PCFT_HUMAN
ID PCFT_HUMAN Reviewed; 459 AA.
AC Q96NT5; Q1HE20; Q86T92; Q8TEG3; Q96FL0;
DT 08-NOV-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 164.
DE RecName: Full=Proton-coupled folate transporter {ECO:0000303|PubMed:17129779};
DE Short=HsPCFT {ECO:0000303|PubMed:18405659};
DE Short=hPCFT {ECO:0000303|PubMed:19762432, ECO:0000303|PubMed:31792273};
DE AltName: Full=Heme carrier protein 1 {ECO:0000303|PubMed:16143108};
DE AltName: Full=PCFT/HCP1 {ECO:0000303|PubMed:17129779};
DE AltName: Full=Solute carrier family 46 member 1 {ECO:0000305};
GN Name=SLC46A1 {ECO:0000303|PubMed:20686069, ECO:0000312|HGNC:HGNC:30521};
GN Synonyms=G21 {ECO:0000303|PubMed:17129779},
GN HCP1 {ECO:0000303|PubMed:16143108}, PCFT {ECO:0000303|PubMed:17446347};
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 [LARGE SCALE MRNA] (ISOFORM 1), AND NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 269-459 (ISOFORM 2).
RC TISSUE=Glial tumor, and Spleen;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (APR-2006) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Eye;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 199-459 (ISOFORM 1).
RC TISSUE=Spinal cord;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP SUBCELLULAR LOCATION.
RX PubMed=16143108; DOI=10.1016/j.cell.2005.06.025;
RA Shayeghi M., Latunde-Dada G.O., Oakhill J.S., Laftah A.H., Takeuchi K.,
RA Halliday N., Khan Y., Warley A., McCann F.E., Hider R.C., Frazer D.M.,
RA Anderson G.J., Vulpe C.D., Simpson R.J., McKie A.T.;
RT "Identification of an intestinal heme transporter.";
RL Cell 122:789-801(2005).
RN [6]
RP FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR
RP LOCATION, TISSUE SPECIFICITY, AND INVOLVEMENT IN HFM.
RX PubMed=17129779; DOI=10.1016/j.cell.2006.09.041;
RA Qiu A., Jansen M., Sakaris A., Min S.H., Chattopadhyay S., Tsai E.,
RA Sandoval C., Zhao R., Akabas M.H., Goldman I.D.;
RT "Identification of an intestinal folate transporter and the molecular basis
RT for hereditary folate malabsorption.";
RL Cell 127:917-928(2006).
RN [7]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=17156779; DOI=10.1016/j.febslet.2006.11.048;
RA Latunde-Dada G.O., Takeuchi K., Simpson R.J., McKie A.T.;
RT "Haem carrier protein 1 (HCP1): expression and functional studies in
RT cultured cells.";
RL FEBS Lett. 580:6865-6870(2006).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, AND VARIANTS HFM SER-113; ARG-147; ARG-318;
RP TRP-376 AND ARG-425.
RX PubMed=17446347; DOI=10.1182/blood-2007-02-077099;
RA Zhao R., Min S.H., Qiu A., Sakaris A., Goldberg G.L., Sandoval C.,
RA Malatack J.J., Rosenblatt D.S., Goldman I.D.;
RT "The spectrum of mutations in the PCFT gene, coding for an intestinal
RT folate transporter, that are the basis for hereditary folate
RT malabsorption.";
RL Blood 110:1147-1152(2007).
RN [9]
RP TISSUE SPECIFICITY.
RX PubMed=17335806; DOI=10.1016/j.yexcr.2007.01.019;
RA Sharma S., Dimasi D., Broeer S., Kumar R., Della N.G.;
RT "Heme carrier protein 1 (HCP1) expression and functional analysis in the
RT retina and retinal pigment epithelium.";
RL Exp. Cell Res. 313:1251-1259(2007).
RN [10]
RP FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP SUBCELLULAR LOCATION.
RX PubMed=17475902; DOI=10.1124/jpet.107.122606;
RA Nakai Y., Inoue K., Abe N., Hatakeyama M., Ohta K.-Y., Otagiri M.,
RA Hayashi Y., Yuasa H.;
RT "Functional characterization of human proton-coupled folate
RT transporter/heme carrier protein 1 heterologously expressed in mammalian
RT cells as a folate transporter.";
RL J. Pharmacol. Exp. Ther. 322:469-476(2007).
RN [11]
RP SUBCELLULAR LOCATION, GLYCOSYLATION AT ASN-58 AND ASN-68, AND MUTAGENESIS
RP OF ASN-58 AND ASN-68.
RX PubMed=18405659; DOI=10.1016/j.bbamem.2008.03.009;
RA Unal E.S., Zhao R., Qiu A., Goldman I.D.;
RT "N-linked glycosylation and its impact on the electrophoretic mobility and
RT function of the human proton-coupled folate transporter (HsPCFT).";
RL Biochim. Biophys. Acta 1778:1407-1414(2008).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [13]
RP FUNCTION, AND TRANSPORTER ACTIVITY.
RX PubMed=18524888; DOI=10.1124/mol.108.045443;
RA Zhao R., Qiu A., Tsai E., Jansen M., Akabas M.H., Goldman I.D.;
RT "The proton-coupled folate transporter: impact on pemetrexed transport and
RT on antifolates activities compared with the reduced folate carrier.";
RL Mol. Pharmacol. 74:854-862(2008).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [15]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=19074442; DOI=10.1074/jbc.m807665200;
RA Zhao R., Min S.H., Wang Y., Campanella E., Low P.S., Goldman I.D.;
RT "A role for the proton-coupled folate transporter (PCFT-SLC46A1) in folate
RT receptor-mediated endocytosis.";
RL J. Biol. Chem. 284:4267-4274(2009).
RN [16]
RP FUNCTION, TRANSPORTER ACTIVITY, AND MUTAGENESIS OF SER-172; HIS-247 AND
RP HIS-281.
RX PubMed=19389703; DOI=10.1074/jbc.m109.008060;
RA Unal E.S., Zhao R., Chang M.H., Fiser A., Romero M.F., Goldman I.D.;
RT "The functional roles of the His247 and His281 residues in folate and
RT proton translocation mediated by the human proton-coupled folate
RT transporter SLC46A1.";
RL J. Biol. Chem. 284:17846-17857(2009).
RN [17]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-58.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [18]
RP FUNCTION, TRANSPORTER ACTIVITY, AND TISSUE SPECIFICITY.
RX PubMed=19762432; DOI=10.1152/ajpgi.00224.2009;
RA Urquhart B.L., Gregor J.C., Chande N., Knauer M.J., Tirona R.G., Kim R.B.;
RT "The human proton-coupled folate transporter (hPCFT): modulation of
RT intestinal expression and function by drugs.";
RL Am. J. Physiol. 298:G248-G254(2010).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-458, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [20]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [21]
RP SUBUNIT, AND SUBCELLULAR LOCATION.
RX PubMed=23601781; DOI=10.1111/febs.12293;
RA Duddempudi P.K., Nakashe P., Blanton M.P., Jansen M.;
RT "The monomeric state of the proton-coupled folate transporter represents
RT the functional unit in the plasma membrane.";
RL FEBS J. 280:2900-2915(2013).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-6 AND SER-458, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [23]
RP SUBCELLULAR LOCATION, TOPOLOGY, AND GLYCOSYLATION AT ASN-58 AND ASN-68.
RX PubMed=25053408; DOI=10.1074/jbc.m114.578252;
RA Wilson M.R., Hou Z., Matherly L.H.;
RT "Substituted cysteine accessibility reveals a novel transmembrane 2-3
RT reentrant loop and functional role for transmembrane domain 2 in the human
RT proton-coupled folate transporter.";
RL J. Biol. Chem. 289:25287-25295(2014).
RN [24]
RP FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP MUTAGENESIS OF TYR-315.
RX PubMed=25608532; DOI=10.1152/ajpcell.00238.2014;
RA Visentin M., Unal E.S., Najmi M., Fiser A., Zhao R., Goldman I.D.;
RT "Identification of Tyr residues that enhance folate substrate binding and
RT constrain oscillation of the proton-coupled folate transporter (PCFT-
RT SLC46A1).";
RL Am. J. Physiol. 308:C631-C641(2015).
RN [25]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF TRP-299.
RX PubMed=25504888; DOI=10.1002/pbc.25364;
RA Najmi M., Zhao R., Fiser A., Goldman I.D.;
RT "Role of the tryptophan residues in proton-coupled folate transporter
RT (PCFT-SLC46A1) function.";
RL Am. J. Physiol. 311:C150-C157(2016).
RN [26]
RP FUNCTION, AND MUTAGENESIS OF PRO-314 AND TYR-315.
RX PubMed=28802835; DOI=10.1016/j.bbamem.2017.08.006;
RA Aluri S., Zhao R., Fiser A., Goldman I.D.;
RT "Residues in the eighth transmembrane domain of the proton-coupled folate
RT transporter (SLC46A1) play an important role in defining the aqueous
RT translocation pathway and in folate substrate binding.";
RL Biochim. Biophys. Acta 1859:2193-2202(2017).
RN [27]
RP FUNCTION, AND TRANSPORTER ACTIVITY.
RX PubMed=29326243; DOI=10.1124/mol.117.110445;
RA Zhao R., Najmi M., Aluri S., Spray D.C., Goldman I.D.;
RT "Concentrative Transport of Antifolates Mediated by the Proton-Coupled
RT Folate Transporter (SLC46A1); Augmentation by a HEPES Buffer.";
RL Mol. Pharmacol. 93:208-215(2018).
RN [28]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF ASP-109.
RX PubMed=30858177; DOI=10.1074/jbc.ra118.005533;
RA Aluri S., Zhao R., Lin K., Shin D.S., Fiser A., Goldman I.D.;
RT "Substitutions that lock and unlock the proton-coupled folate transporter
RT (PCFT-SLC46A1) in an inward-open conformation.";
RL J. Biol. Chem. 294:7245-7258(2019).
RN [29]
RP FUNCTION, ACTIVITY REGULATION, AND MUTAGENESIS OF GLY-158.
RX PubMed=31792273; DOI=10.1038/s41598-019-54367-9;
RA Yamashiro T., Yasujima T., Ohta K., Inoue K., Yuasa H.;
RT "Identification of the amino acid residue responsible for the myricetin
RT sensitivity of human proton-coupled folate transporter.";
RL Sci. Rep. 9:18105-18105(2019).
RN [30]
RP FUNCTION.
RX PubMed=32621820; DOI=10.1016/j.metabol.2020.154306;
RA Li H., Wang D., Wu H., Shen H., Lv D., Zhang Y., Lu H., Yang J., Tang Y.,
RA Li M.;
RT "SLC46A1 contributes to hepatic iron metabolism by importing heme in
RT hepatocytes.";
RL Metabolism 110:154306-154306(2020).
RN [31]
RP FUNCTION, TRANSPORTER ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP SER-318.
RX PubMed=34619546; DOI=10.1016/j.dmpk.2021.100421;
RA Narawa T., Narita Y., Hosokawa S., Itoh T.;
RT "Functional role of serine 318 of the proton-coupled folate transporter in
RT methotrexate transport.";
RL Drug Metab. Pharmacokinet. 41:100421-100421(2021).
RN [32]
RP FUNCTION, TRANSPORTER ACTIVITY, AND MUTAGENESIS OF GLU-185.
RX PubMed=34040256; DOI=10.1038/s41586-021-03579-z;
RA Parker J.L., Deme J.C., Kuteyi G., Wu Z., Huo J., Goldman I.D., Owens R.J.,
RA Biggin P.C., Lea S.M., Newstead S.;
RT "Structural basis of antifolate recognition and transport by PCFT.";
RL Nature 595:130-134(2021).
RN [33]
RP VARIANT HFM CYS-113, AND CHARACTERIZATION OF VARIANT HFM CYS-113.
RX PubMed=18559978; DOI=10.1182/blood-2008-04-150276;
RA Lasry I., Berman B., Straussberg R., Sofer Y., Bessler H., Sharkia M.,
RA Glaser F., Jansen G., Drori S., Assaraf Y.G.;
RT "A novel loss-of-function mutation in the proton-coupled folate transporter
RT from a patient with hereditary folate malabsorption reveals that Arg 113 is
RT crucial for function.";
RL Blood 112:2055-2061(2008).
RN [34]
RP VARIANT HFM GLN-376, CHARACTERIZATION OF VARIANT HFM GLN-376, AND
RP MUTAGENESIS OF ARG-376.
RX PubMed=20686069; DOI=10.1152/ajpcell.00113.2010;
RA Mahadeo K., Diop-Bove N., Shin D., Unal E.S., Teo J., Zhao R., Chang M.H.,
RA Fulterer A., Romero M.F., Goldman I.D.;
RT "Properties of the Arg376 residue of the proton-coupled folate transporter
RT (PCFT-SLC46A1) and a glutamine mutant causing hereditary folate
RT malabsorption.";
RL Am. J. Physiol. 299:C1153-C1161(2010).
RN [35]
RP VARIANT HFM TYR-156, CHARACTERIZATION OF VARIANT HFM TYR-156, AND
RP MUTAGENESIS OF ASP-109 AND ASP-156.
RX PubMed=20805364; DOI=10.1182/blood-2010-06-291237;
RA Shin D.S., Min S.H., Russell L., Zhao R., Fiser A., Goldman I.D.;
RT "Functional roles of aspartate residues of the proton-coupled folate
RT transporter (PCFT-SLC46A1); a D156Y mutation causing hereditary folate
RT malabsorption.";
RL Blood 116:5162-5169(2010).
RN [36]
RP VARIANTS HFM ASP-335 AND ARG-338, AND CHARACTERIZATION OF VARIANTS HFM
RP ASP-335 AND ARG-338.
RX PubMed=21333572; DOI=10.1016/j.ymgme.2011.01.008;
RA Shin D.S., Mahadeo K., Min S.H., Diop-Bove N., Clayton P., Zhao R.,
RA Goldman I.D.;
RT "Identification of novel mutations in the proton-coupled folate transporter
RT (PCFT-SLC46A1) associated with hereditary folate malabsorption.";
RL Mol. Genet. Metab. 103:33-37(2011).
RN [37]
RP VARIANT HFM ARG-425, FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, CHARACTERIZATION OF VARIANT HFM ARG-425, AND MUTAGENESIS OF
RP PRO-425.
RX PubMed=22345511; DOI=10.1152/ajpcell.00435.2011;
RA Shin D.S., Zhao R., Yap E.H., Fiser A., Goldman I.D.;
RT "A P425R mutation of the proton-coupled folate transporter causing
RT hereditary folate malabsorption produces a highly selective alteration in
RT folate binding.";
RL Am. J. Physiol. 302:C1405-C1412(2012).
RN [38]
RP INVOLVEMENT IN HFM.
RX PubMed=23816405; DOI=10.1016/j.gene.2013.06.039;
RA Diop-Bove N., Jain M., Scaglia F., Goldman I.D.;
RT "A novel deletion mutation in the proton-coupled folate transporter (PCFT;
RT SLC46A1) in a Nicaraguan child with hereditary folate malabsorption.";
RL Gene 527:673-674(2013).
RN [39]
RP INVOLVEMENT IN HFM.
RX PubMed=29390264; DOI=10.1097/md.0000000000008712;
RA Tan J., Li X., Guo Y., Xie L., Wang J., Ma J., Jiang L.;
RT "Hereditary folate malabsorption with a novel mutation on SLC46A1: A case
RT report.";
RL Medicine (Baltimore) 96:e8712-e8712(2017).
RN [40]
RP VARIANT HFM LYS-411, CHARACTERIZATION OF VARIANT HFM LYS-411, FUNCTION,
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF ASN-411.
RX PubMed=29344585; DOI=10.1182/bloodadvances.2017012690;
RA Aluri S., Zhao R., Lubout C., Goorden S.M.I., Fiser A., Goldman I.D.;
RT "Hereditary folate malabsorption due to a mutation in the external gate of
RT the proton-coupled folate transporter SLC46A1.";
RL Blood Adv. 2:61-68(2018).
RN [41]
RP VARIANTS HFM VAL-189; ARG-318 AND VAL-392, FUNCTION, AND CHARACTERIZATION
RP OF VARIANTS HFM VAL-189; ARG-318 AND VAL-392.
RX PubMed=31494288; DOI=10.1016/j.clim.2019.108256;
RA Tozawa Y., Abdrabou S.S.M.A., Nogawa-Chida N., Nishiuchi R., Ishida T.,
RA Suzuki Y., Sano H., Kobayashi R., Kishimoto K., Ohara O., Imai K.,
RA Naruto T., Kobayashi K., Ariga T., Yamada M.;
RT "A deep intronic mutation of c.1166-285 T > G in SLC46A1 is shared by four
RT unrelated Japanese patients with hereditary folate malabsorption (HFM).";
RL Clin. Immunol. 208:108256-108256(2019).
RN [42]
RP VARIANT HFM VAL-392, FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, CHARACTERIZATION OF VARIANT VAL-392, AND MUTAGENESIS OF
RP PHE-392.
RX PubMed=32893190; DOI=10.1074/jbc.ra120.014757;
RA Zhan H.Q., Najmi M., Lin K., Aluri S., Fiser A., Goldman I.D., Zhao R.;
RT "A proton-coupled folate transporter mutation causing hereditary folate
RT malabsorption locks the protein in an inward-open conformation.";
RL J. Biol. Chem. 295:15650-15661(2020).
CC -!- FUNCTION: Proton-coupled folate symporter that mediates folate
CC absorption using an H(+) gradient as a driving force (PubMed:17129779,
CC PubMed:17446347, PubMed:17475902, PubMed:19389703, PubMed:19762432,
CC PubMed:25504888, PubMed:30858177, PubMed:31792273, PubMed:34619546,
CC PubMed:29344585, PubMed:31494288, PubMed:32893190). Involved in the
CC intestinal absorption of folates at the brush-border membrane of the
CC proximal jejunum, and the transport from blood to cerebrospinal fluid
CC across the choroid plexus (PubMed:17129779, PubMed:17446347,
CC PubMed:17475902, PubMed:19389703, PubMed:25504888, PubMed:30858177,
CC PubMed:29344585, PubMed:31494288, PubMed:32893190). Functions at acidic
CC pH via alternate outward- and inward-open conformation states
CC (PubMed:34040256, PubMed:32893190). Protonation of residues in the
CC outward open state primes the protein for transport (PubMed:34040256).
CC Binding of folate promotes breaking of salt bridge network and
CC subsequent closure of the extracellular gate, leading to the inward-
CC open state and release of protons and folate (PubMed:34040256). Also
CC able to transport antifolate drugs, such as methotrexate and
CC pemetrexed, which are established treatments for cancer and autoimmune
CC diseases (PubMed:18524888, PubMed:19762432, PubMed:25608532,
CC PubMed:28802835, PubMed:29326243, PubMed:34619546, PubMed:34040256,
CC PubMed:22345511). Involved in FOLR1-mediated endocytosis by serving as
CC a route of export of folates from acidified endosomes
CC (PubMed:19074442). Also acts as a lower-affinity, pH-independent heme
CC carrier protein and constitutes the main importer of heme in the
CC intestine (PubMed:17156779). Imports heme in the retina and retinal
CC pigment epithelium, in neurons of the hippocampus, in hepatocytes and
CC in the renal epithelial cells (PubMed:32621820). Hence, participates in
CC the trafficking of heme and increases intracellular iron content
CC (PubMed:32621820). {ECO:0000269|PubMed:17129779,
CC ECO:0000269|PubMed:17156779, ECO:0000269|PubMed:17446347,
CC ECO:0000269|PubMed:17475902, ECO:0000269|PubMed:18524888,
CC ECO:0000269|PubMed:19074442, ECO:0000269|PubMed:19389703,
CC ECO:0000269|PubMed:19762432, ECO:0000269|PubMed:22345511,
CC ECO:0000269|PubMed:25504888, ECO:0000269|PubMed:25608532,
CC ECO:0000269|PubMed:28802835, ECO:0000269|PubMed:29326243,
CC ECO:0000269|PubMed:29344585, ECO:0000269|PubMed:30858177,
CC ECO:0000269|PubMed:31494288, ECO:0000269|PubMed:31792273,
CC ECO:0000269|PubMed:32621820, ECO:0000269|PubMed:32893190,
CC ECO:0000269|PubMed:34040256, ECO:0000269|PubMed:34619546}.
CC -!- FUNCTION: [Isoform 2]: Inactive isoform which is not able to mediate
CC proton-coupled folate transport. {ECO:0000269|PubMed:17129779}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=folate(in) + H(+)(in) = folate(out) + H(+)(out);
CC Xref=Rhea:RHEA:70159, ChEBI:CHEBI:15378, ChEBI:CHEBI:62501;
CC Evidence={ECO:0000305|PubMed:17129779, ECO:0000305|PubMed:17475902,
CC ECO:0000305|PubMed:19389703, ECO:0000305|PubMed:19762432,
CC ECO:0000305|PubMed:32893190};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6S)-5-methyl-5,6,7,8-tetrahydrofolate(in) + H(+)(in) = (6S)-
CC 5-methyl-5,6,7,8-tetrahydrofolate(out) + H(+)(out);
CC Xref=Rhea:RHEA:70167, ChEBI:CHEBI:15378, ChEBI:CHEBI:18608;
CC Evidence={ECO:0000250|UniProtKB:Q6PEM8};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+)(in) + methotrexate(in) = H(+)(out) + methotrexate(out);
CC Xref=Rhea:RHEA:70163, ChEBI:CHEBI:15378, ChEBI:CHEBI:50681;
CC Evidence={ECO:0000305|PubMed:18524888, ECO:0000305|PubMed:19762432,
CC ECO:0000305|PubMed:22345511, ECO:0000305|PubMed:25608532,
CC ECO:0000305|PubMed:29326243, ECO:0000305|PubMed:32893190,
CC ECO:0000305|PubMed:34619546};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+)(in) + pemetrexed(in) = H(+)(out) + pemetrexed(out);
CC Xref=Rhea:RHEA:70171, ChEBI:CHEBI:15378, ChEBI:CHEBI:63724;
CC Evidence={ECO:0000305|PubMed:18524888, ECO:0000305|PubMed:22345511,
CC ECO:0000305|PubMed:25608532, ECO:0000305|PubMed:29326243,
CC ECO:0000305|PubMed:34040256};
CC -!- ACTIVITY REGULATION: Inhibited by myricetin.
CC {ECO:0000269|PubMed:31792273}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=1.3 uM for folic acid (at pH 5.5) {ECO:0000269|PubMed:17129779,
CC ECO:0000269|PubMed:17475902};
CC KM=1.5 uM for folic acid (at pH 6.0) {ECO:0000269|PubMed:17129779,
CC ECO:0000269|PubMed:17475902};
CC KM=2.7 uM for folic acid (at pH 6.5) {ECO:0000269|PubMed:17129779,
CC ECO:0000269|PubMed:17475902};
CC KM=6.0 uM for folic acid (at pH 7.0) {ECO:0000269|PubMed:17129779,
CC ECO:0000269|PubMed:17475902};
CC KM=56.2 uM for folic acid (at pH 7.5) {ECO:0000269|PubMed:17129779,
CC ECO:0000269|PubMed:17475902};
CC KM=1.77 uM for methotrexate (at pH 5.0)
CC {ECO:0000269|PubMed:34619546};
CC Vmax=378 pmol/min/mg enzyme with methotrexate as substrate (at pH
CC 5.0) {ECO:0000269|PubMed:34619546};
CC Vmax=277 pmol/min/mg enzyme with methotrexate as substrate
CC {ECO:0000269|PubMed:22345511};
CC Vmax=497 pmol/min/mg enzyme with methotrexate as substrate
CC {ECO:0000269|PubMed:32893190};
CC Vmax=197 pmol/min/mg enzyme with pemetrexed as substrate
CC {ECO:0000269|PubMed:25608532};
CC Vmax=102.9 pmol/min/mg enzyme with pemetrexed as substrate
CC {ECO:0000269|PubMed:22345511};
CC pH dependence:
CC Optimum pH is 4.0-5.5. Activity decreases above pH 5.5 and reaches
CC negligible levels at neutral pH and above.
CC {ECO:0000269|PubMed:17129779, ECO:0000269|PubMed:17475902};
CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:23601781}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:17156779,
CC ECO:0000269|PubMed:17446347, ECO:0000269|PubMed:18405659,
CC ECO:0000269|PubMed:23601781, ECO:0000269|PubMed:25053408,
CC ECO:0000269|PubMed:25504888, ECO:0000269|PubMed:29344585,
CC ECO:0000269|PubMed:30858177, ECO:0000269|PubMed:34619546}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:25053408}. Apical cell membrane
CC {ECO:0000269|PubMed:16143108, ECO:0000269|PubMed:17129779,
CC ECO:0000269|PubMed:17475902}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:25053408}. Basolateral cell membrane
CC {ECO:0000269|PubMed:19074442}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:25053408}. Endosome membrane
CC {ECO:0000305|PubMed:19074442}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:25053408}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q6PEM8}. Note=Localizes to the apical membrane
CC of intestinal cells in iron-deficient cells, while it resides in the
CC cytoplasm in iron-replete cells (By similarity). Localizes to the
CC basolateral membrane of choroid plexus (PubMed:19074442).
CC {ECO:0000250|UniProtKB:Q6PEM8, ECO:0000269|PubMed:19074442}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q96NT5-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96NT5-2; Sequence=VSP_016053;
CC -!- TISSUE SPECIFICITY: Expressed at highest level in the upper half of the
CC small intestine (duodenum and jejunum), expression decreases downwardly
CC in the subsequent quarter and is undetectable in the last quarter (the
CC lowest ileum) (PubMed:17129779, PubMed:19762432). Also expressed in
CC kidney, liver, placenta, spleen, retina and retinal pigment epithelium
CC (PubMed:17129779, PubMed:17335806). Lower levels found in testis
CC (PubMed:17129779). Very low levels in brain, lung, stomach, heart and
CC muscle (PubMed:17129779). {ECO:0000269|PubMed:17129779,
CC ECO:0000269|PubMed:17335806, ECO:0000269|PubMed:19762432}.
CC -!- DISEASE: Hereditary folate malabsorption (HFM) [MIM:229050]: Rare
CC autosomal recessive disorder characterized by impaired intestinal
CC folate absorption with folate deficiency resulting in anemia,
CC hypoimmunoglobulinemia with recurrent infections, and recurrent or
CC chronic diarrhea. In many patients, neurological abnormalities such as
CC seizures or intellectual disability become apparent during early
CC childhood, attributed to impaired transport of folates into the central
CC nervous system. When diagnosed early, the disorder can be treated by
CC administration of folate. If untreated, it can be fatal and, if
CC treatment is delayed, the neurological defects can become permanent.
CC {ECO:0000269|PubMed:17129779, ECO:0000269|PubMed:17446347,
CC ECO:0000269|PubMed:18559978, ECO:0000269|PubMed:20686069,
CC ECO:0000269|PubMed:20805364, ECO:0000269|PubMed:21333572,
CC ECO:0000269|PubMed:22345511, ECO:0000269|PubMed:23816405,
CC ECO:0000269|PubMed:29344585, ECO:0000269|PubMed:29390264,
CC ECO:0000269|PubMed:31494288, ECO:0000269|PubMed:32893190}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: Constitutes an important route for the delivery of
CC antifolate drugs, such as methotrexate and pemetrexed, in cancer
CC chemotherapy (PubMed:18524888, PubMed:34040256). Ubiquitously expressed
CC in solid tumors to which it delivers antifolates: within the acid
CC microenvironment of cancer cells, antifolate drugs uptake mediated by
CC SLC46A1/PCFT is increased (PubMed:18524888, PubMed:34040256).
CC {ECO:0000269|PubMed:18524888, ECO:0000269|PubMed:34040256}.
CC -!- SIMILARITY: Belongs to the major facilitator superfamily. SLC46A
CC family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Mendelian genes solute carrier family 46 (folate
CC transporter), member 1 (SLC46A1); Note=Leiden Open Variation Database
CC (LOVD);
CC URL="https://databases.lovd.nl/shared/genes/SLC46A1";
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DR EMBL; AK054669; BAB70789.1; -; mRNA.
DR EMBL; AK074161; BAB84987.1; -; mRNA.
DR EMBL; DQ496103; ABF47092.1; -; Genomic_DNA.
DR EMBL; BC010691; AAH10691.1; -; mRNA.
DR EMBL; AL832613; CAD89945.1; -; mRNA.
DR CCDS; CCDS74019.1; -. [Q96NT5-2]
DR CCDS; CCDS74020.1; -. [Q96NT5-1]
DR RefSeq; NP_001229295.1; NM_001242366.2. [Q96NT5-2]
DR RefSeq; NP_542400.2; NM_080669.5. [Q96NT5-1]
DR AlphaFoldDB; Q96NT5; -.
DR SMR; Q96NT5; -.
DR BioGRID; 125236; 4.
DR IntAct; Q96NT5; 4.
DR MINT; Q96NT5; -.
DR STRING; 9606.ENSP00000480703; -.
DR BindingDB; Q96NT5; -.
DR ChEMBL; CHEMBL1795188; -.
DR DrugBank; DB08878; Aminopterin.
DR DrugBank; DB00158; Folic acid.
DR DrugBank; DB11256; Levomefolic acid.
DR DrugBank; DB00563; Methotrexate.
DR DrugBank; DB00795; Sulfasalazine.
DR DrugCentral; Q96NT5; -.
DR GuidetoPHARMACOLOGY; 1213; -.
DR TCDB; 2.A.1.50.1; the major facilitator superfamily (mfs).
DR GlyGen; Q96NT5; 2 sites.
DR iPTMnet; Q96NT5; -.
DR PhosphoSitePlus; Q96NT5; -.
DR SwissPalm; Q96NT5; -.
DR BioMuta; SLC46A1; -.
DR DMDM; 74732636; -.
DR EPD; Q96NT5; -.
DR jPOST; Q96NT5; -.
DR MassIVE; Q96NT5; -.
DR MaxQB; Q96NT5; -.
DR PaxDb; Q96NT5; -.
DR PeptideAtlas; Q96NT5; -.
DR PRIDE; Q96NT5; -.
DR ProteomicsDB; 77556; -. [Q96NT5-1]
DR ProteomicsDB; 77557; -. [Q96NT5-2]
DR Antibodypedia; 26300; 120 antibodies from 26 providers.
DR DNASU; 113235; -.
DR Ensembl; ENST00000612814.5; ENSP00000480703.1; ENSG00000076351.13. [Q96NT5-1]
DR Ensembl; ENST00000618626.1; ENSP00000483652.1; ENSG00000076351.13. [Q96NT5-2]
DR GeneID; 113235; -.
DR KEGG; hsa:113235; -.
DR MANE-Select; ENST00000612814.5; ENSP00000480703.1; NM_080669.6; NP_542400.2.
DR UCSC; uc032ezi.2; human. [Q96NT5-1]
DR CTD; 113235; -.
DR DisGeNET; 113235; -.
DR GeneCards; SLC46A1; -.
DR GeneReviews; SLC46A1; -.
DR HGNC; HGNC:30521; SLC46A1.
DR HPA; ENSG00000076351; Tissue enhanced (intestine).
DR MalaCards; SLC46A1; -.
DR MIM; 229050; phenotype.
DR MIM; 611672; gene.
DR neXtProt; NX_Q96NT5; -.
DR OpenTargets; ENSG00000076351; -.
DR Orphanet; 90045; Hereditary folate malabsorption.
DR PharmGKB; PA162403775; -.
DR VEuPathDB; HostDB:ENSG00000076351; -.
DR eggNOG; KOG2816; Eukaryota.
DR GeneTree; ENSGT00950000183096; -.
DR InParanoid; Q96NT5; -.
DR OMA; SPRANDE; -.
DR OrthoDB; 17940at2759; -.
DR PhylomeDB; Q96NT5; -.
DR TreeFam; TF315701; -.
DR PathwayCommons; Q96NT5; -.
DR Reactome; R-HSA-196757; Metabolism of folate and pterines.
DR Reactome; R-HSA-917937; Iron uptake and transport.
DR Reactome; R-HSA-9707616; Heme signaling.
DR SignaLink; Q96NT5; -.
DR SIGNOR; Q96NT5; -.
DR BioGRID-ORCS; 113235; 8 hits in 270 CRISPR screens.
DR ChiTaRS; SLC46A1; human.
DR GeneWiki; SLC46A1; -.
DR GenomeRNAi; 113235; -.
DR Pharos; Q96NT5; Tchem.
DR PRO; PR:Q96NT5; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q96NT5; protein.
DR Bgee; ENSG00000076351; Expressed in jejunal mucosa and 128 other tissues.
DR ExpressionAtlas; Q96NT5; baseline and differential.
DR Genevisible; Q96NT5; HS.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB.
DR GO; GO:0031526; C:brush border membrane; IEA:Ensembl.
DR GO; GO:0009986; C:cell surface; HDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005768; C:endosome; IDA:UniProtKB.
DR GO; GO:0010008; C:endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0005542; F:folic acid binding; IEA:UniProtKB-KW.
DR GO; GO:0008517; F:folic acid transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0140211; F:folic acid:proton symporter activity; IDA:UniProtKB.
DR GO; GO:0015232; F:heme transmembrane transporter activity; TAS:Reactome.
DR GO; GO:0015350; F:methotrexate transmembrane transporter activity; ISS:UniProtKB.
DR GO; GO:0015078; F:proton transmembrane transporter activity; IDA:BHF-UCL.
DR GO; GO:0022857; F:transmembrane transporter activity; IBA:GO_Central.
DR GO; GO:0006879; P:cellular iron ion homeostasis; TAS:Reactome.
DR GO; GO:1904447; P:folate import across plasma membrane; IDA:UniProtKB.
DR GO; GO:0098838; P:folate transmembrane transport; IMP:UniProtKB.
DR GO; GO:0046655; P:folic acid metabolic process; TAS:Reactome.
DR GO; GO:0015884; P:folic acid transport; IDA:UniProtKB.
DR GO; GO:0042168; P:heme metabolic process; TAS:Reactome.
DR GO; GO:0098829; P:intestinal folate absorption; IC:BHF-UCL.
DR GO; GO:1902600; P:proton transmembrane transport; IDA:BHF-UCL.
DR GO; GO:0055085; P:transmembrane transport; IBA:GO_Central.
DR Gene3D; 1.20.1250.20; -; 1.
DR InterPro; IPR011701; MFS.
DR InterPro; IPR020846; MFS_dom.
DR InterPro; IPR036259; MFS_trans_sf.
DR InterPro; IPR005829; Sugar_transporter_CS.
DR Pfam; PF07690; MFS_1; 1.
DR SUPFAM; SSF103473; SSF103473; 1.
DR PROSITE; PS50850; MFS; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Cell membrane; Cytoplasm;
KW Disease variant; Disulfide bond; Endosome; Folate-binding; Glycoprotein;
KW Membrane; Phosphoprotein; Reference proteome; Symport; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..459
FT /note="Proton-coupled folate transporter"
FT /id="PRO_0000084851"
FT TOPO_DOM 1..25
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 26..44
FT /note="Helical; Name=TM1"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 45..82
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 83..108
FT /note="Helical; Name=TM2"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 109..112
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 113..135
FT /note="Helical; Name=TM3"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 136..140
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 141..154
FT /note="Helical; Name=TM4"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 155..177
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 178..203
FT /note="Helical; Name=TM5"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 204..208
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 209..227
FT /note="Helical; Name=TM6"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 228..266
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 267..289
FT /note="Helical; Name=TM7"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 290..302
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 303..325
FT /note="Helical; Name=TM8"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 326..331
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 332..351
FT /note="Helical; Name=TM9"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 352..355
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 356..376
FT /note="Helical; Name=TM10"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 377..388
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 389..414
FT /note="Helical; Name=TM11"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 415..422
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TRANSMEM 423..441
FT /note="Helical; Name=TM12"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT TOPO_DOM 442..459
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT BINDING 90
FT /ligand="pemetrexed"
FT /ligand_id="ChEBI:CHEBI:63724"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT BINDING 156
FT /ligand="H(+)"
FT /ligand_id="ChEBI:CHEBI:15378"
FT /note="reversibly protonated residue during proton
FT transport"
FT /evidence="ECO:0000269|PubMed:34040256"
FT BINDING 185
FT /ligand="H(+)"
FT /ligand_id="ChEBI:CHEBI:15378"
FT /note="reversibly protonated residue during proton
FT transport"
FT /evidence="ECO:0000269|PubMed:34040256"
FT BINDING 185
FT /ligand="pemetrexed"
FT /ligand_id="ChEBI:CHEBI:63724"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT BINDING 281
FT /ligand="H(+)"
FT /ligand_id="ChEBI:CHEBI:15378"
FT /note="reversibly protonated residue during proton
FT transport"
FT /evidence="ECO:0000269|PubMed:34040256,
FT ECO:0000305|PubMed:19389703"
FT BINDING 315
FT /ligand="pemetrexed"
FT /ligand_id="ChEBI:CHEBI:63724"
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0007744|PubMed:22814378"
FT MOD_RES 6
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 458
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT CARBOHYD 58
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19159218,
FT ECO:0000269|PubMed:25053408, ECO:0000305|PubMed:18405659"
FT CARBOHYD 68
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:25053408,
FT ECO:0000305|PubMed:18405659"
FT DISULFID 66..298
FT /evidence="ECO:0000250|UniProtKB:F1NJ67"
FT VAR_SEQ 361..388
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_016053"
FT VARIANT 113
FT /note="R -> C (in HFM; loss-of-function mutation; targeted
FT to the plasma membrane but has significantly impaired
FT folate transport activity; dbSNP:rs80338770)"
FT /evidence="ECO:0000269|PubMed:18559978"
FT /id="VAR_058210"
FT VARIANT 113
FT /note="R -> S (in HFM; abolishes folate uptake;
FT dbSNP:rs80338770)"
FT /evidence="ECO:0000269|PubMed:17446347"
FT /id="VAR_032825"
FT VARIANT 147
FT /note="G -> R (in HFM; reduces folate uptake to 13% of
FT normal levels; dbSNP:rs80338771)"
FT /evidence="ECO:0000269|PubMed:17446347"
FT /id="VAR_032826"
FT VARIANT 156
FT /note="D -> Y (in HFM; loss of function measured as
FT methotrexate uptake; dbSNP:rs281875210)"
FT /evidence="ECO:0000269|PubMed:20805364"
FT /id="VAR_067960"
FT VARIANT 189
FT /note="G -> V (in HFM; decreased folate uptake)"
FT /evidence="ECO:0000269|PubMed:31494288"
FT /id="VAR_085918"
FT VARIANT 295
FT /note="T -> A (in dbSNP:rs34552966)"
FT /id="VAR_050302"
FT VARIANT 318
FT /note="S -> R (in HFM; abolishes folate uptake;
FT dbSNP:rs80338772)"
FT /evidence="ECO:0000269|PubMed:17446347,
FT ECO:0000269|PubMed:31494288"
FT /id="VAR_032827"
FT VARIANT 335
FT /note="A -> D (in HFM; loss of function measured as
FT methotrexate uptake; dbSNP:rs281875208)"
FT /evidence="ECO:0000269|PubMed:21333572"
FT /id="VAR_067961"
FT VARIANT 338
FT /note="G -> R (in HFM; loss of function measured as
FT methotrexate uptake; dbSNP:rs281875209)"
FT /evidence="ECO:0000269|PubMed:21333572"
FT /id="VAR_067962"
FT VARIANT 376
FT /note="R -> Q (in HFM; abolishes folate uptake;
FT dbSNP:rs281875211)"
FT /evidence="ECO:0000269|PubMed:20686069"
FT /id="VAR_067963"
FT VARIANT 376
FT /note="R -> W (in HFM; abolishes folate uptake;
FT dbSNP:rs80338773)"
FT /evidence="ECO:0000269|PubMed:17446347"
FT /id="VAR_032828"
FT VARIANT 392
FT /note="F -> V (in HFM; locks the protein into an inward-
FT open conformation, leading to decreased folate uptake; does
FT not affect localization to the cell membrane)"
FT /evidence="ECO:0000269|PubMed:31494288,
FT ECO:0000269|PubMed:32893190"
FT /id="VAR_085919"
FT VARIANT 411
FT /note="N -> K (in HFM; decreased folate uptake)"
FT /evidence="ECO:0000269|PubMed:29344585"
FT /id="VAR_085920"
FT VARIANT 425
FT /note="P -> R (in HFM; strongly decreased folate and
FT methotrexate uptake; dbSNP:rs80338774)"
FT /evidence="ECO:0000269|PubMed:17446347,
FT ECO:0000269|PubMed:22345511"
FT /id="VAR_032829"
FT MUTAGEN 58
FT /note="N->Q: Abolished N-glycosylation without affecting
FT localization to the cell membrane; when associated with Q-
FT 68."
FT /evidence="ECO:0000269|PubMed:18405659"
FT MUTAGEN 68
FT /note="N->Q: Abolished N-glycosylation without affecting
FT localization to the cell membrane; when associated with Q-
FT 58."
FT /evidence="ECO:0000269|PubMed:18405659"
FT MUTAGEN 109
FT /note="D->A,G,E,K,N,S: Loss of methotrexate uptake."
FT /evidence="ECO:0000269|PubMed:20805364"
FT MUTAGEN 109
FT /note="D->A: Complete loss of transport function."
FT /evidence="ECO:0000269|PubMed:25504888"
FT MUTAGEN 156
FT /note="D->E: Does not affect methotrexate uptake."
FT /evidence="ECO:0000269|PubMed:20805364"
FT MUTAGEN 156
FT /note="D->F,K,N,V,W: Loss of methotrexate uptake."
FT /evidence="ECO:0000269|PubMed:20805364"
FT MUTAGEN 156
FT /note="D->G: 2-fold reduction of methotrexate uptake."
FT /evidence="ECO:0000269|PubMed:20805364"
FT MUTAGEN 156
FT /note="D->S: 8-fold reduction of methotrexate uptake."
FT /evidence="ECO:0000269|PubMed:20805364"
FT MUTAGEN 158
FT /note="G->N: Abolished sensitivity to myricetin inhibitor."
FT /evidence="ECO:0000269|PubMed:31792273"
FT MUTAGEN 172
FT /note="S->A: Decreased proton-coupled folate transport."
FT /evidence="ECO:0000269|PubMed:19389703"
FT MUTAGEN 185
FT /note="E->A: Abolished proton-coupled folate transport at
FT pH 5.5 and pH 7.5."
FT /evidence="ECO:0000269|PubMed:34040256"
FT MUTAGEN 185
FT /note="E->N: Abolished proton-coupled folate transport at
FT pH 5.5, while it displays strong proton-coupled folate
FT transporter activity at pH 7.5."
FT /evidence="ECO:0000269|PubMed:34040256"
FT MUTAGEN 247
FT /note="H->A: Decreased proton-coupled folate transport."
FT /evidence="ECO:0000269|PubMed:19389703"
FT MUTAGEN 281
FT /note="H->A: Abolished proton-coupled folate transport."
FT /evidence="ECO:0000269|PubMed:19389703"
FT MUTAGEN 299
FT /note="W->C: About 90% loss of transport function."
FT /evidence="ECO:0000269|PubMed:25504888"
FT MUTAGEN 314
FT /note="P->C: Displays a lower affinity for folate substrate
FT associated with a higher rate of conformational change."
FT /evidence="ECO:0000269|PubMed:28802835"
FT MUTAGEN 315
FT /note="Y->A,P: Displays a lower affinity for folate
FT substrate associated with a higher rate of conformational
FT change."
FT /evidence="ECO:0000269|PubMed:25608532,
FT ECO:0000269|PubMed:28802835"
FT MUTAGEN 318
FT /note="S->A,C: Slightly decreased proton-coupled folate
FT transport."
FT /evidence="ECO:0000269|PubMed:34619546"
FT MUTAGEN 318
FT /note="S->R,K: Abolished proton-coupled folate transport."
FT /evidence="ECO:0000269|PubMed:34619546"
FT MUTAGEN 376
FT /note="R->A,C,E,H,Q,W: Abolishes folate uptake."
FT /evidence="ECO:0000269|PubMed:20686069"
FT MUTAGEN 392
FT /note="F->A,H,W,Y: Decreased methotrexate uptake at low
FT concentration."
FT /evidence="ECO:0000269|PubMed:32893190"
FT MUTAGEN 392
FT /note="F->E,D,K,L,I,Q,T: Abolished methotrexate uptake."
FT /evidence="ECO:0000269|PubMed:32893190"
FT MUTAGEN 392
FT /note="F->M: Does not affect methotrexate uptake at low
FT concentration."
FT /evidence="ECO:0000269|PubMed:32893190"
FT MUTAGEN 411
FT /note="N->A,D,L,Q: Does not affect folate uptake."
FT /evidence="ECO:0000269|PubMed:29344585"
FT MUTAGEN 411
FT /note="N->E,H,K,R: Abolished folate uptake."
FT /evidence="ECO:0000269|PubMed:29344585"
FT MUTAGEN 411
FT /note="N->T: Decreased folate uptake at low folate
FT concentration, while folate uptake is not affected at high
FT folate concentration."
FT /evidence="ECO:0000269|PubMed:29344585"
FT MUTAGEN 425
FT /note="P->K: Strongly decreased folate and methotrexate
FT uptake, while it still binds pemetrexed."
FT /evidence="ECO:0000269|PubMed:22345511"
FT CONFLICT 394
FT /note="A -> G (in Ref. 1; BAB84987)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 459 AA; 49771 MW; 119F89E9E4ACA5F4 CRC64;
MEGSASPPEK PRARPAAAVL CRGPVEPLVF LANFALVLQG PLTTQYLWHR FSADLGYNGT
RQRGGCSNRS ADPTMQEVET LTSHWTLYMN VGGFLVGLFS STLLGAWSDS VGRRPLLVLA
SLGLLLQALV SVFVVQLQLH VGYFVLGRIL CALLGDFGGL LAASFASVAD VSSSRSRTFR
MALLEASIGV AGMLASLLGG HWLRAQGYAN PFWLALALLI AMTLYAAFCF GETLKEPKST
RLFTFRHHRS IVQLYVAPAP EKSRKHLALY SLAIFVVITV HFGAQDILTL YELSTPLCWD
SKLIGYGSAA QHLPYLTSLL ALKLLQYCLA DAWVAEIGLA FNILGMVVFA FATITPLMFT
GYGLLFLSLV ITPVIRAKLS KLVRETEQGA LFSAVACVNS LAMLTASGIF NSLYPATLNF
MKGFPFLLGA GLLLIPAVLI GMLEKADPHL EFQQFPQSP
