ID S22A4_HUMAN Reviewed; 551 AA. AC Q9H015; O14546; DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2007, sequence version 3. DT 27-MAR-2024, entry version 181. DE RecName: Full=Solute carrier family 22 member 4 {ECO:0000305|PubMed:15795384}; DE AltName: Full=Ergothioneine transporter {ECO:0000305|PubMed:10215651}; DE Short=ET transporter {ECO:0000305|PubMed:10215651}; DE Short=ETTh {ECO:0000305|PubMed:10215651}; DE AltName: Full=Organic cation/carnitine transporter 1 {ECO:0000305|PubMed:9426230}; DE Short=OCTN1 {ECO:0000305|PubMed:9426230}; GN Name=SLC22A4 {ECO:0000312|HGNC:HGNC:10968}; GN Synonyms=ETT {ECO:0000305|PubMed:10215651}, OCTN1 GN {ECO:0000305|PubMed:9426230}, UT2H; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, VARIANTS THR-306 AND RP PHE-503, AND MISCELLANEOUS. RC TISSUE=Fetal liver; RX PubMed=9426230; DOI=10.1016/s0014-5793(97)01441-5; RA Tamai I., Yabuuchi H., Nezu J., Sai Y., Oku A., Shimane M., Tsuji A.; RT "Cloning and characterization of a novel human pH-dependent organic cation RT transporter, OCTN1."; RL FEBS Lett. 419:107-111(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TRANSPORTER ACTIVITY, RP BIOPHYSICOCHEMICAL PROPERTIES, AND TISSUE SPECIFICITY. RX PubMed=15795384; DOI=10.1073/pnas.0408624102; RA Gruendemann D., Harlfinger S., Golz S., Geerts A., Lazar A., Berkels R., RA Jung N., Rubbert A., Schoemig E.; RT "Discovery of the ergothioneine transporter."; RL Proc. Natl. Acad. Sci. U.S.A. 102:5256-5261(2005). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15372022; DOI=10.1038/nature02919; RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S., RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.; RT "The DNA sequence and comparative analysis of human chromosome 5."; RL Nature 431:268-274(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Colon; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP FUNCTION, TRANSPORTER ACTIVITY, AND MISCELLANEOUS. RX PubMed=10215651; RA Yabuuchi H., Tamai I., Nezu J., Sakamoto K., Oku A., Shimane M., Sai Y., RA Tsuji A.; RT "Novel membrane transporter OCTN1 mediates multispecific, bidirectional, RT and pH-dependent transport of organic cations."; RL J. Pharmacol. Exp. Ther. 289:768-773(1999). RN [6] RP INDUCTION, TISSUE SPECIFICITY, AND INVOLVEMENT IN RA. RX PubMed=14608356; DOI=10.1038/ng1267; RA Tokuhiro S., Yamada R., Chang X., Suzuki A., Kochi Y., Sawada T., RA Suzuki M., Nagasaki M., Ohtsuki M., Ono M., Furukawa H., Nagashima M., RA Yoshino S., Mabuchi A., Sekine A., Saito S., Takahashi A., Tsunoda T., RA Nakamura Y., Yamamoto K.; RT "An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic RT cation transporter, is associated with rheumatoid arthritis."; RL Nat. Genet. 35:341-348(2003). RN [7] RP MISCELLANEOUS. RX PubMed=15832501; DOI=10.1021/mp0340082; RA Tamai I., Nakanishi T., Kobayashi D., China K., Kosugi Y., Nezu J., Sai Y., RA Tsuji A.; RT "Involvement of OCTN1 (SLC22A4) in pH-dependent transport of organic RT cations."; RL Mol. Pharm. 1:57-66(2004). RN [8] RP FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR RP LOCATION, AND TISSUE SPECIFICITY. RX PubMed=16729965; DOI=10.1016/j.bbrc.2006.05.026; RA Lamhonwah A.M., Tein I.; RT "Novel localization of OCTN1, an organic cation/carnitine transporter, to RT mammalian mitochondria."; RL Biochem. Biophys. Res. Commun. 345:1315-1325(2006). RN [9] RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND TISSUE RP SPECIFICITY. RX PubMed=20601551; DOI=10.1124/dmd.110.032763; RA Sugiura T., Kato S., Shimizu T., Wakayama T., Nakamichi N., Kubo Y., RA Iwata D., Suzuki K., Soga T., Asano M., Iseki S., Tamai I., Tsuji A., RA Kato Y.; RT "Functional expression of carnitine/organic cation transporter RT OCTN1/SLC22A4 in mouse small intestine and liver."; RL Drug Metab. Dispos. 38:1665-1672(2010). RN [10] RP FUNCTION, AND TRANSPORTER ACTIVITY. RX PubMed=22569296; DOI=10.1016/j.lfs.2012.04.027; RA Pochini L., Scalise M., Galluccio M., Indiveri C.; RT "Regulation by physiological cations of acetylcholine transport mediated by RT human OCTN1 (SLC22A4). Implications in the non-neuronal cholinergic RT system."; RL Life Sci. 91:1013-1016(2012). RN [11] RP CAUTION. RX PubMed=28209616; DOI=10.1158/0008-5472.can-16-2548; RA Drenberg C.D., Gibson A.A., Pounds S.B., Shi L., Rhinehart D.P., Li L., RA Hu S., Du G., Nies A.T., Schwab M., Pabla N., Blum W., Gruber T.A., RA Baker S.D., Sparreboom A.; RT "OCTN1 Is a High-Affinity Carrier of Nucleoside Analogues."; RL Cancer Res. 77:2102-2111(2017). RN [12] RP FUNCTION, TRANSPORTER ACTIVITY, AND CAUTION. RX PubMed=29530864; DOI=10.1124/dmd.118.080440; RA Tschirka J., Kreisor M., Betz J., Gruendemann D.; RT "Substrate Selectivity Check of the Ergothioneine Transporter."; RL Drug Metab. Dispos. 46:779-785(2018). RN [13] RP FUNCTION, AND TRANSPORTER ACTIVITY. RX PubMed=33124720; DOI=10.1096/fj.202001497r; RA Yee S.W., Buitrago D., Stecula A., Ngo H.X., Chien H.C., Zou L., RA Koleske M.L., Giacomini K.M.; RT "Deorphaning a solute carrier 22 family member, SLC22A15, through RT functional genomic studies."; RL FASEB J. 34:15734-15752(2020). RN [14] RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=35307651; DOI=10.1124/dmd.121.000748; RA Hau R.K., Klein R.R., Wright S.H., Cherrington N.J.; RT "Localization of Xenobiotic Transporters Expressed at the Human Blood- RT Testis Barrier."; RL Drug Metab. Dispos. 50:770-780(2022). RN [15] RP VARIANTS THR-306 AND GLU-462. RX PubMed=12436193; DOI=10.1007/s100380200088; RA Saito S., Iida A., Sekine A., Ogawa C., Kawauchi S., Higuchi S., RA Nakamura Y.; RT "Catalog of 238 variations among six human genes encoding solute carriers RT (hSLCs) in the Japanese population."; RL J. Hum. Genet. 47:576-584(2002). RN [16] RP CHARACTERIZATION OF VARIANT GLU-462, AND MISCELLANEOUS. RX PubMed=15459889; DOI=10.1002/jps.20190; RA Kawasaki Y., Kato Y., Sai Y., Tsuji A.; RT "Functional characterization of human organic cation transporter OCTN1 RT single nucleotide polymorphisms in the Japanese population."; RL J. Pharm. Sci. 93:2920-2926(2004). RN [17] RP VARIANT PHE-503, FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL RP PROPERTIES, TISSUE SPECIFICITY, AND MISCELLANEOUS. RX PubMed=15107849; DOI=10.1038/ng1339; RA Peltekova V.D., Wintle R.F., Rubin L.A., Amos C.I., Huang Q., Gu X., RA Newman B., Van Oene M., Cescon D., Greenberg G., Griffiths A.M., RA St George-Hyslop P.H., Siminovitch K.A.; RT "Functional variants of OCTN cation transporter genes are associated with RT Crohn disease."; RL Nat. Genet. 36:471-475(2004). RN [18] RP VARIANT PHE-503, CHARACTERIZATION OF VARIANT PHE-503, FUNCTION, TRANSPORTER RP ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND ACTIVITY REGULATION. RX PubMed=22206629; DOI=10.1016/j.bbamem.2011.12.014; RA Pochini L., Scalise M., Galluccio M., Pani G., Siminovitch K.A., RA Indiveri C.; RT "The human OCTN1 (SLC22A4) reconstituted in liposomes catalyzes RT acetylcholine transport which is defective in the mutant L503F associated RT to the Crohn's disease."; RL Biochim. Biophys. Acta 1818:559-565(2012). CC -!- FUNCTION: Transporter that mediates the transport of endogenous and CC microbial zwitterions and organic cations (PubMed:15795384, CC PubMed:10215651, PubMed:16729965, PubMed:20601551, PubMed:22569296, CC PubMed:29530864, PubMed:15107849, PubMed:22206629). Functions as a CC Na(+)-dependent and pH-dependent high affinity microbial symporter of CC potent food-derived antioxidant ergothioeine (PubMed:15795384, CC PubMed:29530864, PubMed:33124720). Transports one sodium ion with one CC ergothioeine molecule (By similarity). Involved in the absorption of CC ergothioneine from the luminal/apical side of the small intestine and CC renal tubular cells, and into non-parenchymal liver cells, thereby CC contributing to maintain steady-state ergothioneine level in the body CC (PubMed:20601551). Also mediates the bidirectional transport of CC acetycholine, although the exact transport mechanism has not been fully CC identified yet (PubMed:22206629). Most likely exports anti-inflammatory CC acetylcholine in non-neuronal tissues, thereby contributing to the non- CC neuronal cholinergic system (PubMed:22569296, PubMed:22206629). CC Displays a general physiological role linked to better survival by CC controlling inflammation and oxidative stress, which may be related to CC ergothioneine and acetycholine transports (PubMed:15795384, CC PubMed:22206629). May also function as a low-affinity Na(+)-dependent CC transporter of L-carnitine through the mitochondrial membrane, thereby CC maintaining intracellular carnitine homeostasis (PubMed:10215651, CC PubMed:16729965, PubMed:15107849). May contribute to regulate the CC transport of cationic compounds in testis across the blood-testis- CC barrier (PubMed:35307651). {ECO:0000250|UniProtKB:Q9R141, CC ECO:0000269|PubMed:10215651, ECO:0000269|PubMed:15107849, CC ECO:0000269|PubMed:15795384, ECO:0000269|PubMed:16729965, CC ECO:0000269|PubMed:20601551, ECO:0000269|PubMed:22206629, CC ECO:0000269|PubMed:22569296, ECO:0000269|PubMed:29530864, CC ECO:0000269|PubMed:35307651}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ergothioneine(out) + Na(+)(out) = ergothioneine(in) + CC Na(+)(in); Xref=Rhea:RHEA:75843, ChEBI:CHEBI:29101, CC ChEBI:CHEBI:134344; Evidence={ECO:0000269|PubMed:15795384, CC ECO:0000269|PubMed:20601551, ECO:0000269|PubMed:29530864, CC ECO:0000269|PubMed:33124720}; CC -!- CATALYTIC ACTIVITY: CC Reaction=acetylcholine(in) = acetylcholine(out); Xref=Rhea:RHEA:74663, CC ChEBI:CHEBI:15355; Evidence={ECO:0000269|PubMed:22206629, CC ECO:0000269|PubMed:22569296}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:74664; CC Evidence={ECO:0000305|PubMed:22206629}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:74665; CC Evidence={ECO:0000305|PubMed:22206629}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(R)-carnitine(out) + Na(+)(out) = (R)-carnitine(in) + CC Na(+)(in); Xref=Rhea:RHEA:72091, ChEBI:CHEBI:16347, CC ChEBI:CHEBI:29101; Evidence={ECO:0000305|PubMed:10215651, CC ECO:0000305|PubMed:16729965}; CC -!- CATALYTIC ACTIVITY: CC Reaction=glycine betaine(out) + Na(+)(out) = glycine betaine(in) + CC Na(+)(in); Xref=Rhea:RHEA:72115, ChEBI:CHEBI:17750, CC ChEBI:CHEBI:29101; Evidence={ECO:0000269|PubMed:33124720}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:72116; CC Evidence={ECO:0000305|PubMed:33124720}; CC -!- ACTIVITY REGULATION: Allosterically activated by intracellular ATP. CC {ECO:0000269|PubMed:22206629}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=21 uM for ergothioneine (at pH 7.4) {ECO:0000269|PubMed:15795384}; CC KM=1000 uM for acetylcholine(in) (at pH 8.0) CC {ECO:0000269|PubMed:22206629}; CC KM=780 uM for acetylcholine(out) (at pH 8.0) CC {ECO:0000269|PubMed:22206629}; CC KM=422.5 uM for (R)-carnitine (at pH 7.5) CC {ECO:0000269|PubMed:16729965}; CC KM=571 uM for (R)-carnitine {ECO:0000269|PubMed:15107849}; CC Vmax=42000 pmol/min/mg enzyme for ergothioneine uptake (at pH 7.4) CC {ECO:0000269|PubMed:15795384}; CC Vmax=160000 pmol/min/mg enzyme for acetylcholine uptake (at pH 8.0) CC {ECO:0000269|PubMed:22206629}; CC Vmax=14000 pmol/min/mg enzyme for acetylcholine export (at pH 8.0) CC {ECO:0000269|PubMed:22206629}; CC Vmax=22.61 pmol/min/mg enzyme for (R)-carnitine uptake (at pH 7.5) CC {ECO:0000269|PubMed:16729965}; CC Vmax=883 pmol/min/mg enzyme for (R)-carnitine uptake CC {ECO:0000269|PubMed:15107849}; CC pH dependence: CC Optimum pH is 6.5-7.0 for ergothioneine uptake and transport CC efficiency decreased at more alkaline pHs. CC {ECO:0000269|PubMed:15795384}; CC -!- SUBUNIT: Interacts with PDZK1. {ECO:0000250|UniProtKB:Q9Z306}. CC -!- SUBCELLULAR LOCATION: Apical cell membrane CC {ECO:0000269|PubMed:20601551}; Multi-pass membrane protein CC {ECO:0000305}. Basal cell membrane {ECO:0000269|PubMed:35307651}; CC Multi-pass membrane protein {ECO:0000305}. Mitochondrion membrane CC {ECO:0000269|PubMed:16729965}; Multi-pass membrane protein CC {ECO:0000305}. Note=Localized to the apical membrane of small CC intestines (PubMed:20601551). Localized to the basal membrane of CC Sertoli cells (PubMed:35307651). {ECO:0000269|PubMed:20601551, CC ECO:0000269|PubMed:35307651}. CC -!- TISSUE SPECIFICITY: Widely expressed (PubMed:9426230). Highly expressed CC in kidney, trachea, ileum, bone marrow and whole blood (PubMed:9426230, CC PubMed:15795384). Expressed in small intestines (PubMed:20601551). CC Weakly expressed in skeletal muscle, prostate, lung, pancreas, CC placenta, heart, uterus, spleen and spinal cord (PubMed:9426230, CC PubMed:15795384, PubMed:16729965). Expressed in testis, primarily to CC the basal membrane of Sertoli cells (PubMed:35307651, PubMed:16729965). CC Expressed in brain (PubMed:16729965). Expressed in liver CC (PubMed:16729965). Highly expressed in intestinal cell types affected CC by Crohn disease, including epithelial cells. Expressed in CD68 CC macrophage and CD43 T-cells but not in CD20 B-cells (PubMed:15107849). CC Predominantly expressed in CD14 cells in peripheral blood mononuclear CC cells (PubMed:14608356). Expressed in fetal liver, kidney and lung CC (PubMed:9426230, PubMed:15795384). {ECO:0000269|PubMed:14608356, CC ECO:0000269|PubMed:15107849, ECO:0000269|PubMed:15795384, CC ECO:0000269|PubMed:16729965, ECO:0000269|PubMed:20601551, CC ECO:0000269|PubMed:35307651, ECO:0000269|PubMed:9426230}. CC -!- INDUCTION: Overexpressed upon TNF treatment. CC {ECO:0000269|PubMed:14608356}. CC -!- DISEASE: Rheumatoid arthritis (RA) [MIM:180300]: An inflammatory CC disease with autoimmune features and a complex genetic component. It CC primarily affects the joints and is characterized by inflammatory CC changes in the synovial membranes and articular structures, widespread CC fibrinoid degeneration of the collagen fibers in mesenchymal tissues, CC and by atrophy and rarefaction of bony structures. CC {ECO:0000269|PubMed:14608356}. Note=Disease susceptibility is CC associated with variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Mediates the Na(+)-independent and pH-dependent CC bidirectional transport of exogenous prototype organic cation CC tetraethylammonium (TEA). {ECO:0000269|PubMed:10215651, CC ECO:0000269|PubMed:15107849, ECO:0000269|PubMed:15459889, CC ECO:0000269|PubMed:15832501, ECO:0000269|PubMed:9426230}. CC -!- SIMILARITY: Belongs to the major facilitator (TC 2.A.1) superfamily. CC Organic cation transporter (TC 2.A.1.19) family. {ECO:0000305}. CC -!- CAUTION: Despite a previous report demonstrating SLC22A4/OCTN1-mediated CC transport of nucleosides such as the endogenous 2'deoxycytidine or the CC anticancer drug cytarabine, another study was unable to verify these CC findings. {ECO:0000269|PubMed:28209616, ECO:0000269|PubMed:29530864}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB007448; BAA23356.1; -; mRNA. DR EMBL; Y09881; CAA71007.1; -; mRNA. DR EMBL; AC008599; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC034220; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC028313; AAH28313.1; -; mRNA. DR CCDS; CCDS4153.1; -. DR RefSeq; NP_003050.2; NM_003059.2. DR AlphaFoldDB; Q9H015; -. DR SMR; Q9H015; -. DR BioGRID; 112470; 207. DR STRING; 9606.ENSP00000200652; -. DR ChEMBL; CHEMBL2073668; -. DR DrugBank; DB00594; Amiloride. DR DrugBank; DB00345; Aminohippuric acid. DR DrugBank; DB00125; Arginine. DR DrugBank; DB01053; Benzylpenicillin. DR DrugBank; DB00122; Choline. DR DrugBank; DB14006; Choline salicylate. DR DrugBank; DB00501; Cimetidine. DR DrugBank; DB00575; Clonidine. DR DrugBank; DB00987; Cytarabine. DR DrugBank; DB01151; Desipramine. DR DrugBank; DB00983; Formoterol. DR DrugBank; DB00536; Guanidine. DR DrugBank; DB00458; Imipramine. DR DrugBank; DB00332; Ipratropium. DR DrugBank; DB00583; Levocarnitine. DR DrugBank; DB01137; Levofloxacin. DR DrugBank; DB00123; Lysine. DR DrugBank; DB01043; Memantine. DR DrugBank; DB06691; Mepyramine. DR DrugBank; DB00184; Nicotine. DR DrugBank; DB01165; Ofloxacin. DR DrugBank; DB01035; Procainamide. DR DrugBank; DB01917; Putrescine. DR DrugBank; DB00908; Quinidine. DR DrugBank; DB00468; Quinine. DR DrugBank; DB14754; Solriamfetol. DR DrugBank; DB03566; Spermidine. DR DrugBank; DB00127; Spermine. DR DrugBank; DB13943; Testosterone cypionate. DR DrugBank; DB13944; Testosterone enanthate. DR DrugBank; DB13946; Testosterone undecanoate. DR DrugBank; DB08837; Tetraethylammonium. DR DrugBank; DB01409; Tiotropium. DR DrugBank; DB00661; Verapamil. DR TCDB; 2.A.1.19.2; the major facilitator superfamily (mfs). DR GlyCosmos; Q9H015; 3 sites, No reported glycans. DR GlyGen; Q9H015; 4 sites, 1 O-linked glycan (1 site). DR iPTMnet; Q9H015; -. DR PhosphoSitePlus; Q9H015; -. DR BioMuta; SLC22A4; -. DR DMDM; 146345508; -. DR EPD; Q9H015; -. DR jPOST; Q9H015; -. DR MassIVE; Q9H015; -. DR PaxDb; 9606-ENSP00000200652; -. DR PeptideAtlas; Q9H015; -. DR ProteomicsDB; 80197; -. DR Antibodypedia; 26020; 179 antibodies from 25 providers. DR DNASU; 6583; -. DR Ensembl; ENST00000200652.4; ENSP00000200652.3; ENSG00000197208.6. DR GeneID; 6583; -. DR KEGG; hsa:6583; -. DR MANE-Select; ENST00000200652.4; ENSP00000200652.3; NM_003059.3; NP_003050.2. DR UCSC; uc003kwq.4; human. DR AGR; HGNC:10968; -. DR CTD; 6583; -. DR DisGeNET; 6583; -. DR GeneCards; SLC22A4; -. DR HGNC; HGNC:10968; SLC22A4. DR HPA; ENSG00000197208; Tissue enhanced (bone). DR MalaCards; SLC22A4; -. DR MIM; 180300; phenotype. DR MIM; 604190; gene. DR neXtProt; NX_Q9H015; -. DR OpenTargets; ENSG00000197208; -. DR PharmGKB; PA332; -. DR VEuPathDB; HostDB:ENSG00000197208; -. DR eggNOG; KOG0255; Eukaryota. DR GeneTree; ENSGT00940000154155; -. DR HOGENOM; CLU_001265_33_4_1; -. DR InParanoid; Q9H015; -. DR OMA; WTSIPTI; -. DR OrthoDB; 1448128at2759; -. DR PhylomeDB; Q9H015; -. DR TreeFam; TF315847; -. DR PathwayCommons; Q9H015; -. DR Reactome; R-HSA-549127; Organic cation transport. DR SignaLink; Q9H015; -. DR BioGRID-ORCS; 6583; 9 hits in 1165 CRISPR screens. DR GeneWiki; SLC22A4; -. DR GenomeRNAi; 6583; -. DR Pharos; Q9H015; Tbio. DR PRO; PR:Q9H015; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; Q9H015; Protein. DR Bgee; ENSG00000197208; Expressed in bronchial epithelial cell and 123 other cell types or tissues. DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB. DR GO; GO:0009925; C:basal plasma membrane; IDA:UniProtKB. DR GO; GO:0031966; C:mitochondrial membrane; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:MGI. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0005277; F:acetylcholine transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0015171; F:amino acid transmembrane transporter activity; IDA:ARUK-UCL. DR GO; GO:0015199; F:amino-acid betaine transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0015226; F:carnitine transmembrane transporter activity; IDA:MGI. DR GO; GO:0030165; F:PDZ domain binding; IPI:BHF-UCL. DR GO; GO:0015651; F:quaternary ammonium group transmembrane transporter activity; IDA:ARUK-UCL. DR GO; GO:0008513; F:secondary active organic cation transmembrane transporter activity; TAS:Reactome. DR GO; GO:0015293; F:symporter activity; IEA:UniProtKB-KW. DR GO; GO:0089718; P:amino acid import across plasma membrane; IDA:ARUK-UCL. DR GO; GO:0009437; P:carnitine metabolic process; IEA:Ensembl. DR GO; GO:0015879; P:carnitine transport; IDA:MGI. DR GO; GO:0015697; P:quaternary ammonium group transport; IDA:ARUK-UCL. DR GO; GO:0006814; P:sodium ion transport; IEA:UniProtKB-KW. DR GO; GO:0006641; P:triglyceride metabolic process; IEA:Ensembl. DR GO; GO:0042908; P:xenobiotic transport; IDA:ARUK-UCL. DR CDD; cd17376; MFS_SLC22A4_5_OCTN1_2; 1. DR Gene3D; 1.20.1250.20; MFS general substrate transporter like domains; 1. DR InterPro; IPR020846; MFS_dom. DR InterPro; IPR005828; MFS_sugar_transport-like. DR InterPro; IPR036259; MFS_trans_sf. DR InterPro; IPR004749; Orgcat_transp/SVOP. DR InterPro; IPR045915; S22A4/5. DR InterPro; IPR005829; Sugar_transporter_CS. DR NCBIfam; TIGR00898; 2A0119; 1. DR PANTHER; PTHR24064; SOLUTE CARRIER FAMILY 22 MEMBER; 1. DR PANTHER; PTHR24064:SF222; SOLUTE CARRIER FAMILY 22 MEMBER 4; 1. DR Pfam; PF00083; Sugar_tr; 1. DR SUPFAM; SSF103473; MFS general substrate transporter; 1. DR PROSITE; PS50850; MFS; 1. DR PROSITE; PS00216; SUGAR_TRANSPORT_1; 1. DR Genevisible; Q9H015; HS. PE 1: Evidence at protein level; KW ATP-binding; Cell membrane; Disease variant; Glycoprotein; Ion transport; KW Membrane; Mitochondrion; Nucleotide-binding; Reference proteome; Sodium; KW Sodium transport; Symport; Transmembrane; Transmembrane helix; Transport. FT CHAIN 1..551 FT /note="Solute carrier family 22 member 4" FT /id="PRO_0000220497" FT TOPO_DOM 1..20 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 21..41 FT /note="Helical; Name=1" FT /evidence="ECO:0000255" FT TOPO_DOM 42..141 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 142..162 FT /note="Helical; Name=2" FT /evidence="ECO:0000255" FT TOPO_DOM 163..171 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 172..192 FT /note="Helical; Name=3" FT /evidence="ECO:0000255" FT TOPO_DOM 193..197 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 198..218 FT /note="Helical; Name=4" FT /evidence="ECO:0000255" FT TOPO_DOM 219..232 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 233..253 FT /note="Helical; Name=5" FT /evidence="ECO:0000255" FT TOPO_DOM 254..257 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 258..278 FT /note="Helical; Name=6" FT /evidence="ECO:0000255" FT TOPO_DOM 279..337 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 338..358 FT /note="Helical; Name=7" FT /evidence="ECO:0000255" FT TOPO_DOM 359..371 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 372..392 FT /note="Helical; Name=8" FT /evidence="ECO:0000255" FT TOPO_DOM 393..399 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 400..420 FT /note="Helical; Name=9" FT /evidence="ECO:0000255" FT TOPO_DOM 421..426 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 427..447 FT /note="Helical; Name=10" FT /evidence="ECO:0000255" FT TOPO_DOM 448..460 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 461..481 FT /note="Helical; Name=11" FT /evidence="ECO:0000255" FT TOPO_DOM 482..486 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 487..507 FT /note="Helical; Name=12" FT /evidence="ECO:0000255" FT TOPO_DOM 508..551 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT BINDING 218..225 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255" FT CARBOHYD 57 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 64 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 91 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VARIANT 306 FT /note="I -> T (in dbSNP:rs272893)" FT /evidence="ECO:0000269|PubMed:12436193, FT ECO:0000269|PubMed:9426230" FT /id="VAR_019528" FT VARIANT 462 FT /note="G -> E (abrogates TEA transport activity; FT dbSNP:rs4646201)" FT /evidence="ECO:0000269|PubMed:12436193, FT ECO:0000269|PubMed:15459889" FT /id="VAR_019529" FT VARIANT 503 FT /note="L -> F (decreased carnitine transport; decreased FT acetylcholine transport; dbSNP:rs1050152)" FT /evidence="ECO:0000269|PubMed:15107849, FT ECO:0000269|PubMed:22206629, ECO:0000269|PubMed:9426230" FT /id="VAR_019530" SQ SEQUENCE 551 AA; 62155 MW; C827A99AA78C9443 CRC64; MRDYDEVIAF LGEWGPFQRL IFFLLSASII PNGFNGMSVV FLAGTPEHRC RVPDAANLSS AWRNNSVPLR LRDGREVPHS CSRYRLATIA NFSALGLEPG RDVDLGQLEQ ESCLDGWEFS QDVYLSTVVT EWNLVCEDNW KVPLTTSLFF VGVLLGSFVS GQLSDRFGRK NVLFATMAVQ TGFSFLQIFS ISWEMFTVLF VIVGMGQISN YVVAFILGTE ILGKSVRIIF STLGVCTFFA VGYMLLPLFA YFIRDWRMLL LALTVPGVLC VPLWWFIPES PRWLISQRRF REAEDIIQKA AKMNNIAVPA VIFDSVEELN PLKQQKAFIL DLFRTRNIAI MTIMSLLLWM LTSVGYFALS LDAPNLHGDA YLNCFLSALI EIPAYITAWL LLRTLPRRYI IAAVLFWGGG VLLFIQLVPV DYYFLSIGLV MLGKFGITSA FSMLYVFTAE LYPTLVRNMA VGVTSTASRV GSIIAPYFVY LGAYNRMLPY IVMGSLTVLI GILTLFFPES LGMTLPETLE QMQKVKWFRS GKKTRDSMET EENPKVLITA F //