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). Cationic amino acid transporters (CAT; SLC7A1 - 4 and 14) play roles in malignant tumors and immune microenvironment (You et al. 2023). Transporters in the APC superfamily influence ferroptosis which may inhibit bone formation and promote bone absorption through oxidative stress, thus leading to osteoporosis. The study of ferroptosis on osteoblasts and osteoclasts may allow for the diagnosis and treatment of osteoporosis (Cao et al. 2023).

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 TMSs, whereas residues involved in uptake are located in the periplasmic loops and the TMSs (Soksawatmaekhin et al., 2006). A hydrophilic cavity is proposed to be formed by TMSs 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 of transport.  The genome wide identification and characterization of the amino acid transporter (AAT) genes regulating seed protein content in chickpea (Cicer arietinum L.) has been published (Kalwan et al. 2023).  Rigid bodies and relative movements of TMSs occur during distinct steps of the transport cycle (Licht et al. 2024). In all transporters with the LeuT fold, the bundle (first two TMSs of each repeat) rotates relative to the hash (third and fourth TMSs). Motions of the arms (fifth TMS) to close or open the intracellular and outer vestibules are common, as is a TMS1a swing, with notable variations in the opening-closing motions of the outer vestibule. These analyses suggest that LeuT-fold transporters layer distinct motions on a common bundle-hash rock and demonstrate that systematic analyses can provide new insights into large structural datasets (Licht et al. 2024).

.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 approximately 45 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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Wunderlich, J. (2022). Updated List of Transport Proteins in. Front Cell Infect Microbiol 12: 926541.

Xiao, J., D. Wang, L. Wang, Y. Jiang, L. Xue, S. Sui, J. Wang, C. Guo, R. Wang, J. Wang, N. Li, H. Fan, and M. Lv. (2020). Increasing L-lysine production in Corynebacterium glutamicum by engineering amino acid transporters. Amino Acids 52: 1363-1374.

Yakubov, E., S. Schmid, A. Hammer, D. Chen, J.K. Dahlmanns, I. Mitrovic, L. Zurabashvili, N. Savaskan, H.H. Steiner, and M. Dahlmanns. (2023). Ferroptosis and PPAR-gamma in the limelight of brain tumors and edema. Front Oncol 13: 1176038.

Yan, R., Y. Li, Y. Shi, J. Zhou, J. Lei, J. Huang, and Q. Zhou. (2020). Cryo-EM structure of the human heteromeric amino acid transporter bAT-rBAT. Sci Adv 6: eaay6379.

Yan, Y., H. Teng, Q. Hang, L. Kondiparthi, G. Lei, A. Horbath, X. Liu, C. Mao, S. Wu, L. Zhuang, M. James You, M.V. Poyurovsky, L. Ma, K. Olszewski, and B. Gan. (2023). SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells. Nat Commun 14: 3673.

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.

You, S., X. Han, Y. Xu, and Q. Yao. (2023). Research progress on the role of cationic amino acid transporter (CAT) family members in malignant tumors and immune microenvironment. Amino Acids. [Epub: Ahead of Print]

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.

Zhang, B., Y. Jin, L. Zhang, H. Wang, and X. Wang. (2022). Pentamidine Ninety Years on: the Development and Applications of Pentamidine and its Analogs. Curr. Med. Chem. [Epub: Ahead of Print]

Zhang, W., H.A. Campbell, S.C. King, and W. Dowhan. (2005). Phospholipids as determinants of membrane protein topology. Phosphatidylethanolamine is required for the proper topological organization of the γ-aminobutyric acid permease (GabP) of Escherichia coli. J. Biol. Chem. 280: 26032-26038.

Zhang, X., X. Zheng, X. Ying, W. Xie, Y. Yin, and X. Wang. (2023). CEBPG suppresses ferroptosis through transcriptional control of SLC7A11 in ovarian cancer. J Transl Med 21: 334.

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


TC#NameOrganismal TypeExample

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).


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

Serine/Threonine transport protein, YifK of 461 aas and 12 TMSs in a probable 6 + 6 TMS arrangement (Khozov et al. 2023).


YifK of Escherichia coli

2.A.3.1.16Uncharacterized transporter YdgFBacilli

YdgF of Bacillus subtilis (P96704)


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).


CycA of Mycobacterium bovis


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


LysP of Lactococcus lactis


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


LysQ (HisP) of Lactococcus lactis


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).


LysP of E. coli


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).


SerP2 of Lactococcus lactis


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).


SerP1 of Lactococcus lactis


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


FywP of Lactococcus lactis


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


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


D-serine/D-alanine/glycine transporter, LysP or AnsP, of 453 aas and 11 TMSs (Xiao et al. 2020).

LysP of Corynebacterium glutamicum


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).


AroP of E. coli


γ-aminobutyrate:H+ symporter, GabP. It also transports a variety of pyridine carboxylates. Phosphatidylethanolamine is required for its proper topological organization(Zhang et al. 2005).


GabP of E. coli


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).


GabP of Bacillus subtilis

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

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).


CycA of E. coli (P0AAE0)


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


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


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)

Lysine permease of 611 aas and 13 putative TMSs, Lyp1.  Extracellular loops affect either the localization or activity of Lyp1. Half of the mutants are located in the extension of extracellular loop 3 or in a predicted alpha-helix in extracellular loop 4 (Van't Klooster et al. 2020). Phosphatidylserine and ergosterol are essential for Lyp1 function, and the transport activity displays a sigmoidal relationship with the concentration of these lipids. Lyp1 requires a relatively high fraction of lipids with one or more unsaturated acyl chains. Possibly a narrow band of lipids immediately surrounding the transmembrane stalk of a model protein allows conformational changes in the protein (Van't Klooster et al. 2020).


Lyp1 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)

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).


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)

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


AGP2 of Saccharomyces cerevisiae (P38090)


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).


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)

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


GAP1 of Candida albicans (Q5AG77)


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


GAP2 of Candida albicans (Q59YT0)


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


GAP4 of Candida albicans (Q59W33)


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


GAP6 of Candida albicans (Q59NZ6)

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

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


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)

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). Tat2 may be a target of the anti-fungal agent, glabridine (Kalli et al. 2023).


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


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


TC#NameOrganismal TypeExample

The plasma membrane polyamine (putrescine, spermidine):H+ uptake symporter, LmPOT1 (inhibited by pentamidine and protonophores) (Hasne and Ullmann, 2005; Zhang et al. 2022).


POT1 of Leishmania major (AAW52506)


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)


POT1.1 of Trypansosoma cruzi


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).


RMV1 of Arabidopsis thaliana


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).


LAT4 of Arabidopsis thaliana


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


PUT1 of Oryza sativa


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


TC#NameOrganismal TypeExample

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).


YjeH of E. coli (P39277)


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


YjeH of Salmonella enterica (serovar Typhimurium) (Q8ZKC0)


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


TC#NameOrganismal TypeExample

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.


AVL-rich protein of Salinispora tropica (A4X503)


Uncharacterized transporter


Uncharacterized porter of Streptomyces coelicolor


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


TC#NameOrganismal TypeExample

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


H.T. of Picrophilus torridus (Q6L0Y3) 


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


CAAT of Thermoplasma acidophilum (Q9HJ13)


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


AAP of Sulfolobus solfataricus (Q97YX9)


Hypothetical protein (H.P.) 


H.P. of Dictyostelium discoideum (Q54KK4)


Uncharacterized transporter


Uncharacterized porter of Streptomyces coelicolor


TC#NameOrganismal TypeExample

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


TC#NameOrganismal TypeExample

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).


PotE of E. coli (P0AAF1)


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


ArcD2 of Lactococcus lactis


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


ArcD1 of Lactococcus lactis


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).


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

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). Both the glutamate- and arginine (AdiC; TC# 2.A.3.2.5)-dependent acid resistance systems increase the internal pH and reverse the transmembrane potential (Richard and Foster 2004).


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

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


HdcP of Streptococcus thermophilus


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


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

Cationic amino acid transporter 3 (CAT-3) (CAT3) (Cationic amino acid transporter y+) (Solute carrier family 7 member 3). Mutations in CAT3 are potential causes of childhood epilepsy (Sourbron et al. 2021).


SLC7A3 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


MG225 of Mycoplasma genitalium

Uncharacterized amino acid transporter


Uncharacterized permease of Streptomyces coelicolor


Uncharacterized APC-3 family member


U-APC3a of Streptomyces coelicolor


Uncharacterized transporter


Uncharacterized transporter of Myxococcus xanthus


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).


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

APC family member of 663 aas and 12 TMSs.


APC porter of Phytophthora infestans


Uncharacterized protein of 490 aas and 12 TMSs


UP of Alicyclobacillus acidoterrestris


Amino acid transporter, PotE, of 475 aas.


PotE of Caldanaerobacter subterraneus subsp. tengcongensis (Thermoanaerobacter tengcongensis)


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


BcaP (CitA) of Lactococcus lactis


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


Amino acid transporter, AAT1 or CAT1, of 594 aas and 14 TMSs. It is a high-affinity permease involved in the transport of the cationic amino acids (e.g., arginine, lysine, histidine, citrulline, valine, and glutamate). It transports mostly basic amino acids, and, to a lesser extent, neutral and acidic amino acids. It probably functions as a proton symporter. It transports histidine with a Km of 35 μM at Ph 4.5, the optimal pH for this system (Frommer et al. 1995).  Amino acid transporter (AAT) genes regulate seed protein content in chickpea (Cicer arietinum L.) (Kalwan et al. 2023).


AAT1 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

solute carrier family 7 (orphan transporter), member 14, SLC7A14 of 771 aas and 15 or 16 TMSs. SLC7A14 mutations occur in patients with inherited retinal dystrophy (autosomal recessive retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) (Guo et al. 2019). It is a pH-dependent, trans-stimulated, low affinity cationic amino acid (e.g., arg and lys) system that is inhibited by α-trimethyl-L-lysine, properties assigned to lysosomal transport system c in human skin fibroblasts (Jaenecke et al. 2012).


SLC7A14 of Homo sapiens


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


SLC7A2 of Homo sapiens


High affinity cationic amino acid transporter 1 (CAT-1) (CAT1, CTR1) (Ecotropic retroviral leukemia receptor homologue) (ERR), (SLC7a1) (System Y+ basic amino acid transporter) (Closs 1996). It takes up Arginine, Lysine and Ornithine. Its gene shows increased expression in various cancers such as colorectal cancer (CRC) (Okita et al. 2020). Treatment of a blood-brain barrier (BBB) mimetic with CAT-1 substrates as well as knockdown of CAT-1 expression yielded increases in leptin transport.Thus, an amino acid transporter is a regulator of leptin BBB transport in the iPSC-derived BBB model. These results provide insight into regulation of hormone transport across the BBB (Shi et al. 2022).  It is a possible drug target for pheochromocytomas and paragangliomas (PPGLs), rare neuroendocrine tumors (Vit et al. 2023).


SLC7A1 of Homo sapiens


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


TC#NameOrganismal TypeExample

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).


Ctr (Hnm1) of Saccharomyces cerevisiae

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

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


Uga4 of Saccharomyces cerevisiae (NP_010071)


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

FungiBio5 of Saccharomyces cerevisiae (P53744)

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).


Tpo5 of Saccharomyces cerevisiae


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).


Thi9 of Schizosaccharomyces pombe (Q9UT18)


Uncharacterized amino acid transporter


Uncharacterized permease of Streptomyces coelicolor


SwnT of 501 aas and 12 TMSs in a 6 + 6 TMS arrangement. Slafractonia leguminicola infects red clover and other legumes, causing black patch disease. This fungus produces two mycotoxins, slaframine and swainsonine, that are toxic to livestock grazing on clover hay or pasture infested with S. leguminicola. Swainsonine toxicosis causes locoism, while slaframine causes slobbers syndrome. SwnT may play a role in pathogenesis in addition to mycotoxin transport (Das et al. 2023).

SwnT of Slafractonia leguminicola


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


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


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)


MtbP of Methanoscarina acetivorans (Q8TN67).


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


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


MG226 of Mycoplasma genitalium

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


TC#NameOrganismal TypeExample

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.


GadC of Lactococcus lactis


The GadC homologue


YcaM of E.coli (P75835)


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.  Both this glutamate- and the arginine (AdiC; TC#2.A.3.2.5)-dependent acid resistance systems increase the internal pH and reverse the transmembrane potential (Richard and Foster 2004).


GadC of E. coli (C8U8G2)


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


YgjI of E. coli


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


YjeM of E. coli


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


AcaP of Lactococcus lactis


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


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))


TC#NameOrganismal TypeExample

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 and their derivatives (Kinne et al., 2011; Krause and Hinz 2017; Krause and Hinz 2019).  The chicken orthologue transports thyrold hormones, especially T2, with low affinity (Nele Bourgeois et al. 2016). Lat1 transports 26 biologically active ultrashort peptides (USPs) into cells as is also true of LAT2 and PEPT1 (Khavinson et al. 2023). The sizes and structures of ligand-binding sites of the amino acid transporters LAT1, LAT2, and of the peptide transporter PEPT1 are sufficient for the transport of the 26 biologically active di-, tri-, and tetra-peptides. Comparative analyses of the binding of all possible di- and tri-peptides (8400 compounds) at the binding sites of the LAT and PEPT family transporters was considered (Khavinson et al. 2023). The 26 biologically active USPs systematically showed higher binding scores to LAT1, LAT2, and PEPT1, as compared with di- and tri-peptides. Most of the 26 studied USPs were found to bind to the LAT1, LAT2, and PEPT1 transporters more efficiently than the previously known substrates or inhibitors of these transporters. Peptides ED, DS, DR, EDR, EDG, AEDR, AEDL, KEDP, and KEDG, and peptoids DS7 and KE17 with negatively charged Asp- or Glu- amino acid residues at the N-terminus and neutral or positively charged residues at the C-terminus of the peptide were found to be the most effective ligands of the transporters under investigation. It can be assumed that the antitumor effect of the KE, EW, EDG, and AEDG peptides could be associated with their ability to inhibit the LAT1, LAT2, and PEPT1 amino acid transporters (Khavinson et al. 2023). LAT1 enables T cell activation under inflammatory conditions in mice (Ogbechi et al. 2023).


LAT1 of Rattus norvegicus (Q63016)


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


AAT-9 of Caenorhabditis elegans (Q9NA91)


The aromatic-preferring amino acid transporter (ArpAT or Slc7a15). 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).  It is expressed in the CNS (Sreedharan et al. 2011).


ArpAT of Mus musculus (Q50E62)


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).


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)

Low-affinity methionine permease, MUP3

FungiMUP3 of Saccharomyces cerevisiae

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


FrlA of Escherichia coli


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. It also forms a complex with SLC3A2 heavy chain (CD98hc, 4F2hc or MDU1 (TC# 8.A.9.2.2). 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). xCT is a cancer stem cell-related target and can be used to develop preclinical therapeutic approaches, able to hamper tumor growth and dissemination (Ruiu et al. 2019). Residues involved in substrate binding have been proposed based on in silico approaches (Sharma and Anirudh 2019). The tissue distribution of xCT in chickens has been determined (Choi et al. 2020). xCT supports tumor cell growth through glutathione-based oxidative stress resistance, and mutations can enhance its stability (Oda et al. 2020). Signals of pseudo-starvation unveiled that SLC7A11 is key determinant in the control of Treg (T) cell proliferative potential (Procaccini et al. 2021). xCT antiporter function inhibits HIV-1 infection (Rabinowitz et al. 2021). SLC7A11 providess a gateway of metabolic perturbation and ferroptosis vulnerability in cancer (Lee and Roh 2022). CEBPG (CCAAT Enhancer Binding Protein Gamma) suppresses ferroptosis through transcriptional control of SLC7A11 in ovarian cancer (Zhang et al. 2023). xCT protects cancer cells from oxidative stress and is overexpressed in many cancers. Yan et al. 2023 reported that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H2O2, a common oxidative stress inducer, its high overexpression dramatically increases H2O2-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H2O2 treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). Additionally, high overexpression of SLC7A11 promotes tumor growth but suppresses tumor metastasis, likely because metastasizing cancer cells with high expression of SLC7A11 are particularly susceptible to oxidative stress. Our findings reveal that xCT expression level dictates cancer cells' sensitivity to oxidative stress and suggests a context-dependent role for SLC7A11 in tumor biology (Yan et al. 2023).  By inhibiting the xCT transporter or AMPA receptors in vivo, brain swelling and peritumoral alterations can be mitigated (Yakubov et al. 2023). Butyrate enhances erastin-induced ferroptosis of osteosarcoma cells by regulating the ATF3/SLC7A11 pathway(Nie et al. 2023).  It shows increased activity in ovarian cancer and may be a theraputic target (Fantone et al. 2024; Han et al. 2024).


SLC7A11 (xCT) of Homo sapiens


B(0,+)-type amino acid transporter 1 (B(0,+)AT) (Glycoprotein-associated amino acid transporter b0,+AT1) (Solute carrier family 7 member 9).  The cryo-EM structure of the human heteromeric amino acid transporter b(0,+)AT-rBAT complex has been solved (Yan et al. 2020). The two subunits, a heavy chain and a light chain are linked by a disulfide bridge. The light chain forms a heterodimer with rBAT, a heavy chain which mediates the membrane trafficking of b(0,+)AT. The b(0,+)AT-rBAT complex is an obligatory exchanger, which mediates the influx of cystine and cationic amino acids and the efflux of neutral amino acids in the kidney and small intestine. Yan et al. 2020 reported the cryo-EM structure of the human b(0,+)AT-rBAT complex alone and in complex with an arginine substrate at resolutions of 2.7 and 2.3 Å, respectively. The overall structure is a dimer of heterodimers. Arg is bound to the substrate binding site in an occluded pocket. The cryoEM structure reveals a heterotetrameric protein assembly composed of two heavy and two light chain subunits, respectively. The  interaction between the two units is mediated by dimerization of the heavy chain subunits and does not include participation of the light chain subunits (Wu et al. 2020). The b((0,+))AT1 transporter adopts a LeuT fold and is in an inward-facing conformation. An amino-acid-binding pocket is formed by transmembrane helices 1, 6, and 10 and is conserved among SLC7 transporters.


SLC7A9 of Homo sapiens


L-type neutral amino acid transporter, ASUR4 (Na+-independent) of 507 aas and 12 TMSs. Pregabalin (PGB), a drug for the treatment of epilepsy, neuropathic pain, fibromyalgia, and generalized anxiety disorder, may be transported by L-type transporters (Su et al. 2005).


ASUR4 of Xenopus laevis (O13020)


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).


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

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).


SLC7A7 of Homo sapiens


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).


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

Large neutral amino acids transporter small subunit 1 (4F2 light chain) (4F2 LC) (4F2LC) (CD98 light chain; SLC3A2; LAT1) (Integral membrane protein E16) (L-type amino acid transporter 1) (hLAT1) (Solute carrier family 7 member 5) (y+ system cationic and neutral 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 several large neutral L-amino acids, Lat1 in conjunction with 4F2hc, transports S-nitroso-L-cysteine (Li and Whorton 2007), is important for transport of certain drugs into the brain, and is important for cancer (Lee et al. 2019). LAT1/CD98 mediates a Na+ and pH-independent antiport of amino acids (Scalise et al. 2018). It has been demonstrated that the preferred substrate is histidine, but many large amino acids are also sustrates. CD98 is not required for transport, being plausibly involved in routing LAT1 to the plasma membrane. Homology models have been built on the basis of the AdiC transporter from E.coli. Crucial residues for substrate recognition and gating have been identified using a combined approach of bioinformatics and site-directed mutagenesis coupled to functional assays. LAT1 is involved in important human diseases such as neurological disorders and cancer (Scalise et al. 2018). The cryo-EM structure of the human LAT1-CD98hc heterodimer at 3.3-A resolution has been determined (Lee et al. 2019). LAT1 features a canonical Leu T-fold and exhibits an unusual loop structure on transmembrane helix 6, creating an extended cavity that might accommodate bulky amino acids and drugs. CD98hc engages with LAT1 through extracellular, transmembrane and putative cholesterol-mediated interactions. The SLC7A5 (LAT1) gene, which encodes the main transmembrane transporter of large neutral amino acids and of thyroid hormones, exists as variants, one of which is responsible for obesity in patients with phenylketonuria (Bik-Multanowski et al. 2020). SLC7A5 functions in mTORC1 ativation in late endosomes (Jin et al. 2021). It is the main transporter for phenylalanine, and management precautions for risk of obesity are necessary among infants with PKU carrying the rs113883650 variant of the LAT1 gene (Bik-Multanowski et al. 2022). CD98hc is expressed in pancreatic ductal adenocarcinomas in increased amounts (Bianconi et al. 2022). Human LAT1 (SLC7A5) transports amino acids, thyroid hormones, and drugs such as the Parkinson's disease drug levodopa (L-Dopa). It is found in the blood-brain barrier, testis, bone marrow, and placenta, and its dysregulation has been associated with various neurological diseases, such as autism and epilepsy, as well as cancer (Hutchinson et al. 2022). The inhibitor specificities of LAT1 have been described (Hutchinson et al. 2022). SLC7A5 and SLC7A11 can be manipuated to eliminate the barrier to successful CAR-T therapy (Panetti et al. 2022).  Targeting glutamine metabolic reprogramming of SLC7A5 enhances the efficacy of anti-PD-1 in triple-negative breast cancer (Huang et al. 2023). The human LAT1-4F2hc (SLC7A5-SLC3A2) transporter complex has been implicated in physiological and pathophysiological characteristics (Kahlhofer and Teis 2022).  Four cholesterol-binding sites (CHOL1-4) were identified in a recent LAT1-apo inward-open conformation cryo-EM structure. Hutchinson and Schlessinger 2024 explored the interactions between LAT1 and cholesterol. Their findings suggested that CHOL3 forms the most stable and favorable interactions within LAT1. Fat mass and obesity-associated protein (FTO) mediated m6A modification of circFAM192A promotes gastric cancer proliferation by suppressing SLC7A5 decay (Wu et al. 2024).


SLC7A5 of Homo sapiens


Unchracterized transporter


Uncharacterized permease of Streptomyces coelicolor


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).


AAT-6 of Caenorhabditis elegans


Serine/threonine exchanger, SteT


SteT of Cecembia lonarensis


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


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)

Putative amino acid porter of 512 aas and 14 TMSs.


Amino acid porter of Sulfolobus islandica


Putative polyamine transporter of 537 aas and 12 TMSs


Putative polyamine porter of Mycoplasma (Acholeplasma) florum


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).


CD98lc of Drosophila melanogaster


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


MUP1 of Saccharomyces cerevisiae (P50276)


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). xCT is involved in the export of intracellular glutamate in exchange for extracellular cystine. Glutamate is the main neurotransmitter in the retina and plays a key metabolic role as a major anaplerotic substrate in the tricarboxylic acid cycle to generate adenosine triphosphate (ATP) (Knight et al. 2023). Glutamate is also involved in the outer plexiform glutamate-glutamine cycle, which links photoreceptors and supporting Müller cells and assists in maintaining photoreceptor neurotransmitter supply. Knight et al. 2023 investigated the role of xCT, the light chain subunit responsible for antiporter function, in glutamate pathways in the mouse retina using an xCT knockout mouse. As xCT is a glutamate exporter, loss of xCT function could influence the presynaptic metabolism of photoreceptors and postsynaptic levels of glutamate, and this proved to be true. Loss of xCT function resulted in glutamate metabolic disruption through the accumulation of glutamate in photoreceptors and a reduced uptake of glutamate by Müller cells, which in turn decreases glutamine production. These findings support the idea that xCT plays a role in the presynaptic metabolism of photoreceptors and postsynaptic levels of glutamate and derived neurotransmitters in the retina. (Knight et al. 2023).  Loss of xCT function results in glutamate metabolic disruption through the accumulation of glutamate in photoreceptors and a reduced uptake of glutamate by Müller cells, which in turn decreases glutamine production.


xCT of Mus musculus (Q9WTR6)


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). Lat1 transports 26 biologically active ultrashort peptides (USPs) into cells as is also true of LAT2 and PEPT1 (Khavinson et al. 2023). The sizes and structures of ligand-binding sites of the amino acid transporters LAT1, LAT2, and of the peptide transporter PEPT1 are sufficient for the transport of the 26 biologically active di-, tri-, and tetra-peptides. Comparative analyses of the binding of all possible di- and tri-peptides (8400 compounds) at the binding sites of the LAT and PEPT family transporters was considered (Khavinson et al. 2023). The 26 biologically active USPs systematically showed higher binding scores to LAT1, LAT2, and PEPT1, as compared with di- and tri-peptides. Most of the 26 studied USPs were found to bind to the LAT1, LAT2, and PEPT1 transporters more efficiently than the previously known substrates or inhibitors of these transporters. Peptides ED, DS, DR, EDR, EDG, AEDR, AEDL, KEDP, and KEDG, and peptoids DS7 and KE17 with negatively charged Asp- or Glu- amino acid residues at the N-terminus and neutral or positively charged residues at the C-terminus of the peptide were found to be the most effective ligands of the transporters under investigation. It can be assumed that the antitumor effect of the KE, EW, EDG, and AEDG peptides could be associated with their ability to inhibit the LAT1, LAT2, and PEPT1 amino acid transporters (Khavinson et al. 2023).


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)

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).


AAT1 of Caenorhabditis elegans (Q19834)


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


TC#NameOrganismal TypeExample

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). GerAB is an α-helical transmembrane protein containing a water channel. Alanine binds transiently to specific sites on GerAB, initiating L-alanine-mediated signaling by GerAB, which facilitates early events in spore germination (Blinker et al. 2021).

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


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


SGP of Paenibacillus mucilaginosus