| 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. They occur in bacteria, archaea, yeast, fungi, unicellular eukaryotic protists, slime molds, plants and animals. 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 4F2 cell surface antigen heavy chain of Homo sapiens (spP08195). 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).
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.
|
| References: |
Brechtel, C.E. and S.C. King. (1998). 4-aminobutyrate (GABA) transporters from the amine-polyamine-choline superfamily: substrate specificity and ligand recognition profile of the 4-aminobutyrate permease from Bacillus subtilis. Biochem. J. 333: 565-571.
|
Cabrera-Martinez, R.-M., F. Tovar-Rojo, V.R. Vepachedu, and P. Setlow. (2003). Effects of overexpression of nutrient receptors on germination of spores of Bacillus subtilis. J. Bacteriol. 185: 2457-2464.
|
Closs, E.I., L.M. Albritton, J.W. Kim, and J.M. Cunningham. (1993). Identification of a low affinity, high capacity transporter of cationic amino acids in mouse liver. J. Biol. Chem. 268: 7538-7544.
|
Cosgriff, A.J. and A.J. Pittard. (1997). A topological model for the general aromatic amino acid permease, AroP, of Escherichia coli. J. Bacteriol. 179: 3317-3323.
|
Cosgriff, A.J., G. Brasier, J. Pi, C. Dogovski, J.P. Sarsero, and A.J. Pittard. (2000). The study of AroP-PheP chimeric proteins and identification of a residue involved in tryptophan transport. J. Bacteriol. 182: 2207-2217.
|
Didion, T., B. Regenberg, M.U. Jřrgensen, M.C. Kielland-Brandt, and H.A. Andersen. (1998). The permease homologue Ssy1p controls the expression of amino acid and peptide transporter genes in Saccharomyces cerevisiae. Mol. Microbiol. 27: 643-650.
|
Farcasanu, I.C., M. Mizunuma, D. Hirata, and T. Miyakawa. (1998). Involvement of histidine permease (Hip1p) in manganese transport in Saccharomyces cerevisiae. Mol. Gen. Genet. 259: 541-548.
|
Fischer, W.-N., B. André, D. Rentsch, S. Krolkiewics, M. Tegeder, K. Breitkreuz, and W.B. Frommer. (1998). Amino acid transport in plants. Trends Plant Sci. 3: 188-195.
|
Gasol, E., M. Jiménez-Vidal, J. Chillarón, A. Zorzano, and M. Palacín. (2004). Membrane topology of system xc- light subunit reveals a re-entrant loop with substrate-restricted accessibility. J. Biol. Chem. 279: 31228-31236.
|
Gong, S., H. Richard, and J.W. Foster. (2003). YjdE (AdiC) is the arginine:agmatine antiporter essential for arginine-dependent acid resistance in Escherichia coli. J. Bacteriol. 185: 4402-4409.
|
Habermeier, A., S. Wolf, U. Martiné, P. Gräf, and E.I. Closs. (2003). Two amino acid residues determine the low substrate affinity of human cationic amino acid transporter-2A. J. Biol. Chem. 278: 19492-19499.
|
Hu, L.A. and S.C. King. (1998a). Functional significance of the "signature cysteine" in helix 8 of the Escherichia coli 4-aminobutyrate transporter from the amine-polyamine-choline superfamily. J. Biol. Chem. 273: 20162-20167.
|
Hu, L.A. and S.C. King. (1998b). Functional sensitivity of polar surfaces on transmembrane helix 8 and cytoplasmic loop 8-9 of the Escherichia coli GABA (4-aminobutyrate) transporter encoded by gabP: mutagenic analysis of a consensus amphipathic region found in transporters from bacteria to mammals. Biochem. J. 330: 771-776.
|
Hu, L.A. and S.C. King. (1998c). Membrane topology of the Escherichia coli γ-aminobutyrate transporter: implications on the topology and mechanism of prokaryotic and eukaryotic transporters from the APC superfamily. Biochem. J. 336: 69-76.
|
Isnard, A.D., D. Thomas, and Y. Surdin-Kerjan. (1996). The study of methionine uptake in Saccharomyces cerevisiae reveals a new family of amino acid permeases. J. Mol. Biol. 262: 473-484.
|
Iyer, R., C. Williams, and C. Miller. (2003). Arginine-agmatine antiporter in extreme acid resistance in Escherichia coli. J. Bacteriol. 185: 6556-6561.
|
Jack, D.L., I.T. Paulsen, and M.H. Saier, Jr. (2000). The amino acid/polyamine/organocation (APC) superfamily of transporters specific for amino acids, polyamines and organocations. Microbiology 146: 1797-1814.
|
Kanai, Y., Y. Fukasawa, S.H. Cha, H. Segawa, A. Chairoungdua, D.K. Kim, H. Matsuo, J.Y. Kim, K. Miyamoto, E. Takeda, and H. Endou. (2000). Transport properties of a system y+L neutral and basic amino acid transporter. J. Biol. Chem. 275: 20787-20793.
|
Kashiwagi, K., S. Shibuya, H. Tomitori, A. Kuraishi, and K. Igaragshi. (1997). Excretion and uptake of putrescine by the PotE protein in Escherichia coli. J. Biol. Chem. 272: 6318-6323.
|
Lorca, G., B. Winnen, and M.H. Saier, Jr. (2003). Identification of the L-aspartate transporter in Bacillus subtilis. J. Bacteriol. 185: 3218-3222.
|
Mastroberardino, L., B. Spindler, R. Pfeiffer, P.J. Skelly, J. Loffing, C.B. Shoemaker, and F. Verrey. (1998). Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Nature 395: 288-291.
|
Matsuo, H., Y. Kanai, J.Y. Kim, A. Chairoungdua, D.K. Kim, J. Inatomi, Y. Shigeta, H. Ishimine, S. Chaekuntode, K. Tachampa, H.W. Choi, E. Babu, J. Fukuda, and H. Endou. (2002). Identification of a novel Na+-independent acidic amino acid transporter with structural similarity to the member of a heterodimeric amino acid transporter family associated with unknown heavy chains. J. Biol. Chem. 277: 21017-21026.
|
Meier, C., Z. Ristic, S. Klauser, and F. Verrey. (2002). Activation of system L heterodimeric amino acid exchangers by intracellular substrates. EMBO J. 21: 580-589.
|
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.
|
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.
|
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., 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.
|
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.
|
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.
|
Sophianopoulou, V. and G. Diallinas. (1995). Amino acid transporters of lower eukaryotes: regulation, structure and topogenesis. FEMS Microbiol. Rev. 16: 53-75.
|
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.
|
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.
|
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.
|
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.
|
| Examples: |
| TC# | Name | Organismal Type | Example |
| 2.A.3.1 The Amino Acid Transporter (AAT) Family |
|
| 2.A.3.1.1 | Phenylalanine:H+ symporter
| Bacteria | PheP of E. coli |
| |
| 2.A.3.1.2 | Lysine:H+ symporter
| Bacteria | LysP of E. coli |
| |
| 2.A.3.1.3 | Aromatic amino acid:H+ symporter
| Bacteria | AroP of E. coli |
| |
| 2.A.3.1.4 | γ-amino butyrate:H+ symporter (also transports a variety of pyridine carboxylates)
| Bacteria | GabP of E. coli |
| |
| 2.A.3.1.5 | β-alanine/γ-aminobutyrate: H+ symporter
| Bacteria | GabP of Bacillus subtilis |
| |
| 2.A.3.1.6 | Proline-specific permease (ProY)
| Bacteria | ProY of Salmonella typhimurium |
| |
| 2.A.3.1.7 | D-Serine/D-alanine/glycine:H+ symporter
| Bacteria | CycA of E. coli |
| |
| 2.A.3.1.8 | Asparagine permease (AnsP)
| Bacteria | AnsP of Salmonella typhimurium |
| |
| 2.A.3.1.9 | Histidine permease HutT
| Bacteria | HutT of Pseudomonas putida |
| |
| 2.A.3.1.10 | S-Methylmethionine permease, MmuP
| Bacteria | MmuP of E. coli |
| |
| 2.A.3.1.11 | L-Arginine permease, RocE | Bacteria | RocE of Bacillus subtilis |
| |
| 2.A.3.2 The Basic Amino Acid/Polyamine Antiporter (APA) Family |
|
| 2.A.3.2.1 | Putrescine:ornithine antiporter; putrescine:H+ symporter
| Bacteria | PotE of E. coli |
| |
| 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)
| Bacteria | CadB of E. coli |
| |
| 2.A.3.2.3 | Arginine:ornithine antiporter
| Bacteria | ArcD of Pseudomonas aeruginosa |
| |
| 2.A.3.2.4 | Lysine permease
| Bacteria | LysI of Corynebacterium glutamicum |
| |
| 2.A.3.2.5 | Arginine:agmatine antiporter (Gong et al., 2003; Iyer et al., 2003) | Bacteria | YjdE (AdiC) of E. coli (P39269) |
| |
| 2.A.3.3 The Cationic Amino Acid Transporter (CAT) Family |
|
| 2.A.3.3.1 | System Y+ high affinity basic amino acid transporter (CAT1) (ecotropic retrovival leukemia virus receptor (ERR)) (transports arginine, lysine and ornithine; Na+-independent)
| Mammals | CAT1(ERR) of Mus musculus |
| |
| 2.A.3.3.2 | Low affinity basic amino acid transporter (CAT2) (T-cell early activation protein (TEA)) (transports arginine, lysine and ornithine; Na+-independent) (Habermeier et al., 2003)
| Mammals | CAT2(TEA) of Mus musculus |
| |
| 2.A.3.3.3 | Amino acid transporter, AAT1
| Plants | AAP1 of Arabidopsis thaliana |
| |
| 2.A.3.4 The Amino Acid/Choline Transporter (ACT) Family |
|
| 2.A.3.4.1 | Choline permease
| Yeast | Ctr (Hnm1) of Saccharomyces cerevisiae |
| |
| 2.A.3.4.2 | γ-aminobutyric acid (GABA) permease (GabA)
| Yeast, fungi | GabA of Emericella nidulans |
| |
| 2.A.3.5 The Ethanolamine Transporter (EAT) Family |
|
| 2.A.3.5.1 | Ethanolamine import permease
| Bacteria | Ethanolamine permease of Rhodococcus erythropolis |
| |
| 2.A.3.5.2 | Probable methylamine import permease | Archaea | Methylamine permease of Methanosarcineae acetivorans, MA0143 |
| |
| 2.A.3.6 The Archaeal/Bacterial Transporter (ABT) Family |
|
| 2.A.3.6.1 | Putative cationic amino acid permease
| Archaea | Cat-1 of Archeoglobus fulgidus |
| |
| 2.A.3.7 The Glutamate:GABA Antiporter (GGA) Family |
|
| 2.A.3.7.1 | Glutamate:γ-aminobutyrate antiporter
| Bacteria | GadC of Lactococcus lactis |
| |
| 2.A.3.8 The L-type Amino Acid Transporter (LAT) Family |
|
| 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]).
| Animals | LAT1 of Rattus norvegicus |
| |
| 2.A.3.8.2 | L-type neutral amino acid transporter, ASUR4 (Na+-independent)
| Animals | ASUR4 of Xenopus laevis |
| |
| 2.A.3.8.3 | Neutral and cationic amino acid transporter, SPRM1 (Na+-independent)
| Animals | SPRM1 of Schistosoma mansoni |
| |
| 2.A.3.8.4 | L-methionine transporter, MUP1
| Yeast | MUP1 of Saccharomyces cerevisiae |
| |
| 2.A.3.8.5 | Cystine/glutamate antiporter, xCT
| Animals | xCT of Mus musculus |
| |
| 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]).
| Animals | LAT2 of Rattus norvegicus |
| |
| 2.A.3.8.7 | y+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.
| Animals | y+LAT1 of Rattus norvegicus |
| |
| 2.A.3.8.8 | Aspartate/glutamate Na+-independent transporter, AGT1 | Animals | AGT1 of Mus musculus |
| |
| 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., 2004). | Animals | AAT1 of Caenorhabditis elegans (CAA92459) |
| |
| 2.A.3.9 The Spore Germination Protein (SGP) Family |
|
| 2.A.3.9.1 | Spore germination protein A2 (AB) (amino acid [L-alanine] receptor)
| Gram-positive bacteria | GerAB of Bacillus subtilis |
| |
| 2.A.3.9.2 | Spore germination protein B2 (BB) (amino acid [D-alanine and L-asparagine] receptor)
| Gram-positive bacteria | GerBB of Bacillus subtilis |
| |
| 2.A.3.9.3 | Spore germination protein K2 (KB) (probable amino acid receptor) | Gram-positive bacteria | GerKB of Bacillus subtilis |
| |
| 2.A.3.10 The Yeast Amino Acid Transporter (YAT) Family |
|
| 2.A.3.10.1 | High affinity histidine permease (also implicated in Mn2+ efflux; Co2+, Ni2+, Zn2+ and Cu2+ uptake)
| Yeast, fungi | Hip1 of Saccharomyces cerevisiae |
| |
| 2.A.3.10.2 | General amino acid permease (all L-amino acids and some D-amino acids)
| Yeast | Gap1 of Saccharomyces cerevisiae |
| |
| 2.A.3.10.3 | Proline permease
| Yeast | Put4 of Saccharomyces cerevisiae |
| |
| 2.A.3.10.4 | Arginine permease
| Yeast | Can1 of Saccharomyces cerevisiae |
| |
| 2.A.3.10.5 | High affinity glutamine permease
| Yeast | Gnp1 of Saccharomyces cerevisiae |
| |
| 2.A.3.10.6 | Leu/Val/Ile amino acid permease
| Yeast | Bap2 of Saccharomyces cerevisiae |
| |
| 2.A.3.10.7 | Asn/Gln permease
| Yeast | Agp1 of Saccharomyces cerevisiae |
| |
| 2.A.3.10.8 | Tryptophan permease
| Yeast | Tat2 of Saccharomyces cerevisiae |
| |
| 2.A.3.10.9 | Val/Tyr/Trp permease
| Yeast | Val1 (Tat1) of Saccharomyces cerevisiae |
| |
| 2.A.3.10.10 | Lysine permease
| Yeast | Lyp1 of Saccharomyces cerevisiae |
| |
| 2.A.3.10.11 | Basic amino acid permease
| Yeast | Alp1 of Saccharomyces cerevisiae |
| |
| 2.A.3.10.12 | Leucine sensor/transcription factor
| Yeast | Ssy1 of Saccharomyces cerevisiae |
| |
| 2.A.3.10.13 | Dicarboxylic amino acid permease
| Yeast | Dip5 of Saccharomyces cerevisiae |
| |
| 2.A.3.10.14 | General amino acid permease with broad specificity, SAM3
| Yeast | Agp3 of Saccharomyces cerevisiae |
| |
| 2.A.3.10.15 | S-adenosylmethionine uptake permease, SAM3
| Yeast | SAM3 (YPL274w) of Saccharomyces cerevisiae |
| |
| 2.A.3.10.16 | S-methylmethionine uptake permease, Mmp1
| Yeast | Mmp1 (YLL061w) of Saccharomyces cerevisiae |
| |
| 2.A.3.10.17 | General amino acid uptake permease, GAP1 | Fungi | GAP1 of Hebeloma cylindrosporum |
| |
| 2.A.3.10.18 | The aromatic amino acid and leucine permease, ArlP (may be a general amino acid permease for neutral and basic [but not acidic] amino acids) | Fungi | ArlP of Penicillium chrysogenum |
| |
| 2.A.3.11 The Aspartate/Glutamate Transporter (AGT) Family |
|
| 2.A.3.11.1 | The aspartate uptake permease, YveA (also transports L-aspartate hydroxamate and glutamate, and possibly asparagine and glutamine; Lorca et al., 2003) | Bacteria and archaea | YveA of Bacillus subtilis |
| |