporter. Sci Rep 6: 33776.

Wei, C.Y., M.X. Zhu, N.H. Lu, R. Peng, X. Yang, P.F. Zhang, L. Wang, and J.Y. Gu. (2019). Bioinformatics-based analysis reveals elevated MFSD12 as a key promoter of cell proliferation and a potential therapeutic target in melanoma. Oncogene 38: 1876-1891.

Wijesena, H.R. and S.M. Schmutz. (2015). A Missense Mutation in SLC45A2 Is Associated with Albinism in Several Small Long Haired Dog Breeds. J Hered 106: 285-288.

Wiriyasermkul, P., S. Moriyama, and S. Nagamori. (2020). Membrane transport proteins in melanosomes: Regulation of ions for pigmentation. Biochim. Biophys. Acta. Biomembr 1862: 183318.

Wunderlich, J. (2022). Updated List of Transport Proteins in. Front Cell Infect Microbiol 12: 926541.

Xie, J., S. Ruan, Z. Zhu, M. Wang, Y. Cao, M. Ou, P. Yu, and J. Shi. (2021). Database mining analysis revealed the role of the putative H/sugar transporter solute carrier family 45 in skin cutaneous melanoma. Channels (Austin) 15: 496-506.

Yasunaga, M., S. Saijou, S. Hanaoka, T. Anzai, R. Tsumura, and Y. Matsumura. (2019). Significant antitumor effect of an antibody against TMEM180, a new colorectal cancer-specific molecule. Cancer Sci 110: 761-770.

Yousef, M.S. and L. Guan. (2009). A 3D structure model of the melibiose permease of Escherichia coli represents a distinctive fold for Na+ symporters. Proc. Natl. Acad. Sci. USA 106: 15291-15296.

Zhang, C. and R. Turgeon. (2009). Downregulating the sucrose transporter VpSUT1 in Verbascum phoeniceum does not inhibit phloem loading. Proc. Natl. Acad. Sci. USA 106: 18849-18854.


TC#NameOrganismal TypeExample

Melibiose permease. Catalyzes the coupled stoichiometric symport of a galactoside with a cation (either Na+, Li+, or H+). Based on LacY, a 3-d model has been derived (Yousef and Guan, 2009). Asp55 and Asp59 are essential for Na+ binding. Asp124 may play a critical role by allowing Na+-induced conformational changes and sugar binding. Asp19 may facilitate melibiose binding (Granell et al., 2010).  The alternate access mechanism fits better into a flexible gating mechanism rather than the archetypical helical rigid- body rocker-switch mechanism (Wang et al. 2016).  Crystal structures of Salmonella typhimurium MelB in two conformations, representing an outward partially occluded and an outward inactive state (Ethayathulla et al. 2014). MelB adopts a typical MFS fold and contains a previously unidentified cation-binding motif. Three conserved acidic residues form a pyramidal-shaped cation-binding site for Na+, Li+ or H+, which is in close proximity to the sugar-binding site. Both cosubstrate-binding sites are mainly contributed by the residues from the amino-terminal domain (Ethayathulla et al. 2014). The Glucose Enzyme IIA protein of the PTS binds MelB either in the absence or presence of a galactoside, and binding decreases the affinity for melibiose, giving rise to inducer exclusion (Saier 1989; Hariharan and Guan 2014).

Gram-negative bacteria

MelB of E. coli (A7ZUZ0)


Probable fucosyl-α-1,6-N-acetylglucosamine uptake porter, AlfD (next to and in an operon with a fucosidase (AlfA) specific for this disaccharide which is present in mammalian glycoproteins, glycolipids and milk (Rodríguez-Díaz et al. 2012).


AlfD of Lactobacillus casei


Uncharacterized protein, probably a sugar:H+ symporter of 474 aas and 12 TMSs, YjmB,  The gene was from a marine sediment metagenome.

YjmB of Lokiarchaeum sp. GC14_75


TC#NameOrganismal TypeExample

Lactose permease, LacS. Mediates uptake of β-galactooligosaccharides, lactitol, and a broad range of prebiotic β-galactosides that selectively stimulate beneficial gut microbiota (Andersen et al., 2011). 

Gram-positive bacteria

LacS of Streptococcus thermophilus

2.A.2.2.2Raffinose permease Gram-positive bacteria RafP of Pediococcus pentosaceus

Galactose permease of 462 aas and 12 TMSs.  Transports galactose (Grossiord et al. 2003).

Gram-positive bacteria

GalP of Lactococcus lactis


TC#NameOrganismal TypeExample

Glucuronide permease, UidB, GusB, UidP (Liang et al., 2005; Moraes and Reithmeier 2012)

Gram-negative bacteria

GusB of E. coli

2.A.2.3.10Transmembrane protein 180AnimalsTMEM180 of Homo sapiens

Putative transporter


Putative transporter of Trypanosoma cruzi


Putative sugar transporter


TT_P0219 pf Thermus thermophilus


Probable sugar transporting MFS-2 symporter of 444 aas and 12 TMSs.

MFS carrier of Candidatus Thorarchaeota archaeon


Probable sugar:cation symporter, MFSD13A or TMEM180, with 517 aas and 12 TMSs with the N- and C-termini reported to be exposed extracellularly (Anzai and Matsumura 2019). It has anti-tumor activity (Yasunaga et al. 2019) and is highly expressed in colorectal cancer (CRC) (Anzai et al. 2021; Shiraishi et al. 2021). It is also a schizophrenia risk factor (Wang et al. 2021).

TMEM180 of Homo sapiens


Probable sulfoquinovose importer of 467 aas and 12 TMSs (Denger et al. 2014). Sulphoquinovose (SQ, 6-deoxy-6-sulphoglucose) is the polar headgroup of the plant sulpholipid in the photosynthetic membranes of all higher plants, mosses, ferns, algae, most photosynthetic bacteria, and some non-photosynthetic bacteria. It is part of the surface layer of some Archaea. The estimated annual production of SQ is 10,000,000,000 tonnes (10 petagrams) (Denger et al. 2014).

Sulfoquinovose importer of E. coli


MfsD2B or SLC59A2 protein of 504 aas and 12 TMSs (). It is a cation-dependent lipid transporter that specifically mediates export of sphingosine-1-phosphate from red blood cells and platelets (Vu et al. 2017). Sphingosine-1-phosphate is a signaling sphingolipid, and its export from red blood cells into in the plasma is required for red blood cell morphology. It does not transport lysophosphatidylcholine (LPC).

MfsD2B of Homo sapiens


Putative sugar: cation symporter, GPH, of 548 aas and 12 TMSs in a 6 + 6 TMS arrangement (Wunderlich 2022).

GPH of Plasmodium falciparum

2.A.2.3.2Pentoside permease Gram-positive bacteria XynC (YnaJ) of Bacillus subtilis

Isoprimeverose (α-D xylopyranosyl-(1,6)-D-glucopyranose) permease [xylose is not a substrate] (Heuberger et al., 2001)

Gram-positive bacteria

XylP of Lactobacillus pentosus

2.A.2.3.4Probable α-xyloside uptake permease, YicJ (Laikova et al., 2001)BacteriaYicJ of E. coli (P31435)
2.A.2.3.5Probable β-xyloside uptake permease, YagG (Laikova et al., 2001)BacteriaYagG of E. coli (P75683)

The putative cellobiose porter, BglT (Rodionov et al. 2010)


BglT of Shewanella amazonensis (A1S5F2)


The putative arabinoside porter, AraT (Rodionov et al., 2010)


AraT of Shewanella sp. MR-4 (Q0HIQ0)


Major Facilitator Superfamily Domain containing 2A, MFSD2A or SLC59A1 (543aas, 12 TMSs). It is the omega-3-fatty acid transporter that plays a role in thermogenesis via β-adrenergic signaling. Takes up Tunicamycin (TM), a mixture of related species of nucleotide sugar analogs fatty-acylated with alkyl chains of varying lengths and degrees of unsaturation, produced by several Streptomyces species (Bassik and Kampmann, 2011; Reiling et al., 2011).  It is a sodium-dependent lysophosphatidylcholine (LPC) symporter expressed at the blood-brain barrier endothelium. It is the primary route for import of docosahexaenoic acid and other long-chain fatty acids into foetal and adult brain, and is essential for mouse and human brain growth and function (Quek et al. 2016). In addition to a conserved sodium-binding site, three structural features were identified: A phosphate headgroup binding site, a hydrophobic cleft to accommodate a hydrophobic hydrocarbon tail, and three sets of ionic locks that stabilize the outward-open conformation. Ligand docking studies and biochemical assays identified Lys436 as a key residue for transport. It forms a salt bridge with the negative charge on the phosphate headgroup. Mfsd2a transports structurally related acylcarnitines but not a lysolipid without a negative charge, demonstrating the necessity of a negative charged headgroup interaction with Lys436 for transport. These findings support a novel transport mechanism by which LPCs are flipped within the transporter cavity by pivoting about Lys436 leading to net transport from the outer to the inner leaflet of the plasma membrane (Quek et al. 2016). Docosahexaenoic acid is an omega-3 fatty acid that is essential for neurological development and function, and it is supplied to the brain and eyes predominantly from dietary sources. This nutrient is transported across the blood-brain and blood-retina barriers as lysophosphatidylcholine. The structure of MFSD2A has been determined using single-particle cryo-EM (Cater et al. 2021). The transporter is in an inward-facing conformation and features a large amphipathic cavity that contains the Na+-binding site and a bound lysolipid substrate. This structure reveals details of how MFSD2A interacts with substrates and how Na+-dependent conformational changes allow for the release of these substrates into the membrane through a lateral gate. This atypical MFS transporter mediates the uptake of lysolipids into the brain. Homozygous variants in the MFSD2A gene cause severe primary microcephaly, brain malformations, developmental delay, and epilepsy (Khuller et al. 2021). Bi-allelic MFSD2A variants cause autosomal recessive primary microcephaly type 15 and broaden the phenotypic spectrum associated with these pathogenic variants, emphasizing the role of MFSD2A in early brain development. Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A have been documented (Bergman et al. 2023).


MFSD2A of Homo sapiens (Q8NA29)


Inner membrane symporter YihP


YihP of E. coli


TC#NameOrganismal TypeExample

Liu et al. 2023Sucrose:H+ symporter, Suc1 or Sut1. It provides osmotic driving force for anther dehiscence, pollen germination and pollen tube growth and also transports other glucosides such as maltose and phenylglucosides. Km (sucrose)= 0.5 mM. (Stadler et al., 1999)).  In wheat (Triticum aesticum), there are at least three isoforms designated Sut2A, Sut2B and Sut2D (Deol et al. 2013). The ortholog in the common bean, Phaseolus vulgaris (SUT1.1), has been characterized as a high affinity sucrose:H+ symporter (Santiago et al. 2020). SUTs in rice play a role in the apoplastic loading as a major phloem loading strategy (Wang et al. 2021). Some Suts can transport sucrose, glucose, fructose and mannose (Liu et al. 2023).



Suc1 of Arabidopsis thaliana


Proton:glucose symporter A; proton-associated sugar transporter A  (PAST-A) (present in brain and deleted in neuroblastoma 5 (DNb-5).  Solute carrier family 45 member 1, SLC45A1 (Bartölke et al. 2014).


SLC45A1 of Homo sapiens


Sucrose transport protein SUT5 (Sucrose permease 5) (Sucrose transporter 5) (OsSUT5) (Sucrose-proton symporter 5). Sucrose transporter proteins (SUTs) play roles in the phloem loading and unloading of sucrose. The SUT gene family was identified in four Solanaceae species (Capsicum annuum, Solanum lycopersicum, S. melongena, and S. tuberosum) and 14 other plant species ranging from lower and higher plants. The analysis was performed by integration of chromosomal distribution, gene structure, conserved motifs, evolutionary relationship and expression profiles during pepper growth under stresses (Chen et al. 2022).


SUT5 of Oryza sativa subsp. japonica


Sucrose:H+ symporter, SUC5.  Also transports biotin and possibly maltose (Pommerrenig et al. 2012).


SUC5 of Arabidopsis thaliana


Scratch, orthologue 1, SCRT; SLC45A2; transports sucrose into pigment-containing vesicles or granules.  Mutations give rise to oculocutaneous albinism (Meyer et al. 2011).


SCRT of Drosophila melanogaster


Melanocyte-specific antigen or melanoma antigen, MatP, Slc45a2, Aim-1, AIM1, at the mouse underwhite locus.  Regulated by a melanocyte-specific transcription factor essential for pigmentation, MITF (Du and Fisher 2002). Mutations in MatP in humans cause oculocutaneous albinism type IV (OCA4), an autosomal recessive inherited disorder which is characterized by reduced biosynthesis of melanin pigmentation in skin, hair and eyes. The MATP protein consists of 530 amino acids which contains 12 TMSs (Kamaraj and Purohit 2016).  The D93N mutation causes oculocutaneous albinism 4 (OCA4), and the L374F mutatioin correlates with light pigmentation in European populations. Corresponding mutations were produced in the related and well-characterized sucrose transporter from rice, OsSUT1, and transport activity was measured by heterologous expression in Xenopus laevis oocytes and 14C-sucrose uptake in yeast. The D93N mutant had completly lost transport activity while the L374F mutant showed a 90% decrease in transport activity, although the substrate affinity was unaffected (Kamaraj and Purohit 2016).  Mutations in MATP protein showed loss of stability and became more flexible, which alter its structural conformation and function (Kamaraj and Purohit 2016).

Aim1 of Mus musculus


Putative glycoside transporter of 401 aas and 12 TMSs.

UP of Entamoeba histolytica


Maltose/sucrose H+:symporter, Sut1 (maltose, Km = 6 μM; sucrose, Km = 36 μM) of 553 aas and 12 TMSs in a 4 + 2 + 2 + 4 TMS arrangement (Reinders and Ward 2001). Thus, unlike S. cerevisiae, S. pombe utilizes maltose transporters derived from a protein from an ancestor of the plant SUTs.


Sut1 of Schizosaccharomyces pombe


Phloem-localized sucrose:H+ symporter, Sut1 (mediates sucrose uptake or efflux dependent on the sucrose gradient and the pmf; Carpaneto et al., 2005). Sut1 is a sucrose protein symporter. Protons can move in the absence of sucrose (Carpaneto et al., 2010), but upon addition of sucrose, it becomes a symporter.  Arg-188 in the rice orthologue and homologues are essential (Sun and Ward 2012).


Sut1 of Zea mays (BAA83501)


Sucrose:H+ symporter, Suc3 or Sut3 of 464 aas. Expressed in cells adjacent to the vascular tissue and in a carpel cell layer). Km (sucrose)= 1.9 mM; maltose is a competitor (Meyer et al., 2000).


Suc3 of Arabidopsis thaliana

2.A.2.4.4The brain proton:associated sugar (glucose) transporter, PAST-A (Shimokawa et al., 2002)Animals PAST-A of Rattus norvegicus (Q8K4S3)

The proton:sucrose uptake symporter, Sut1 (Zhang & Turgeon et al., 2009).


Sut1 of Verbascum phoeniceum (D1GC38)


Vacuolar sucrose;H+ symporter, Suc4, catalyzes sucrose export from vacuoles (Schulz et al., 2011). The interactome of the sucrose transporter, StSUT4, in potato is connected to ethylene and calcium signaling (Garg et al. 2022).


Suc4 of Arabidopsis thaliana (Q9FE59)


Solute carrier family 45, member 4, SLC45A4.  Transports sucrose by a proton symport mechanism.  Found ubiquitously throughout the tissues of the body (Bartölke et al. 2014).


SLC45A4 of Homo sapiens


solute carrier family 45, member 3, Slc45A3.  Sucrose:proton symporter associated with prostate cancer and myelination (Bartölke et al. 2014). Four members of the SLC45 family, SLC45A1-SLC45A4, were differentially expressed in melanoma, but only SLC45A2 and SLC45A3 had prognostic guiding values (Xie et al. 2021).


SLC45A3 of Homo sapiens


Solute carrier family 45, member 2, Slc45A2, also called melanocyte-restricted antigen or melanoma antigen, PatP or Aim1.  Transports sucrose, glucose and fructose with protons, possibly into vesicular structures that contain melanin (Vitavska et al. 2018).  Found in skin and hair; involved in pigmentation (Bartölke et al. 2014).  Defects give rise to oculocutaneous albinism (Meyer et al. 2011). One such mutation in dogs, G493D in TMS 11, gives rise to albinisms (Wijesena and Schmutz 2015). OCA type IV (OCA4, OMIM) develops due to homozygous or compound heterozygous mutations in the solute carrier family 45, member 2 (SLC45A2) gene, and many mutations in this human gene have been identified (Inagaki et al. 2006; Tóth et al. 2017). It interacts with 14-3-3 proteins (see TC# 8.A.98). Multiple pathogenic variants in SLC45A2 give rise to oculocutaneous albinism (Lewis and Girisha 2019). Reviewed by Wiriyasermkul et al. 2020. Four members of the SLC45 family, SLC45A1-SLC45A4, were differentially expressed in melanoma, but only SLC45A2 and SLC45A3 had prognostic guiding values (Xie et al. 2021).


SLC45A2 of Homo sapiens


TC#NameOrganismal TypeExample

Saturated and unsaturated oligogalacturonide transporter, TogT (transports di- to tetrasaccharide pectin degradation products which consist of D-galacuronate, sometimes with 4-deoxy-L-threo-5- hexosulose uronate at the reducing position)

Bacteria TogT of Erwinia chrysanthemi 3937

The putative rhamnogalacturonide porter, RhiT (Rodionov et al. 2004).


RhiT of Erwinia carotovora subsp. atroseptica (Q6D188)


TC#NameOrganismal TypeExample

The maltose/maltooligosaccharide transporter, MalI (541 aas) (Lohmiller et al., 2008).


MalI of Caulobacter crescentus (Q9A612)


The putative maltose porter, MalT (Rodionov et al., 2010)


MalT of Shewanella oneidensis (Q8EEC4)


TC#NameOrganismal TypeExample

The insect Bm-re (Bombyx mori red eye) protein; mutants lose ommochromes as well as pigmentation of eggs, eyes, and bodies. May function in pigment transport (Osanai-Futahashi et al., 2012).


Bm-re of Bombyx mori (I0IYT1)


Bm-re homologue of Tribolium castaneum (Osanai-Futahashi et al., 2012).


Bm-re homologue of Tribolium castaneum (D6W6W0)


MFSD12, melanosome and lysosome cysteine transporter, of 480 aas and 12 TMSs. It is associated with skin pigmentation in humans, mice, dogs and horses (Crawford et al. 2017; Adhikari et al. 2019; Hédan et al. 2019; Tanaka et al. 2019). Its upregulated expression is observed in melanomas, and elevated MFSD12 levels promote cell proliferation by promoting cell cycle progression (Wei et al. 2019). MFSD12 interference inhibited tumor growth and lung metastasis in melanoma. It mediates the import of cysteine into melanosomes and lysosomes (Adelmann et al. 2020). MFSD12 is required to maintain normal levels of cystine - the oxidized dimer of cysteine - in melanosomes, and to produce cysteinyldopas, the precursors of pheomelanin synthesis made in melanosomes via cysteine oxidation. MFSD12 is necessary for the import of cysteine into melanosomes and, in non-pigmented cells, lysosomes. Loss of MFSD12 reduced the accumulation of cystine in lysosomes of fibroblasts from patients with cystinosis, a lysosomal-storage disease caused by inactivation of the lysosomal cystine exporter, cystinosin (TC# 2.A.43.1.1). Thus, MFSD12 is an essential component of the cysteine importer for melanosomes and lysosomes (Adelmann et al. 2020).

MFSD12 of Homo sapiens