2.A.3 The Amino Acid-Polyamine-Organocation (APC) Superfamily

The APC superfamily of transport proteins includes members that function as solute:cation symporters and solute:solute antiporters (Saier, 2000; Wong et al. 2012; Schweikhard and Ziegler 2012). They occur in bacteria, archaea, yeast, fungi, unicellular eukaryotic protists, slime molds, plants and animals (Saier, 2000). They vary in length, being as small as 350 residues and as large as 850 residues. The smaller proteins are generally of prokaryotic origin while the larger ones are of eukaryotic origin. Most of them possess twelve transmembrane α-helical spanners but have a re-entrant loop involving TMSs 2 and 3 (Gasol et al., 2004). Members of one family within the APC superfamily (SGP; TC# 2.A.3.9) are amino acid receptors rather than transporters (Cabrera-Martinez et al., 2003), and are truncated at their C-termini, relative to the transporters, having 10 TMSs (Jack et al., 2000). The eukaryotic members of another family (CAT; TC# 2.A.3.3) and the members of a prokaryotic family (AGT; TC #2.A.3.11) have 14 TMSs (Lorca et al., 2003). The larger eukaryotic and archaeal proteins possess N- and C-terminal hydrophilic extensions. Some animal proteins, for example, those in the LAT family (TC# 2.A.3.8) including ASUR4 (gbY12716) and SPRM1 (gbL25068) associate with a type 1 transmembrane glycoprotein that is essential for insertion or activity of the permease and forms a disulfide bridge with it. These glycoproteins include the CD98 heavy chain protein of Mus musculus (gbU25708) and the orthologous 4F2 cell surface antigen heavy chain of Homo sapiens (spP08195). The latter protein is required for the activity of the cystine/glutamate antiporter (2.A.3.8.5) which maintains cellular redox balance and cysteine/glutathione levels (Sato et al., 2005). They are members of the rBAT family of mammalian proteins (TC #8.A.9). Two APC family members, LAT1 and LAT2 (TC #2.A.3.8.7), transport a neurotoxicant, the methylmercury-L-cysteine complex, by molecular mimicry (Simmons-Willis et al., 2002). Hip1 of S. cerevisiae (TC #2.A.3.1.5) has been implicated in heavy metal transport. Distant constituents of the APC superfamily are the AAAP family (TC# 2.A.18), the ArAAP family (TC# 2.A.42) and the STP family (TC# 2.A.43). Some of these proteins exhibit 11 TMSs. Eukaryotic members of this superfamily have been reviewed by Wipf et al. (2002) and Fischer et al. (1998).

In CadB of E. coli (2.A.3.2.2), amino acid residues involved in both uptake and excretion, or solely in excretion, are located in the cytoplasmic loops and the cytoplasmic side of transmembrane segments, whereas residues involved in uptake are located in the periplasmic loops and the transmembrane segments (Soksawatmaekhin et al., 2006). A hydrophilic cavity is proposed to be formed by the transmembrane segments II, III, IV, VI, VII, X, XI, and XII (Soksawatmaekhin et al., 2006). Based on 3-d structures of APC superfamily members, Rudnick (2011) has proposed the pathway for transport and suggested a 'rocking bundle' mechanism.

Shaffer et al. (2009) have presented the crystal structure of apo-ApcT, a proton-coupled broad-specificity amino acid transporter, at 2.35 Å resolution. The structure contains 12 transmembrane helices, with the first 10 consisting of an inverted structural repeat of 5 transmembrane helices like LeuT (TC #2.A.22.4.2). The ApcT structure reveals an inward-facing, apo state and an amine moiety of Lys158 located in a position equivalent to the Na2 ion of LeuT. They proposed that Lys158 is central to proton-coupled transport and that the amine group serves the same functional role as the Na2 ion in LeuT, thus demonstrating common principles among proton- and sodium-coupled transporters.

The structure and function of the cadaverine-lysine antiporter, CadB (2.A.3.2.2), and the putrescine-ornithine antiporter, PotE (2.A.3.2.1), in E. coli have been evaluated using model structures based on the crystal structure of AdiC (2.A.3.2.5), an agmatine-arginine antiporter. The central cavity of CadB, containing the substrate binding site is wider than that of PotE, mirroring the different sizes of cadaverine and putrescine. The size of the central cavity of CadB and PotE is dependent on the angle of transmembrane helix 6 (TM6) against the periplasm. Tyr(73), Tyr(89), Tyr(90), Glu(204), Tyr(235), Asp(303), and Tyr(423) of CadB, and Cys(62), Trp(201), Glu(207), Trp(292), and Tyr(425) of PotE are strongly involved in the antiport activities. In addition, Trp(43), Tyr(57), Tyr(107), Tyr(366), and Tyr(368) of CadB are involved preferentially in cadaverine uptake at neutral pH, while only Tyr(90) of PotE is involved preferentially in putrescine uptake. The results indicated that the central cavity of CadB consists of TMs 2, 3, 6, 7, 8, and 10, and that of PotE consists of TMs 2, 3, 6, and 8. Several residues are necessary for recognition of cadaverine in the periplasm because the level of cadaverine is much lower than that of putrescine at neutral pH.

The roughly barrel-shaped AdiC subunit of approx45 Å diameter consists of 12 transmembrane helices, TMS1 and TMS6 being interrupted by short non-helical stretches in the middle of their transmembrane spans (Fang et al., 2009). Biochemical analysis of homologues places the amino and carboxy termini on the intracellular side of the membrane. TM1–TM10 surround a large cavity exposed to the extracellular solution. These ten helices comprise two inverted structural repeats. TM1–TM5 of AdiC align well with TM6–TM10 turned 'upside down' around a pseudo-two-fold axis nearly parallel to the membrane plane. Thus, TMS1 pairs with TMS6, TMS2 with TMS7, and etc.. Helices TMS11 and TMS12, non-participants in this repeat, provide most of the 2,500 Å2 homodimeric interface. AdiC mirrors the common fold observed unexpectedly in four phylogenetically unrelated families of Na+-coupled solute transporters: BCCT (2.A.15), NCS1 (2.A.39), SSS (2.A.21) and NSS (2.A.22) (Fang et al., 2009).

Transport reactions catalyzed by APC family members include:

Solute:proton symport - S (out) + nH+ (out) → S (in) + nH+ (in)

Solute:solute antiport - S1 (out) + S2 (in) ⇌ S1 (in) + S2 (out)



This family belongs to the APC Superfamily.

 

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Mochizuki T., Kimata Y., Uemura S. and Abe F. (2015). Retention of chimeric Tat2-Gap1 permease in the endoplasmic reticulum induces unfolded protein response in Saccharomyces cerevisiae. FEMS Yeast Res. 15(5).

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

Nagane, M., E. Kanai, Y. Shibata, T. Shimizu, C. Yoshioka, T. Maruo, and T. Yamashita. (2018). Sulfasalazine, an inhibitor of the cystine-glutamate antiporter, reduces DNA damage repair and enhances radiosensitivity in murine B16F10 melanoma. PLoS One 13: e0195151.

Neef, J., V.F. Andisi, K.S. Kim, O.P. Kuipers, and J.J. Bijlsma. (2011). Deletion of a cation transporter promotes lysis in Streptococcus pneumoniae. Infect. Immun. 79: 2314-2323.

Nele Bourgeois, M.A., S.L. Van Herck, P. Vancamp, J. Delbaere, C. Zevenbergen, S. Kersseboom, V.M. Darras, and T.J. Visser. (2016). CHARACTERIZATION OF CHICKEN THYROID HORMONE TRANSPORTERS. Endocrinology en20152025. [Epub: Ahead of Print]

Newell JL., Keyari CM., McDaniel SW., Diaz PJ., Natale NR., Patel SA. and Bridges RJ. (2014). Novel di-aryl-substituted isoxazoles act as noncompetitive inhibitors of the system Xc(-) cystine/glutamate exchanger. Neurochem Int. 73:132-8.

Noens, E.E. and J.S. Lolkema. (2015). Physiology and substrate specificity of two closely related amino acid transporters, SerP1 and SerP2, of Lactococcus lactis. J. Bacteriol. 197: 951-958.

Oppegård, C., M. Kjos, J.W. Veening, J. Nissen-Meyer, and T. Kristensen. (2016). A putative amino acid transporter determines sensitivity to the two-peptide bacteriocin plantaricin JK. Microbiologyopen. [Epub: Ahead of Print]

Phalip, V., I. Kuhn, Y. Lemoine, and J.M. Jeltsch. (1999). Characterization of the biotin biosynthesis pathway in Saccharomyces cerevisiae and evidence for a cluster containing BIO5, a novel gene involved in vitamer uptake. Gene 232: 43-51.

Pi, J. and A.J. Pittard. (1996). Topology of the phenylalanine-specific permease of Escherichia coli. J. Bacteriol. 178: 2650-2655.

Pi, J., H. Chow, and A.J. Pittard. (2002). Study of second-site suppression in the pheP gene for the phenylalanine transporter of Escherichia coli. J. Bacteriol. 184: 5842-5847.

Pi, J., P.J. Wookey, and A.J. Pittard. (1993). Site-directed mutagenesis reveals the importance of conserved charged residues for the transport activity of the PheP permease of Escherichia coli. J. Bacteriol. 175: 7500-7504.

Pineda, M., E. Fernández, D. Torrents, R. Estévez, C. López, M. Camps, J. Lloberas, A. Zorzano, and M. Palacín. (1999). Identification of a membrane protein, LAT-2, that co-expresses with 4F2 heavy chain, and l-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. J. Biol. Chem. 274: 19738-19744.

Poulsen, P., R.F. Gaber, and M.C. Kielland-Brandt. (2008). Hyper- and hyporesponsive mutant forms of the Saccharomyces cerevisiae Ssy1 amino acid sensor. Mol. Membr. Biol. 25: 164-176.

Prager, G.W., C.C. Féral, C. Kim, J. Han, and M.H. Ginsberg. (2007). CD98hc (SLC3A2) interaction with the integrin beta subunit cytoplasmic domain mediates adhesive signaling. J. Biol. Chem. 282: 24477-24484.

Pulvermacher, S.C., L.T. Stauffer, and G.V. Stauffer. (2009). Role of the sRNA GcvB in regulation of cycA in Escherichia coli. Microbiology 155: 106-114.

Rauschmeier M., Schuppel V., Tetsch L. and Jung K. (2014). New insights into the interplay between the lysine transporter LysP and the pH sensor CadC in Escherichia coli. J Mol Biol. 426(1):215-29.

Reig, N., C. Del Rio, F. Casagrande, M. Ratera, J.L. Gelpi, D. Torrents, P.J. Henderson, H. Xie, S.A. Baldwin, A. Zorzano, D. Fotiadis, and M. Palacin. (2007). Functional and structural characterization of the first prokaryotic member of the L-amino acid transporter (LAT) family: A model for APC transporters. J. Biol. Chem. 282: 13270-13281.

Reizer, J., K. Finley, D. Kakuda, C.L. MacLeod, A. Reizer, and M.H. Saier, Jr. (1993). Mammalian integral membrane receptors are homologous to facilitators and antiporters of yeast, fungi, and eubacteria. Prot. Sci. 2: 20-30.

Reynolds, B., P. Roversi, R. Laynes, S. Kazi, C.A. Boyd, and D.C. Goberdhan. (2009). Drosophila expresses a CD98 transporter with an evolutionarily conserved structure and amino acid-transport properties. Biochem. J. 420: 363-372.

Rodionov, D.A., A.G. Vitreschak, A.A. Mironov, and M.S. Gelfand. (2003). Regulation of lysine biosynthesis and transport genes in bacteria: yet another RNA riboswitch? Nucleic Acids Res. 31: 6748-6757.

Rodríguez-Banqueri, A., E. Errasti-Murugarren, P. Bartoccioni, L. Kowalczyk, A. Perálvarez-Marín, M. Palacín, and J.L. Vázquez-Ibar. (2016). Stabilization of a prokaryotic LAT transporter by random mutagenesis. J Gen Physiol. [Epub: Ahead of Print]

Rouillon, A., Y. Surdin-Kerjan, and D. Thomas (1999). Transport of Sulfonium compounds: characterization of the S-adneosylmethionine and S-methylmethionine permeases from the yeast Saccharomyces cerevisiae. J. Biol. Chem. 274: 28096-28105.

Saier, M.H., Jr. (2000). Families of transmembrane transporters selective for amino acids and their derivatives. Microbiology 146: 1775-1795.

Sanders, J.W., K. Leenhouts, J. Burghoorn, J.R. Brands, G. Venema, and J. Kok. (1998). A chloride-inducible acid resistance mechanism in Lactococcus lactis and its regulation. Mol. Microbiol. 27: 299-310.

Sato, H., A. Shiiya, M. Kimata, K. Maebara, M. Tamba, Y. Sakakura, N. Makino, F. Sugiyama, K. Yagami, T. Moriguchi, S. Takahashi, and S. Bannai. (2005). Redox imbalance in cystine/glutamate transporter-deficient mice. J. Biol. Chem. 280: 37423-37429.

Sato, H., M. Tamba, T. Ishii, and S. Bannai. (1999). Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J. Biol. Chem. 274: 11455-11458.

Schweikhard, E.S. and C.M. Ziegler. (2012). Amino Acid secondary transporters: toward a common transport mechanism. Curr Top Membr 70: 1-28.

Segawa, H., Y. Fukasawa, K. Miyamoto, E. Takeda, H. Endou, and Y. Kanai. (1999). Identification and functional characterization of a Na+-independent neutral amino acid transporter with broad substrate selectivity. J. Biol. Chem. 274: 19745-19751.

Seth, A. and N.D. Connell. (2000). Amino acid transport and metabolism in mycobacteria: cloning, interruption, and characterization of an L-arginine/γ-aminobutyric acid permease in Mycobacterium bovis BCG. J. Bacteriol. 182: 919-927.

Shaffer, P.L., A. Goehring, A. Shankaranarayanan, and E. Gouaux. (2009). Structure and mechanism of a Na+-independent amino acid transporter. Science 325: 1010-1014.

Simmons-Willis, T.A., A.S. Koh, T.W. Clarkson, and N. Ballatori. (2002). Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. Biochem. J. 367: 239-246.

Soksawatmaekhin, W., A. Kuraishi, K. Sakata, K. Kashiwagi, and K. Igarashi. (2004). Excretion and uptake of cadaverine by CadB and its physiological functions in Escherichia coli. Mol. Microbiol. 51: 1401-1412.

Soksawatmaekhin, W., T. Uemura, N. Fukiwake, K. Kashiwagi, and K. Igarashi. (2006). Identification of the cadaverine recognition site on the cadaverine-lysine antiporter CadB. J. Biol. Chem. 281: 29213-29220.

Sophianopoulou, V. and G. Diallinas. (1995). Amino acid transporters of lower eukaryotes: regulation, structure and topogenesis. FEMS Microbiol. Rev. 16: 53-75.

Soysa R., Venselaar H., Poston J., Ullman B. and Hasne MP. (2013). Structural model of a putrescine-cadaverine permease from Trypanosoma cruzi predicts residues vital for transport and ligand binding. Biochem J. 452(3):423-32.

Tachihara, K., T. Uemura, K. Kashiwagi, and K. Igarashi. (2005). Excretion of putrescine and spermidine by the protein encoded by YKL174c (TPO5) in Saccharomyces cerevisiae. J. Biol. Chem. 280: 12637-12642.

Tian, X., X. Meng, L. Wang, Y. Song, D. Zhang, Y. Ji, X. Li, and C. Dong. (2015). Molecular cloning, mRNA expression and tissue distribution analysis of Slc7a11 gene in alpaca (Lama paco) skins associated with different coat colors. Gene 555: 88-94.

Tomitori, H., K. Kashiwagi, and K. Igarashi. (2012). Structure and function of polyamine-amino acid antiporters CadB and PotE in Escherichia coli. Amino Acids 42: 733-740.

Trip, H., M.E. Evers, W.N. Konings, and A.J.M. Driessen. (2002). Cloning and characterization of an aromatic amino acid and leucine permease of Penicillium chrysogenum. Biochim. Biophys. Acta 1565: 73-80.

Trip, H., N.L. Mulder, and J.S. Lolkema. (2013). Cloning, expression, and functional characterization of secondary amino acid transporters of Lactococcus lactis. J. Bacteriol. 195: 340-350.

Uemura, T., K. Kashiwagi, and K. Igarashi. (2007). Polyamine uptake by DUR3 and SAM3 in Saccharomyces cerevisiae. J. Biol. Chem. 282: 7733-7741.

Veljkovic, E., A. Bacconi, A. Stetak, A. Hajnal, S. Stasiuk, P.J. Skelly, I. Forster, C.B. Shoemaker, and F. Verrey. (2004). Aromatic amino acid transporter AAT-9 of Caenorhabditis elegans localizes to neurons and muscle cells. J. Biol. Chem. 279: 49268-49273.

Veljkovic, E., S. Stasiuk, P.J. Skelly, C.B. Shoemaker, and F. Verrey. (2004). Functional characterization of Caenorhabditis elegans heteromeric amino acid transporters. J. Biol. Chem. 279: 7655-7662.

Vogl, C., C.M. Klein, A.F. Batke, M.E. Schweingruber, and J. Stolz. (2008). Characterization of Thi9, a novel thiamine (Vitamin B1) transporter from Schizosaccharomyces pombe. J. Biol. Chem. 283: 7379-7389.

Wang, J., A. Shanmugam, S. Markand, E. Zorrilla, V. Ganapathy, and S.B. Smith. (2015). Sigma 1 receptor regulates the oxidative stress response in primary retinal Müller glial cells via NRF2 signaling and system xc(-), the Na+-independent glutamate-cystine exchanger. Free Radic Biol Med 86: 25-36.

Wehrmann, A., S. Morakkabati, R. Krämer, H. Sahm, and L. Eggeling. (1995). Functional analysis of sequences adjacent to dapE of Corynebacterium glutamicum reveals the presence of aroP, which encodes the aromatic amino acid transporter. J. Bacteriol. 177: 5991-5993.

Wiame, E. and E. Van Schaftingen. (2004). Fructoselysine 3-epimerase, an enzyme involved in the metabolism of the unusual Amadori compound psicoselysine in Escherichia coli. Biochem. J. 378: 1047-1052.

Widhalm, J.R., M. Gutensohn, H. Yoo, F. Adebesin, Y. Qian, L. Guo, R. Jaini, J.H. Lynch, R.M. McCoy, J.T. Shreve, J. Thimmapuram, D. Rhodes, J.A. Morgan, and N. Dudareva. (2015). Identification of a plastidial phenylalanine exporter that influences flux distribution through the phenylalanine biosynthetic network. Nat Commun 6: 8142.

Wipf, D., M. Benjdia, M. Tegeder, and W.B. Frommer. (2002). Characterization of a general amino acid permease from Hebeloma cylindrosporum. FEBS Lett. 528: 119-124.

Wipf, D., U. Ludewig, M. Tegeder, D. Rentsch, W. Koch, and W.B. Frommer. (2002). Conservation of amino acid transporters in fungi, plants and animals. Trends Biochem. Sci. 27: 139-147.

Wong, F.H., J.S. Chen, V. Reddy, J.L. Day, M.A. Shlykov, S.T. Wakabayashi, and M.H. Saier, Jr. (2012). The amino acid-polyamine-organocation superfamily. J. Mol. Microbiol. Biotechnol. 22: 105-113.

Yang J., Tan Q., Zhu W., Chen C., Liang X. and Pan L. (2014). Cloning and molecular characterization of cationic amino acid transporter y(+)LAT1 in grass carp (Ctenopharyngodon idellus). Fish Physiol Biochem. 40(1):93-104.

Young, G.B., D.L. Jack, D.W. Smith, and M.H. Saier, Jr. (1999). The amino acid/auxin:proton symport permease family. Biochim. Biophys. Acta 1415: 306-322.

Zaprasis, A., T. Hoffmann, L. Stannek, K. Gunka, F.M. Commichau, and E. Bremer. (2014). The γ-Aminobutyrate Permease GabP Serves as the Third Proline Transporter of Bacillus subtilis. J. Bacteriol. 196: 515-526.

Zheng, S., S. Shuman, and B. Schwer. (2007). Sinefungin resistance of Saccharomyces cerevisiae arising from Sam3 mutations that inactivate the AdoMet transporter or from increased expression of AdoMet synthase plus mRNA cap guanine-N7 methyltransferase. Nucleic Acids Res. 35(20):6895-6903.

Zomot, E. and I. Bahar. (2011). Protonation of glutamate 208 induces the release of agmatine in an outward-facing conformation of an arginine/agmatine antiporter. J. Biol. Chem. 286: 19693-19701.



2.A.3.1 The Amino Acid Transporter (AAT) Family


Examples:

TC#NameOrganismal TypeExample
2.A.3.1.1

Phenylalanine:H+ symporter, PheP of 458 aas and 12 established TMSs (Pi and Pittard 1996; Pi et al. 2002).  Catalytic residues have been identified (Pi et al. 1993), and interhelical interactions have been proposed (Dogovski et al. 2003).

Bacteria

PheP of E. coli

 
2.A.3.1.10S-Methylmethionine permease, MmuP BacteriaMmuP of E. coli
 
2.A.3.1.11L-Arginine permease, RocEBacteriaRocE of Bacillus subtilis
 
2.A.3.1.12Aromatic amino acid permease, AroP (Wehrmann et al., 1995)Bacteria AroP of Corynebacterium glutamicum (Q46065)
 
2.A.3.1.13Putrescine importer, PuuP (Kurihara et al., 2005)BacteriaPuuP of E. coli (P76037)
 
2.A.3.1.14Low-affinity putrescine importer PlaPBacteriaPlaP of Escherichia coli
 
2.A.3.1.15Probable transport protein YifKBacteriaYifK of Escherichia coli
 
2.A.3.1.16Uncharacterized transporter YdgFBacilli

YdgF of Bacillus subtilis (P96704)

 
2.A.3.1.17

D-serine/L-alanine/D-alanine/glycine/D-cycloserine uptake porter of 556 aas, CycA.  Can be mutated to D-cycloserine (a seconary line antitubercular drug) resistance (Chen et al. 2012).

Actinobacteria

CycA of Mycobacterium bovis

 
2.A.3.1.18

The lysine specific transporter, LysP of 488 aas and 12 TMSs (Trip et al. 2013).

Firmicutes

LysP of Lactococcus lactis

 
2.A.3.1.19

Transporter of lysine, histidine and arginine, HisP or LysQ, of 477 aas and 12 TMSs (Trip et al. 2013).

Firmicutes

LysQ (HisP) of Lactococcus lactis

 
2.A.3.1.2

Lysine:H+ symporter. Forms a stable complex with CadC to allow lysine-dependent adaptation to acidic stress (Rauschmeier et al. 2013). The Salmonella orthologue is 95% identical to the E. coli protein and is highly specific for Lysine. Residues involved in lysine binding have been identified (Kaur et al. 2014).

Bacteria

LysP of E. coli

 
2.A.3.1.20

Serine transporter, SerP2 or YdgB, of 459 aas and 12 TMSs (Trip et al. 2013). Transports L-alanine (Km = 20 μM), D-alanine (Km = 38 μM), L-serine, D-serine (Km = 356 μM) and glycine (Noens and Lolkema 2015). The encoding gene is adjacent to the one encoding SerP1 (TC# 2.A.3.1.21).

Firmicutes

SerP2 of Lactococcus lactis

 
2.A.3.1.21

Serine uptake transporter, SerP1, of 259 aas and 12 TMSs (Trip et al. 2013). L-serine is the highest affinity substrate (Km = 18 μM), but SerP1 also transports L-threonine and L-cysteine (Km values = 20 - 40 μM).  Does not transport D-serine (Noens and Lolkema 2015). The encoding gene is adjacent to a paralogue (serP2) with broad specificity for D- and L-small semipolar amino acids and glycine (see TC# 2.A.3.1.20).

Firmicutes

SerP1 of Lactococcus lactis

 
2.A.3.1.22

Transporter for phenylalainine, tyrosine and tryptophan of 449 aas and 12 TMSs, FywP or YsjA (Trip et al. 2013).

Firmicutes

FywP of Lactococcus lactis

 
2.A.3.1.23

ProY of 457 aas and 12 TMSs.  96% identical to ProY of Salmonella enterica, a cryptic proline transporter in this organism (Liao et al. 1997).

ProY of E. coli

 
2.A.3.1.24

Asparagine transporter of 499 aas and 12 TMSs, 91% identical to the orthologue in Salmonella enterica (2.A.3.1.8) (Jennings et al. 1995).

AnsP of E. coli

 
2.A.3.1.3

Aromatic amino acid:H+ symporter, AroP of 457 aas and 12 TMSs (Cosgriff and Pittard 1997). Transports phenylalanine, tyrosine and tryptophan (Honoré and Cole 1990).

Bacteria

AroP of E. coli

 
2.A.3.1.4γ-aminobutyrate:H+ symporter (also transports a variety of pyridine carboxylates) BacteriaGabP of E. coli
 
2.A.3.1.5

β-alanine/γ-aminobutyrate/proline/3,4-dehydroproline:H+ symporter, GabP (Ferson et al. 1996; Zaprasis et al. 2014).  Also transports 3-aminobutyrate, 3-aminopropanoate, cis-4-aminobutenoate (Brechtel and King 1998).

Bacteria

GabP of Bacillus subtilis

 
2.A.3.1.6Proline-specific permease (ProY) BacteriaProY of Salmonella typhimurium
 
2.A.3.1.7

D-Serine/D-alanine/glycine/D-cycloserine:H+ symporter (regulated by the small RNA, GcvB; Pulvermacher et al., 2009).  The system is active after growth in minimal medium but not after growth in complex medium (Baisa et al. 2013).

Bacteria

CycA of E. coli (P0AAE0)

 
2.A.3.1.8

Asparagine permease (AnsP) of 497 aas and 12 TMSs (Jennings et al. 1995).

Bacteria

AnsP of Salmonella typhimurium

 
2.A.3.1.9Histidine permease HutT BacteriaHutT of Pseudomonas putida
 


2.A.3.10 The Yeast Amino Acid Transporter (YAT) Family


Examples:

TC#NameOrganismal TypeExample
2.A.3.10.1High affinity histidine permease (also implicated in Mn2+ efflux; Co2+, Ni2+, Zn2+ and Cu2+ uptake) Yeast, fungiHip1 of Saccharomyces cerevisiae (P06775)
 
2.A.3.10.10Lysine permease YeastLyp1 of Saccharomyces cerevisiae (P32487)
 
2.A.3.10.11Basic amino acid permease YeastAlp1 of Saccharomyces cerevisiae (P38971)
 
2.A.3.10.12Leucine sensor/transcription factor. Mutants hyper- and hyposensitive to inducer (Poulsen et al., 2008) suggest a sensor mechanism involving outward and inward facing conformations. YeastSsy1 of Saccharomyces cerevisiae (Q03770)
 
2.A.3.10.13Dicarboxylic amino acid permease YeastDip5 of Saccharomyces cerevisiae (P53388)
 
2.A.3.10.14General amino acid permease with broad specificity, Agp3 YeastAgp3 of Saccharomyces cerevisiae (P43548)
 
2.A.3.10.15

S-adenosylmethionine uptake permease, SAM3 (also takes up polyamines, glutamate, lysine and the toxic S-adenosylmethionine analogue sinefungin) (Uemura et al., 2007; Zheng et al., 2007; Kashiwagi and Igarashi 2011).

Yeast

SAM3 or Agp3 (YPL274w) of Saccharomyces cerevisiae (Q08986)

 
2.A.3.10.16S-methylmethionine uptake permease, Mmp1 YeastMmp1 (YLL061w) of Saccharomyces cerevisiae (Q12372)
 
2.A.3.10.17General amino acid uptake permease, GAP1FungiGAP1 of Hebeloma cylindrosporum (Q8J266)
 
2.A.3.10.18The aromatic amino acid and leucine permease, ArlP (may be a general amino acid permease for neutral and basic [but not acidic] amino acids)FungiArlP of Penicillium chrysogenum (Q8NKC4)
 
2.A.3.10.19

The high affinity polyamine (spermidine > putrescine)/carnitine, low affinity amino acid transporter, AGP2 (Aouida et al., 2005; Uemura et al., 2007)

Yeast

AGP2 of Saccharomyces cerevisiae (P38090)

 
2.A.3.10.2

General amino acid permease (all L-amino acids and some D-amino acids as well as β-alanine, polyamines and GABA). Systematic mutational analysis of the intracellular regions of yeast Gap1 permease revealed multiple intracellular regions involved in its secretion, transport activity, and down-regulation (Igarashi and Kashiwagi 2010; Merhi et al., 2011). GAP1 is a "transceptor", fuctioning in both transport and reception, necessary for cAMP-independent activation of the Protein Kinase A pathway under conditions of re-addition of amino acids to cells previously starved for amino acids (Diallinas 2017).

Yeast

Gap1 of Saccharomyces cerevisiae (P19145)

 
2.A.3.10.20The high affinity basic amino acid (Arg, Lys, His) transporter, Can1 (Matijekova and Sychrova, 1997)YeastCan1 of Candida albicans (P43059)
 
2.A.3.10.21The basic amino acid (canavanine sensitivity) transporter, Cat1 (Aspuria and Tamanoi, 2008).YeastCat1 of Schizosaccharomyces pombe (Q9URZ4)
 
2.A.3.10.22Arbuscular mycorrhizal fungal proline:H+ symporter, AAP1 (binds and probably transports nonpolar, hydrophobic amino acids) (Cappellazzo et al., 2008).FungiAAP1 of Glomus mosseae (Q2VQZ4)
 
2.A.3.10.23

Amino acid permease, GAP1. Transports Arg, Met, Leu and Phe (Kraidlova et al., 2011).

Yeast

GAP1 of Candida albicans (Q5AG77)

 
2.A.3.10.24

General amino and permease and transceptor, GAP2. Transports all amino acids including citruline and eight tested toxic amino acid derivatives (Kraidlova et al., 2011).

Yeast

GAP2 of Candida albicans (Q59YT0)

 
2.A.3.10.25

Arginine transporter, GAP4 (Kraidlova et al., 2011)

Yeast

GAP4 of Candida albicans (Q59W33)

 
2.A.3.10.26

General amino acid porter, GAP6. Transports almost all amino acids tested except arginine and citruline (Kraidlova et al., 2011).

Yeast

GAP6 of Candida albicans (Q59NZ6)

 
2.A.3.10.27Valine amino-acid permease (Branched-chain amino-acid permease 3)FungiBAP3 of Saccharomyces cerevisiae
 
2.A.3.10.28

Probable amino-acid permease Meu22 (Meiotic expression up-regulated protein 22)

Yeast

Meu22 of Schizosaccharomyces pombe

 
2.A.3.10.3Proline permease YeastPut4 of Saccharomyces cerevisiae (P15380)
 
2.A.3.10.4Arginine permease YeastCan1 of Saccharomyces cerevisiae (P04817)
 
2.A.3.10.5High affinity glutamine permease YeastGnp1 of Saccharomyces cerevisiae (P48813)
 
2.A.3.10.6Leu/Val/Ile amino acid permease YeastBap2 of Saccharomyces cerevisiae (P38084)
 
2.A.3.10.7Asn/Gln permease YeastAgp1 of Saccharomyces cerevisiae (P25376)
 
2.A.3.10.8

Tryptophan permease, Tat2. Regulated via endocytosis by ATP-binding Cassette Transporters, Pdr5 (3.A.1.205.1) and Yor1 (3.A.208.3) as well as a seven-transmembrane protein, RSB1 (9.A.27.1.2) (Johnson et al., 2010).  Residues involved in binding and catalysis have been identified (Kanda and Abe 2013).  residues and regions important for proper folding and ER retention have been identified (Mochizuki et al. 2015).

Yeast

Tat2 of Saccharomyces cerevisiae (P38967)

 
2.A.3.10.9Val/Tyr/Trp permease YeastVal1 (Tat1) of Saccharomyces cerevisiae (P38085)
 


2.A.3.11 The Aspartate/Glutamate Transporter (AGT) Family


Examples:

TC#NameOrganismal TypeExample
2.A.3.11.1The aspartate uptake permease, YveA (also transports L-aspartate hydroxamate and glutamate, and possibly asparagine and glutamine; Lorca et al., 2003)Bacteria and archaeaYveA of Bacillus subtilis
 


2.A.3.12 The Polyamine:H+ Symporter (PHS) Family


Examples:

TC#NameOrganismal TypeExample
2.A.3.12.1The plasma membrane polyamine (putrescine, spermidine):H+ uptake symporter, LmPOT1 (inhibited by pentamidine and protonophores) (Hasne and Ullmann, 2005)ProtozoansPOT1 of Leishmania major (AAW52506)
 
2.A.3.12.2

The putriscene-cadaverine polyamine uptake porter, POT1.1 (613aas; 12-13 TMSs) Also called PAT12; transports paraquot as well as polyamines (Soysa et al. 2013; Fujita and Shinozaki 2014)

Euglenozoa

POT1.1 of Trypansosoma cruzi

 
2.A.3.12.3

Plasma membrane polyamine/paraquot uptake transporter of 490 aas, RMV1. Also called PUT3 and LAT1. Mutations give rise to partial paraquot (a toxic common herbicide that generates superoxide and reactive oxygen species (ROS)) (Fujita and Shinozaki 2014).

Plants

RMV1 of Arabidopsis thaliana

 
2.A.3.12.4

Golgi polyamine/paraquot uptake transporter of 478 aas, LAT4. Also called PUT2 and PAR1.  Mutations give rise to paraquot resistance (Par1) both in A. thaliana and in rice.  Probably present in the chloroplast membrane (Fujita and Shinozaki 2014).

Plants

LAT4 of Arabidopsis thaliana

 
2.A.3.12.5

Spermidine-preferring polyamine transporter, PUT1 of 531 aas.  Also transports paraquot (Fujita and Shinozaki 2014).

Plants

PUT1 of Oryza sativa

 


2.A.3.13 The Amino Acid Efflux (AAE) Family


Examples:

TC#NameOrganismal TypeExample
2.A.3.13.1

The hydrophobic amino acid efflux transporter, YjeH (exports L-methionine and other neutral, hydrophobic amino acids such as Leu, Ile and Val; R. Figge, personal communication; Liu et al. 2015).

Bacteria

YjeH of E. coli (P39277)

 
2.A.3.13.2

The Ceftriaxone resistance porter, YjeH (Hu et al. 2007).

Proteobacteria

YjeH of Salmonella enterica (serovar Typhimurium) (Q8ZKC0)

 
2.A.3.13.3

L-Leucine uptake porter, YjeH, of 426 aas and 11 or 12 TMSs (Deutschbauer et al. 2011).

YjeH of Shewanella oneidensis

 


2.A.3.14 The Unknown APC-1 (U-APC1) Family


Examples:

TC#NameOrganismal TypeExample
2.A.3.14.1

APC family member; Ala/Val/Leu-rich protein encoded within an operon that also encodes a 23S rRNA methyl transferase, RumA. Two half sized TrkA proteins are encoded within an operon that is divergently transcribed. Possibly, they regulate transport.

Bacteria

AVL-rich protein of Salinispora tropica (A4X503)

 
2.A.3.14.2

Uncharacterized transporter

Actinobacteria

Uncharacterized porter of Streptomyces coelicolor

 
2.A.3.14.3

APC protein with 610 aas and 12 TMSs.  77% identical to an orthologue in Weissella viridescens that serves as a receptor or uptake transporter for the two peptide bacteriocin, plantaricin JK (1.C.30.1.1) (Oppegård et al. 2016; Ekblad et al. 2017).

APC uptake porter of Weissella confusa

 


2.A.3.15 The Unknown APC-2 (U-APC2) Family


Examples:

TC#NameOrganismal TypeExample
2.A.3.15.1

Hypothetical transporter  (H.T.) (442 aas; 13 TMSs)

Archaea

H.T. of Picrophilus torridus (Q6L0Y3) 

 
2.A.3.15.2

Cationic amino acid transporter, CAAT (462 aas; 12 TMSs) 

Archaea

CAAT of Thermoplasma acidophilum (Q9HJ13)

 
2.A.3.15.3

Amino acid permease (AAP) (417 aas; 12 TMSs) 

Archaea

AAP of Sulfolobus solfataricus (Q97YX9)

 
2.A.3.15.4

Hypothetical protein (H.P.) 

Eukaryotes

H.P. of Dictyostelium discoideum (Q54KK4)

 
2.A.3.15.5

Uncharacterized transporter

Actinobacteria

Uncharacterized porter of Streptomyces coelicolor

 
Examples:

TC#NameOrganismal TypeExample


2.A.3.2 The Basic Amino Acid/Polyamine Antiporter (APA) Family


Examples:

TC#NameOrganismal TypeExample
2.A.3.2.1

Putrescine:ornithine antiporter for putrescine export; putrescine:H+ symporter for uptake (Igarashi and Kashiwagi 1996). Modeling tools have been used to gain information about the structures and functions of CadB and PotE in E. coli (Tomitori et al., 2012).

Bacteria

PotE of E. coli (P0AAF1)

 
2.A.3.2.10

Arginine/Ornithine antiporter of 497 aas and 13 TMSs, ArcD2 (Trip et al. 2013).

Firmicutes

ArcD2 of Lactococcus lactis

 
2.A.3.2.11

Arginine/Ornithine antiporter of 526 aas and 14 TMSs (Trip et al. 2013).

Firmicutes

ArcD1 of Lactococcus lactis

 
2.A.3.2.2

Cadaverine:lysine antiporter [Catalyzes cadaverine uptake via H+ symport (Km=21μM) and cadaverine export (Km=300 μM) via cadaverine:lysine antiport.] (Soksawatmaekhin et al., 2004). Modeling tools have been used to gain information about the structures and functions of CadB and PotE in E. coli (Tomitori et al., 2012).

Bacteria

CadB of E. coli (P0AAE8)

 
2.A.3.2.3Arginine:ornithine antiporter BacteriaArcD of Pseudomonas aeruginosa
 
2.A.3.2.4Lysine permease BacteriaLysI of Corynebacterium glutamicum
 
2.A.3.2.5

Homodimeric electrogenic arginine (Km=80μM):agmatine antiporter, AdiC, involved in extreme acid resistance (Fang et al., 2007; Gong et al., 2003; Iyer et al., 2003). A projection structure at 6.5 Å resolution has been published (Casagrande et al., 2008), and the 3.2 Å resolution X-ray structure was determined by Fang et al., 2009 and Gao et al., 2009. Protonation of glutamate 208 induces release of agmatine in the outward-facing conformation (Zomot and Bahar, 2011). The 3.0 Å structure of an Arg-bound form in an open-to-out conformation completed the picture of the major states of the porter during the transport cycle (Kowalczyk et al., 2011). Aromatic residues may regulate access to both the outward- and inward-facing states (Krammer et al. 2016).

Bacteria

YjdE (AdiC) of E. coli (P39269)

 
2.A.3.2.6Putative lysine uptake permease, YvsH (Rodionov et al., 2003)BacteriaYvsH of Bacillus subtilis (CAA11718)
 
2.A.3.2.7Arginine/agmatine antiporterBacteriaAaxC of Chlamydia pneumoniae
 
2.A.3.2.8Putative arginine/ornithine antiporterBacteriaYdgI of Escherichia coli
 
2.A.3.2.9

The histidine/histamine antiporter, HdcP of 490 aas and 13 TMSs (Trip et al. 2013).

Firmictues

HdcP of Streptococcus thermophilus

 


2.A.3.3 The Cationic Amino Acid Transporter (CAT) Family


Examples:

TC#NameOrganismal TypeExample
2.A.3.3.1System Y+ high affinity basic amino acid transporter (CAT1) (ecotropic retrovival leukemia virus receptor (ERR)) (transports arginine, lysine and ornithine; Na+-independent) MammalsCAT1(ERR) of Mus musculus
 
2.A.3.3.10Cationic amino acid transporter 3 (CAT-3) (CAT3) (Cationic amino acid transporter y+) (Solute carrier family 7 member 3)AnimalsSLC7A3 of Homo sapiens
 
2.A.3.3.11Cationic amino acid transporter 8, vacuolarPlantsCAT8 of Arabidopsis thaliana
 
2.A.3.3.12Cationic amino acid transporter 5PlantsCAT5 of Arabidopsis thaliana
 
2.A.3.3.13Cationic amino acid transporter 2, vacuolarPlantsCAT2 of Arabidopsis thaliana
 
2.A.3.3.14Cationic amino acid transporter 4, vacuolarPlantsCAT4 of Arabidopsis thaliana
 
2.A.3.3.15Uncharacterized protein MG225

Bacteria

MG225 of Mycoplasma genitalium
 
2.A.3.3.16

Uncharacterized amino acid transporter

Actinobacteria

Uncharacterized permease of Streptomyces coelicolor

 
2.A.3.3.17

Uncharacterized APC-3 family member

Actinobacteria

U-APC3a of Streptomyces coelicolor

 
2.A.3.3.18

Uncharacterized transporter

Proteobacteria

Uncharacterized transporter of Myxococcus xanthus

 
2.A.3.3.19

Histamine uptake transporter; involved in the utilization of histamine as a nitrogen source.  In an operon with two histamine catabilic enzymes, and all are induced by hsitamine (Johnson et al. 2008).

Proteobacteria

Histamine uptake transporter of Pseudomonas aeruginosa

 
2.A.3.3.2Low affinity basic amino acid transporter (CAT2) (T-cell early activation protein (TEA)) (transports arginine, lysine and ornithine; Na+-independent) (Habermeier et al., 2003) MammalsCAT2(TEA) of Mus musculus
 
2.A.3.3.20

APC family member of 663 aas and 12 TMSs.

Fungi

APC porter of Phytophthora infestans

 
2.A.3.3.21

Uncharacterized protein of 490 aas and 12 TMSs

Firmicutes

UP of Alicyclobacillus acidoterrestris

 
2.A.3.3.22

Amino acid transporter, PotE, of 475 aas.

Firmicutes

PotE of Caldanaerobacter subterraneus subsp. tengcongensis (Thermoanaerobacter tengcongensis)

 
2.A.3.3.23

Branched chain amino acid (Leucine/isoleucine/valine) uptake transporter of 469 aas and 12 TMSs, BcaP or CitA (den Hengst et al. 2006).

Firmicutes

BcaP (CitA) of Lactococcus lactis

 
2.A.3.3.24

Plastidic cationic amino acid transporter, CAT, of 582 aas and 14 TMSs.  Exports phenylalanine, tyrosine and tryptophan our of chloroplasts into the cytoplasm (Widhalm et al. 2015).

CAT of Petunia hybrida

 
2.A.3.3.3Amino acid transporter, AAT1 PlantsAAP1 of Arabidopsis thaliana
 
2.A.3.3.4The amino acid transporter, CAT6. Mediates electrogenic transport of large neutral and cationic amino acids in preference to other amino acids. Present in lateral root primordia, flowers and seeds (Hammes et al., 2006)PlantsCAT6 of Arabidopsis thaliana (Q9LZ20)
 
2.A.3.3.5The brain L-cationic (Arg, Lys, Orn, 2,4-diamino-n-butyrate) transporter, CAT3 (capacity of trans-stimulation by internal Arg) (Ito and Groudine, 1997)AnimalsCAT3 of Mus musculus (P70423)
 
2.A.3.3.6 solute carrier family 7 (orphan transporter), member 4AnimalsSLC7A4 of Homo sapiens
 
2.A.3.3.7 solute carrier family 7 (orphan transporter), member 14AnimalsSLC7A14 of Homo sapiens
 
2.A.3.3.8

Low affinity cationic amino acid transporter 2 (CAT-2) (CAT2) (Solute carrier family 7 member 2) (Closs 1996).

Animals

SLC7A2 of Homo sapiens

 
2.A.3.3.9

High affinity cationic amino acid transporter 1 (CAT-1) (CAT1) (Ecotropic retroviral leukemia receptor homologue) (Ecotropic retrovirus receptor homologue) (ERR) (Solute carrier family 7 member 1) (System Y+ basic amino acid transporter) (Closs 1996).

Animals

SLC7A1 of Homo sapiens

 


2.A.3.4 The Amino Acid/Choline Transporter (ACT) Family


Examples:

TC#NameOrganismal TypeExample
2.A.3.4.1

The single high affinity plasma membrane choline transporter of 563 aas and 12 TMSs. Expression of the CTR/HNM1 gene in wild-type cells is regulated by phospholipid precursors, inositol and choline, but no such effect is seen in cells bearing mutations in the phospholipid regulatory genes INO2, INO4 and OPI1. There is no regulation by INO2 and OPI1 in the absence of a conserved decamer motif. However constructs lacking this sequence are still controlled by INO4. Other substrates of the choline permease, i.e., ethanolamine, nitrogen mustard and nitrogen half mustard do not regulate expression of CTR/HNM1 (Li and Brendel 1993). Exposing cells to increasing levels of choline results in two different regulatory mechanisms. Initial exposure to choline results in a rapid decrease in Hnm1-mediated transport activity, whereas chronic exposure results in Hnm1 degradation through an endocytic mechanism that depends on the ubiquitin ligase Rsp5 and the casein kinase 1 redundant pair Yck1/Yck2 (Fernández-Murray et al. 2013).

Yeast

Ctr (Hnm1) of Saccharomyces cerevisiae

 
2.A.3.4.2γ-aminobutyric acid (GABA) permease, GabA Yeast, fungiGabA of Emericella nidulans
 
2.A.3.4.3

γ-aminobutyric acid (GABA) permease, Uga4 (also transports the polyamine, putrescine) (Uemura et al., 2007; Kashiwagi and Igarashi 2011).

Yeast

Uga4 of Saccharomyces cerevisiae (NP_010071)

 
2.A.3.4.4

The 7-keto-8-aminopelargonic acid (KAPA) transporter, Bio5 (Phalip et al., 1999).

FungiBio5 of Saccharomyces cerevisiae (P53744)
 
2.A.3.4.5

The polyamine (putrescine > spermidine > spermine) exporter, Tpo5p (Ykl174c) [found in the Golgi or post-Golgi secretory vesicles; induction:spermine > spermidine > putrescine] (Igarashi and Kashiwagi 2010).

Yeast

Tpo5 of Saccharomyces cerevisiae

 
2.A.3.4.6

The thiamine (vitamin B1) transporter, Thi9 (SPAC9.10). Uptake is inhibited by pyrithiamine, oxythiamine, amprolium, and the thiazole part of thiamine indicating that these compounds are substrates of Thi9 (Vogl et al., 2008).

Yeast

Thi9 of Schizosaccharomyces pombe (Q9UT18)

 
2.A.3.4.7

Uncharacterized amino acid transporter

Actinobacteria

Uncharacterized permease of Streptomyces coelicolor

 


2.A.3.5 The Ethanolamine Transporter (EAT) Family


Examples:

TC#NameOrganismal TypeExample
2.A.3.5.1Ethanolamine import permease BacteriaEthanolamine permease of Rhodococcus erythropolis
 
2.A.3.5.2Probable methylamine import permeaseArchaeaMethylamine permease of Methanosarcina acetivorans MA0143
 


2.A.3.6 The Archaeal/Bacterial Transporter (ABT) Family


Examples:

TC#NameOrganismal TypeExample
2.A.3.6.1Putative cationic amino acid permease ArchaeaCat-1 of Archaeoglobus fulgidus
 
2.A.3.6.2The putative permease, MtbP (MA2426) (possibly a methyl amine uptake porter; D.J. Ferguson, personal communication) (12 putative TMSs)

Archaea

MtbP of Methanoscarina acetivorans (Q8TN67).

 
2.A.3.6.3

ApcT, a proton coupled broad specificity amino acid transporter.  3-d structure available at 2.3Å resolution (3GIA_A; Shaffer et al., 2009).

Archaea

ApcT of Methanocaldococcus jannaschii (Q58026)

 
2.A.3.6.4Inner membrane transport protein YbaTBacteria

YbaT of Escherichia coli

 
2.A.3.6.5Uncharacterized protein MG226

Bacteria

MG226 of Mycoplasma genitalium
 


2.A.3.7 The Glutamate:GABA Antiporter (GGA) Family


Examples:

TC#NameOrganismal TypeExample
2.A.3.7.1

Glutamate:γ-aminobutyrate antiporter of 477 aas and 12 TMSs, GadC.  Expression of gadCB in L. lactis in the presence of chloride is increased when the culture pH decreases to low levels, while glutamate stimulated gadCB expression (Sanders et al. 1998). These genes encode a glutamate-dependent acid resistance mechanism that is optimally active when needed for acid neutralization.

Bacteria

GadC of Lactococcus lactis

 
2.A.3.7.2

The GadC homologue

Bacteria

YcaM of E.coli (P75835)

 
2.A.3.7.3

Glutamate:GABA antiporter, GadC (YcaM). GadC, transports GABA/Glu only under acidic conditions, with no detectable activity at pH  values higher than 6.5 (Ma et al., 2012). Ma et al. (2012) determined the crystal structure of GadC at 3.1 Å resolution under basic conditions. GadC, comprising 12 TMSs, exists in a closed state, with its carboxy-terminal domain serving as a plug to block an otherwise inward-open conformation. Structural and biochemical analyses revealed the essential transport residues, identified the transport path and suggested a transport mechanism involving the rigid-body rotation of a helical bundle for GadC and other amino acid antiporters.

Bacteria

GadC of E. coli (C8U8G2)

 
2.A.3.7.4

Inner membrane transporter, YgjI or GadC. Catalyzes L-glutamate:γ-amino butyrate (GABA) antiport (De Biase and Pennacchietti 2012).

Bacteria

YgjI of E. coli

 
2.A.3.7.5

Inner membrane transporter, YjeM of 500 aas and 12 TMSs. Probably an amino acid transporter, possibly an amino acid:organic amine antiporter.

Bacteria

YjeM of E. coli

 
2.A.3.7.6

Aspartate/Glutamate transporter of 488 aas and 12 TMSs, AcaP (Trip et al. 2013).

Firmicutes

AcaP of Lactococcus lactis

 
2.A.3.7.7

Putriscine/agmatine transporter of 466 aas and 12 TMSs, AguD or YrfD (Trip et al. 2013).

Firmicutes

AguD of Lactococcus lactis

 


2.A.3.8 The L-type Amino Acid Transporter (LAT) Family (Many LAT family members function as heterooligomers with rBAT and/or 4F2hc (TC #8.A.9))


Examples:

TC#NameOrganismal TypeExample
2.A.3.8.1

L-type neutral amino acid transporter, LAT1 (Na+-independent) (prefers amino acids with branched or aromatic side chains: Phe, Ile, Leu, Val, Trp, His; catalyzes obligatory exchange with μM affinities on the outside and mM affinities on the inside [1000x difference]). Both LAT1 and LAT2 (2.A.3.8.6) catalyze uptake of S-nitroso-L-cysteine. These and other LAT family members are specifically inhibited by 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (Li and Whorton, 2005). Mediates tryptophan:kynurenine exchange (Kaper et al., 2007). Also transports thyroid hormones (Kinne et al., 2011).  The chicken orthologue transports thyrold hormones, especially T2, with low affinity (Nele Bourgeois et al. 2016). Transports certain thyroid hormones and their derivatives (Krause and Hinz 2017).

Animals

LAT1 of Rattus norvegicus (Q63016)

 
2.A.3.8.10

Aromatic amino acid exchanger, AAT-9 (Veljkovic et al., 2004b)

Animals

AAT-9 of Caenorhabditis elegans (Q9NA91)

 
2.A.3.8.11

The aromatic-preferring amino acid transporter (ArpAT). Functions with rBAT or 4F2hc (8.A.9) and transports preferentially tyr and 3,4-dihydroxyphenylalanine (L-DOPA), but also ala, glu, ser, cys and arg by a Na+-independent mechanism (present in mouse, rat, dog and chicken, but silenced in humans and chimps)(Fernández et al., 2005; Sato et al., 2005)

Animals

ArpAT of Mus musculus (Q50E62)

 
2.A.3.8.12

The Ser/Thr exchange transporter (SteT) (also transports aromatic amino acids with lower efficiency) (Reig et al., 2007). The substrate-bound state of SteT shows increased conformational flexibility and kinetic stability, enabling transport of substrate across the cell membrane (Bippes et al. 2009). TMS8 sculpts the substrate-binding site and undergoes conformational changes during the transport cycle of SteT (Bartoccioni et al., 2010). Mutations allow substrate binding but not translocation. Other mutations stabilize the protein and result in higher production levels (Rodríguez-Banqueri et al. 2016).

Bacteria

SteT of Bacillus subtilis (O34739)

 
2.A.3.8.13The Asc-type small neutral D- and L-amino acid:H+ symport transporter-1, Asc-1 (Slc7a10). Also transports amino acid related compounds. Heterodimeric; associates with 4F2hc (TC# 8.A.9.2.1) Most highly expressed in brain and lung, but to a lesser degree in placenta and small intestine. (Fukasawa et al., 2000) AnimalsAsc-1 of Mus musculus (P63115)
 
2.A.3.8.14The Asc-type small neutral L-amino acid:H+ symport transporter-2 (Asc-2). Does not associate with 4F2hc or rBAT, but probably associates with some comparable heavy chain. Doesn't transport some substrates of Asc-1 such as α-aminoisobutyric acid and β-alanine (Chairoungdua et al., 2001) AnimalsAsc-2 of Mus musculus (Q8VIE6)
 
2.A.3.8.15The b0,+ amino acid (cystine) transporter associated with the cystinuria-related type II membrane glycoprotein, BAT1 which forms a heterodimer with rBAT (TC# 8.A.9.1.1). Present in the apical membrane of renal proximal tubules (Chairoungdua et al., 1999)AnimalsBAT1 of Rattus norvegicus (P82252)
 
2.A.3.8.16

Low-affinity methionine permease, MUP3

FungiMUP3 of Saccharomyces cerevisiae
 
2.A.3.8.17

Putative fructoselysine transporter FrlA (Wiame and Van Schaftingen 2004). Also transports psicoselysine. 

Bacteria

FrlA of Escherichia coli

 
2.A.3.8.18

Cystine/glutamate antiporter (Amino acid transport system xCT) (Calcium channel blocker resistance protein CCBR1) (Solute carrier family 7 member 11).  The pathology and development of non-competive diaryl-isoxazole inhibitors have been presented (Newell et al. 2013).  In Lama paco (alpaca), the Slc7a11 porter of 503 aas and 12 TMSs probably functions in melanogenesis and coat color regulation (Tian et al. 2015).  It interacts with mucin-1 (MUC1-C; P15941) which forms a complex with xCT.  Together they maintain glutathione levels and redox balance and influence cancer development (Hasegawa et al. 2016). xCT is the receptor for Kaposi's sarcoma-associated herpesvirus (KSHV, human herpesvirus 8), the causative agent of Kaposi's sarcoma and other lymphoproliferative syndromes often associated with HIV/AIDS (Kaleeba and Berger 2006). Sulfasalazine is an inhibitor of xCT that is known to increase cellular oxidative stress, giving it anti-tumor potential, but it seems to have many side effects (Nagane et al. 2018).

Animals

SLC7A11 (xCT) of Homo sapiens

 
2.A.3.8.19B(0,+)-type amino acid transporter 1 (B(0,+)AT) (Glycoprotein-associated amino acid transporter b0,+AT1) (Solute carrier family 7 member 9)AnimalsSLC7A9 of Homo sapiens
 
2.A.3.8.2L-type neutral amino acid transporter, ASUR4 (Na+-independent) AnimalsASUR4 of Xenopus laevis (O13020)
 
2.A.3.8.20

Large neutral amino acids transporter small subunit 2 (L-type amino acid transporter 2) (hLAT2) (Solute carrier family 7 member 8). Certain detergents stabilize and allow purification of the 4F2hc-LAT2 complex, allowing the measurement of substrate binding. In addition, an improved 3D map could be obtained (Meury et al. 2014).  Transports many amino acids including thyroid hormones 3',3-T2 and T3 (Hinz et al. 2015; Kinne et al. 2015).

Animals

SLC7A8 of Homo sapiens

 
2.A.3.8.21Asc-type amino acid transporter 1 (Asc-1) (Solute carrier family 7 member 10)AnimalsSLC7A10 of Homo sapiens
 
2.A.3.8.22

Y+L amino acid transporter 1 (Monocyte amino acid permease 2) (MOP-2) (Solute carrier family 7 member 7) (y(+)L-type amino acid transporter 1) (Y+LAT1) (y+LAT-1).  It transports cationic amino acids such as arginine and lysine out of the cell. Arginine, in particular, is critical for T-cell activation and function in the immune response, and Y+L   plays a role in the pathogenesis of T-cell acute lymphoblastic leukemia (Ji et al. 2018).

Animals

SLC7A7 of Homo sapiens

 
2.A.3.8.23

Y+L amino acid transporter 2 (Cationic amino acid transporter, y+ system) (Solute carrier family 7 member 6) (y(+)L-type amino acid transporter 2) (Y+LAT2) (y+LAT-2).  Transports certain thyroid hormones and their derivatives as well as multiple amino acids(Krause and Hinz 2017).

Animals

SLC7A6 of Homo sapiens

 
2.A.3.8.24Solute carrier family 7 member 13 (Sodium-independent aspartate/glutamate transporter 1) (X-amino acid transporter 2)AnimalsSLC7A13 of Homo sapiens
 
2.A.3.8.25

Large neutral amino acids transporter small subunit 1 (4F2 light chain) (4F2 LC) (4F2LC) (CD98 light chain) (Integral membrane protein E16) (L-type amino acid transporter 1) (hLAT1) (Solute carrier family 7 member 5) (y+ system cationic amino acid transporter).  The heavy chain, CD98hc, modulates integrin signaling, plays a role in cell-to-cell fusion, and is essential for Brucella infection (Keriel et al. 2015).  In addition to L-amino acids, Lat1 in conjunction with 4F2hc, transports S-nitroso-L-cysteine (Li and Whorton 2007).

Animals

SLC7A5 of Homo sapiens

 
2.A.3.8.26

Unchracterized transporter

Actinobacteria

Uncharacterized permease of Streptomyces coelicolor

 
2.A.3.8.27

Amino acid transporter 6 (AAT-6). Interacts with NRFL-1, the C. elegans NHERF orthologue to promote localization to the intestinal luminal membrane (Hagiwara et al. 2012).

Animals

AAT-6 of Caenorhabditis elegans

 
2.A.3.8.28

Serine/threonine exchanger, SteT

Bacteriodetes

SteT of Cecembia lonarensis

 
2.A.3.8.29

Cationic amino acid transporter, y+LAT1.  95% identical to a characterized carp orthologue (Yang et al. 2013).

Animals

y+LAT1 cationic amino acid transporter of Danio rerio (Zebra fish)

 
2.A.3.8.3The schistosome neutral and cationic amino acid transporter, SPRM1lc (Na+-independent), (takes up phe, arg, lys, ala, gln, his, trp and leu; functions with SPRM1hc (TC# 8.A.9.3.1) (Krautz-Peterson et al., 2007) AnimalsSPRM1lc of Schistosoma mansoni (Q26594)
 
2.A.3.8.30

Putative amino acid porter of 512 aas and 14 TMSs.

Crenarchaea

Amino acid porter of Sulfolobus islandica

 
2.A.3.8.31

Putative polyamine transporter of 537 aas and 12 TMSs

Tenericutes

Putative polyamine porter of Mycoplasma (Acholeplasma) florum

 
2.A.3.8.32

Large neutral amino acid transporter, CD98lc (LAT), of 442 aas.  Functions with CD98hc (TC# 8.A.9.2.3) (Reynolds et al. 2009).  CD98hc also modulates integrin signaling (Prager et al. 2007), plays a role in cell-to-cell fusion, and is essential for Brucella infection (Keriel et al. 2015).

Animals

CD98lc of Drosophila melanogaster

 
2.A.3.8.4

L-methionine transporter, MUP1.  Also transports selenomethionine (SeMet) (Kitajima et al. 2010).

Yeast

MUP1 of Saccharomyces cerevisiae (P50276)

 
2.A.3.8.5

Cystine/glutamate antiporter, xCT (requires the 4F2hc protein (TC #8.A.9.2.1)). Functions in the generation of glutathione and plays a role in the oxidative stress response (Wang et al. 2015).

Animals

xCT of Mus musculus (Q9WTR6)

 
2.A.3.8.6

L-type neutral amino acid transporter, LAT2 (Na+-independent with broad specificity for all L-isomers of neutral amino acids; preferred substrate: Phe, His, Trp, Ile, Val, Leu, Gln, Cys, Ser; catalyzes obligatory exchange with μM affinities on the outside and mM affinities on the inside [1000x difference]). Both LAT2 and LAT1 (2.A.3.8.1) catalyze uptake of S-nitro-L-cysteine (Li and Whorton, 2005). Also transports thyroid hormones (Kinne et al., 2011).

Animals

LAT2 of Rattus norvegicus (Q9WVR6)

 
2.A.3.8.7y+LAT1 (transports neutral amino acids (i.e., Leu) in symport with Na+, Li+ or H+ in 1:1 stoichiometry; transports basic amino acids (i.e., Lys) by facilitated diffusion without a symported cation). Also transports the neurotoxicant, methylmercury-L-cysteine by molecular mimicry. Causes the Lysinuric protein intolerance condition in humans (Q9UM01) (Broer, 2008). Animalsy+LAT1 of Rattus norvegicus (Q9QZ66)
 
2.A.3.8.8Aspartate/glutamate Na+-independent transporter, AGT1AnimalsAGT1 of Mus musculus (Q91WN3)
 
2.A.3.8.9

Heteromeric amino acid transporter #1 (transports most neutral aas with highest rates for Ala and Ser (Km≈100 μM)). They function by obligatory aa:aa exchange (Veljkovic et al., 2004b).

Animals

AAT1 of Caenorhabditis elegans (Q19834)

 


2.A.3.9 The Spore Germination Protein (SGP) Family


Examples:

TC#NameOrganismal TypeExample
2.A.3.9.1

Spore germination protein A2 (AB) (amino acid [L-alanine] receptor.) GerAA, GerAB and GerAC form a receptor complex in the spore inner membrane. GerAC is a lipoprotein (Cooper and Moir, 2011).

Gram-positive bacteria

GerAB of Bacillus subtilis (P07869)

 
2.A.3.9.2Spore germination protein B2 (BB) (amino acid [D-alanine and L-asparagine] receptor) Gram-positive bacteriaGerBB of Bacillus subtilis
 
2.A.3.9.3Spore germination protein K2 (KB) (probable amino acid receptor)Gram-positive bacteriaGerKB of Bacillus subtilis
 
2.A.3.9.4Spore germination protein YndEBacilli

YndE of Bacillus subtilis

 
2.A.3.9.5

Spore germination protein of 368 aas and 10 TMSs.  Maps adjacent to a putative ABC transporter of unknown specificity (F8FLY8, F8FLY7, F8FLY5). 

Firmicutes

SGP of Paenibacillus mucilaginosus