Full text data of SLC19A1
SLC19A1
(FLOT1, RFC1)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Folate transporter 1; FOLT (Intestinal folate carrier 1; IFC-1; Placental folate transporter; Reduced folate carrier protein; RFC; Solute carrier family 19 member 1)
Folate transporter 1; FOLT (Intestinal folate carrier 1; IFC-1; Placental folate transporter; Reduced folate carrier protein; RFC; Solute carrier family 19 member 1)
hRBCD
IPI00299186
IPI00299186 solute carrier family 19 member 1 isoform b solute carrier family 19 member 1 isoform b membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 1 n/a n/a n/a n/a 2 n/a n/a integral membrane protein n/a found at its expected molecular weight found at molecular weight
IPI00299186 solute carrier family 19 member 1 isoform b solute carrier family 19 member 1 isoform b membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 1 n/a n/a n/a n/a 2 n/a n/a integral membrane protein n/a found at its expected molecular weight found at molecular weight
UniProt
P41440
ID S19A1_HUMAN Reviewed; 591 AA.
AC P41440; B2R7U8; B7Z8C3; E9PFY4; O00553; O60227; Q13026; Q9BTX8;
read moreDT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2000, sequence version 3.
DT 22-JAN-2014, entry version 117.
DE RecName: Full=Folate transporter 1;
DE Short=FOLT;
DE AltName: Full=Intestinal folate carrier 1;
DE Short=IFC-1;
DE AltName: Full=Placental folate transporter;
DE AltName: Full=Reduced folate carrier protein;
DE Short=RFC;
DE AltName: Full=Solute carrier family 19 member 1;
GN Name=SLC19A1; Synonyms=FLOT1, RFC1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ARG-27.
RC TISSUE=Placenta;
RX PubMed=7826387; DOI=10.1006/bbrc.1995.1096;
RA Prasad P.D., Ramamoorthy S., Leibach F.H., Ganapathy V.;
RT "Molecular cloning of the human placental folate transporter.";
RL Biochem. Biophys. Res. Commun. 206:681-687(1995).
RN [2]
RP SEQUENCE REVISION TO 490-527.
RA Prasad P.D.;
RL Submitted (APR-1996) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ARG-27.
RX PubMed=7615551; DOI=10.1074/jbc.270.29.17299;
RA Wong S.C., Proefke A., Bhushan A., Matherly L.H.;
RT "Isolation of human cDNAs that restore methotrexate sensitivity and
RT reduced folate carrier activity in methotrexate transport-defective
RT Chinese hamster ovary cells.";
RL J. Biol. Chem. 270:17468-17475(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ARG-27.
RC TISSUE=Testis;
RX PubMed=7641195;
RA Moscow J.A., Gong M., He R., Sgagias M.K., Dixon K.H., Anzick S.L.,
RA Meltzer P.S., Cowan K.H.;
RT "Isolation of a gene encoding a human reduced folate carrier (RFC1)
RT and analysis of its expression in transport-deficient, methotrexate-
RT resistant human breast cancer cells.";
RL Cancer Res. 55:3790-3794(1995).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Lymphoma;
RX PubMed=7852378; DOI=10.1074/jbc.270.7.2987;
RA Williams F.M., Flintoff W.F.;
RT "Isolation of a human cDNA that complements a mutant hamster cell
RT defective in methotrexate uptake.";
RL J. Biol. Chem. 270:2987-2992(1995).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ARG-27.
RC TISSUE=Liver;
RA Tolner B.M., Roy K., Sirotnak F.M.;
RT "Structural analysis of the human RFC1 gene encoding a folate
RT transporter and alternatively spliced transcripts with 5' end
RT heterogeneity.";
RL Submitted (MAR-1997) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Small intestine;
RX PubMed=9041240; DOI=10.1053/gast.1997.v112.pm9041240;
RA Nguyen T.T., Dyer D.L., Dunning D.D., Rubin S.A., Grant K.E.,
RA Said H.M.;
RT "Human intestinal folate transport: cloning, expression, and
RT distribution of complementary RNA.";
RL Gastroenterology 112:783-791(1997).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Thymus, and Tongue;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10830953; DOI=10.1038/35012518;
RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T.,
RA Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y.,
RA Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K.,
RA Polley A., Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D.,
RA Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W.,
RA Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S.,
RA Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E.,
RA Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P.,
RA Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H.,
RA Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E.,
RA Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F.,
RA Lehrach H., Reinhardt R., Yaspo M.-L.;
RT "The DNA sequence of human chromosome 21.";
RL Nature 405:311-319(2000).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND VARIANT
RP ARG-27.
RC TISSUE=Brain;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [12]
RP TOPOLOGY.
RX PubMed=10347183; DOI=10.1074/jbc.274.23.16269;
RA Ferguson P.L., Flintoff W.F.;
RT "Topological and functional analysis of the human reduced folate
RT carrier by hemagglutinin epitope insertion.";
RL J. Biol. Chem. 274:16269-16278(1999).
RN [13]
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 [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-499 AND SER-503, AND
RP MASS SPECTROMETRY.
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.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [16]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
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.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
CC -!- FUNCTION: Transporter for the intake of folate. Uptake of folate
CC in human placental choriocarcinoma cells occurs by a novel
CC mechanism called potocytosis which functionally couples three
CC components, namely the folate receptor, the folate transporter,
CC and a V-type H(+)-pump.
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P41440-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P41440-2; Sequence=VSP_042891;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=P41440-3; Sequence=VSP_044497;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Placenta, liver, and to a much smaller extent,
CC in lung.
CC -!- PTM: Heavily glycosylated.
CC -!- SIMILARITY: Belongs to the reduced folate carrier (RFC)
CC transporter (TC 2.A.48) family.
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DR EMBL; U15939; AAA98442.1; -; mRNA.
DR EMBL; U19720; AAC50180.1; -; mRNA.
DR EMBL; S78996; AAB35058.1; -; mRNA.
DR EMBL; U17566; AAA74914.1; -; mRNA.
DR EMBL; U92873; AAC26162.1; -; Genomic_DNA.
DR EMBL; U92869; AAC26162.1; JOINED; Genomic_DNA.
DR EMBL; U92870; AAC26162.1; JOINED; Genomic_DNA.
DR EMBL; U92871; AAC26162.1; JOINED; Genomic_DNA.
DR EMBL; U92872; AAC26162.1; JOINED; Genomic_DNA.
DR EMBL; AF004354; AAB61417.1; -; mRNA.
DR EMBL; AK303168; BAH13909.1; -; mRNA.
DR EMBL; AK313125; BAG35945.1; -; mRNA.
DR EMBL; AL163302; CAB90483.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BX322561; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471079; EAX09331.1; -; Genomic_DNA.
DR EMBL; BC003068; AAH03068.1; -; mRNA.
DR PIR; I38924; I38924.
DR PIR; I52728; I52728.
DR RefSeq; NP_001192135.1; NM_001205206.1.
DR RefSeq; NP_001192136.1; NM_001205207.1.
DR RefSeq; NP_919231.1; NM_194255.2.
DR RefSeq; XP_005261220.1; XM_005261163.1.
DR UniGene; Hs.736903; -.
DR UniGene; Hs.84190; -.
DR ProteinModelPortal; P41440; -.
DR STRING; 9606.ENSP00000308895; -.
DR BindingDB; P41440; -.
DR ChEMBL; CHEMBL4833; -.
DR GuidetoPHARMACOLOGY; 1014; -.
DR TCDB; 2.A.48.1.1; the reduced folate carrier (rfc) family.
DR PhosphoSite; P41440; -.
DR DMDM; 12643280; -.
DR PaxDb; P41440; -.
DR PRIDE; P41440; -.
DR DNASU; 6573; -.
DR Ensembl; ENST00000311124; ENSP00000308895; ENSG00000173638.
DR Ensembl; ENST00000380010; ENSP00000369347; ENSG00000173638.
DR Ensembl; ENST00000485649; ENSP00000441772; ENSG00000173638.
DR GeneID; 6573; -.
DR KEGG; hsa:6573; -.
DR UCSC; uc002zhl.2; human.
DR CTD; 6573; -.
DR GeneCards; GC21M046913; -.
DR HGNC; HGNC:10937; SLC19A1.
DR HPA; HPA024802; -.
DR MIM; 600424; gene.
DR neXtProt; NX_P41440; -.
DR Orphanet; 306574; Methotrexate dose selection.
DR PharmGKB; PA327; -.
DR eggNOG; NOG241030; -.
DR HOVERGEN; HBG054198; -.
DR InParanoid; P41440; -.
DR KO; K14609; -.
DR OMA; HILWNVV; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR GeneWiki; SLC19A1; -.
DR GenomeRNAi; 6573; -.
DR NextBio; 25575; -.
DR PRO; PR:P41440; -.
DR ArrayExpress; P41440; -.
DR Bgee; P41440; -.
DR CleanEx; HS_FLOT1; -.
DR CleanEx; HS_RFC1; -.
DR CleanEx; HS_SLC19A1; -.
DR Genevestigator; P41440; -.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0005542; F:folic acid binding; IEA:UniProtKB-KW.
DR GO; GO:0008517; F:folic acid transporter activity; TAS:ProtInc.
DR GO; GO:0015350; F:methotrexate transporter activity; TAS:ProtInc.
DR GO; GO:0046655; P:folic acid metabolic process; TAS:Reactome.
DR InterPro; IPR002666; Folate_carrier.
DR InterPro; IPR016196; MFS_dom_general_subst_transpt.
DR InterPro; IPR028339; RFC.
DR PANTHER; PTHR10686; PTHR10686; 1.
DR Pfam; PF01770; Folate_carrier; 1.
DR PIRSF; PIRSF028739; Folate_carrier; 1.
DR PIRSF; PIRSF500793; Folate_transporter_1; 1.
DR SUPFAM; SSF103473; SSF103473; 2.
DR TIGRFAMs; TIGR00806; rfc; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Complete proteome; Folate-binding;
KW Glycoprotein; Membrane; Phosphoprotein; Polymorphism;
KW Reference proteome; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 591 Folate transporter 1.
FT /FTId=PRO_0000178660.
FT TOPO_DOM 1 23 Cytoplasmic (Probable).
FT TRANSMEM 24 44 Helical; (Probable).
FT TOPO_DOM 45 70 Extracellular (Probable).
FT TRANSMEM 71 89 Helical; (Probable).
FT TOPO_DOM 90 95 Cytoplasmic (Probable).
FT TRANSMEM 96 116 Helical; (Probable).
FT TOPO_DOM 117 123 Extracellular (Probable).
FT TRANSMEM 124 144 Helical; (Probable).
FT TOPO_DOM 145 159 Cytoplasmic (Probable).
FT TRANSMEM 160 177 Helical; (Probable).
FT TOPO_DOM 178 186 Extracellular (Probable).
FT TRANSMEM 187 203 Helical; (Probable).
FT TOPO_DOM 204 259 Cytoplasmic (Probable).
FT TRANSMEM 260 287 Helical; (Probable).
FT TOPO_DOM 288 309 Extracellular (Probable).
FT TRANSMEM 310 327 Helical; (Probable).
FT TOPO_DOM 328 333 Cytoplasmic (Probable).
FT TRANSMEM 334 354 Helical; (Probable).
FT TOPO_DOM 355 360 Extracellular (Probable).
FT TRANSMEM 361 378 Helical; (Probable).
FT TOPO_DOM 379 394 Cytoplasmic (Probable).
FT TRANSMEM 395 419 Helical; (Probable).
FT TOPO_DOM 420 433 Extracellular (Probable).
FT TRANSMEM 434 454 Helical; (Probable).
FT TOPO_DOM 455 591 Cytoplasmic (Probable).
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 474 474 Phosphoserine (By similarity).
FT MOD_RES 485 485 Phosphoserine (By similarity).
FT MOD_RES 499 499 Phosphoserine.
FT MOD_RES 503 503 Phosphoserine.
FT CARBOHYD 58 58 N-linked (GlcNAc...) (Potential).
FT VAR_SEQ 1 63 MVPSSPAVEKQVPVEPGPDPELRSWRHLVCYLCFYGFMAQI
FT RPGESFITPYLLGPDKNFTREQ -> MRPQPAEPAPGGRGN
FT EACSIHSE (in isoform 2).
FT /FTId=VSP_042891.
FT VAR_SEQ 432 591 FQLYSVYFLILSIIYFLGAMLDGLRHCQRGHHPRQPPAQGL
FT RSAAEEKAAQALSVQDKGLGGLQPAQSPPLSPEDSLGAVGP
FT ASLEQRQSDPYLAQAPAPQAAEFLSPVTTPSPCTLCSAQAS
FT GPEAADETCPQLAVHPPGVSKLGLQCLPSDGVQNVNQ ->
FT NEELHVASLSLWKSHLRLAADTLSSEGSSGSGPRSWFLSPT
FT LRAALHGPVCPSEVCPS (in isoform 3).
FT /FTId=VSP_044497.
FT VARIANT 27 27 H -> R (in dbSNP:rs1051266).
FT /FTId=VAR_020210.
FT VARIANT 558 558 A -> V (in dbSNP:rs35786590).
FT /FTId=VAR_052404.
FT CONFLICT 62 63 EQ -> DE (in Ref. 1 and 4).
FT CONFLICT 268 268 R -> P (in Ref. 1; AAA98442).
FT CONFLICT 457 457 H -> D (in Ref. 4; AAB35058).
FT CONFLICT 483 483 A -> R (in Ref. 4; AAB35058).
FT CONFLICT 549 549 C -> S (in Ref. 1, 4, 5 and 6).
SQ SEQUENCE 591 AA; 64868 MW; 0437B1615F5517EB CRC64;
MVPSSPAVEK QVPVEPGPDP ELRSWRHLVC YLCFYGFMAQ IRPGESFITP YLLGPDKNFT
REQVTNEITP VLSYSYLAVL VPVFLLTDYL RYTPVLLLQG LSFVSVWLLL LLGHSVAHMQ
LMELFYSVTM AARIAYSSYI FSLVRPARYQ RVAGYSRAAV LLGVFTSSVL GQLLVTVGRV
SFSTLNYISL AFLTFSVVLA LFLKRPKRSL FFNRDDRGRC ETSASELERM NPGPGGKLGH
ALRVACGDSV LARMLRELGD SLRRPQLRLW SLWWVFNSAG YYLVVYYVHI LWNEVDPTTN
SARVYNGAAD AASTLLGAIT SFAAGFVKIR WARWSKLLIA GVTATQAGLV FLLAHTRHPS
SIWLCYAAFV LFRGSYQFLV PIATFQIASS LSKELCALVF GVNTFFATIV KTIITFIVSD
VRGLGLPVRK QFQLYSVYFL ILSIIYFLGA MLDGLRHCQR GHHPRQPPAQ GLRSAAEEKA
AQALSVQDKG LGGLQPAQSP PLSPEDSLGA VGPASLEQRQ SDPYLAQAPA PQAAEFLSPV
TTPSPCTLCS AQASGPEAAD ETCPQLAVHP PGVSKLGLQC LPSDGVQNVN Q
//
ID S19A1_HUMAN Reviewed; 591 AA.
AC P41440; B2R7U8; B7Z8C3; E9PFY4; O00553; O60227; Q13026; Q9BTX8;
read moreDT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2000, sequence version 3.
DT 22-JAN-2014, entry version 117.
DE RecName: Full=Folate transporter 1;
DE Short=FOLT;
DE AltName: Full=Intestinal folate carrier 1;
DE Short=IFC-1;
DE AltName: Full=Placental folate transporter;
DE AltName: Full=Reduced folate carrier protein;
DE Short=RFC;
DE AltName: Full=Solute carrier family 19 member 1;
GN Name=SLC19A1; Synonyms=FLOT1, RFC1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ARG-27.
RC TISSUE=Placenta;
RX PubMed=7826387; DOI=10.1006/bbrc.1995.1096;
RA Prasad P.D., Ramamoorthy S., Leibach F.H., Ganapathy V.;
RT "Molecular cloning of the human placental folate transporter.";
RL Biochem. Biophys. Res. Commun. 206:681-687(1995).
RN [2]
RP SEQUENCE REVISION TO 490-527.
RA Prasad P.D.;
RL Submitted (APR-1996) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ARG-27.
RX PubMed=7615551; DOI=10.1074/jbc.270.29.17299;
RA Wong S.C., Proefke A., Bhushan A., Matherly L.H.;
RT "Isolation of human cDNAs that restore methotrexate sensitivity and
RT reduced folate carrier activity in methotrexate transport-defective
RT Chinese hamster ovary cells.";
RL J. Biol. Chem. 270:17468-17475(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ARG-27.
RC TISSUE=Testis;
RX PubMed=7641195;
RA Moscow J.A., Gong M., He R., Sgagias M.K., Dixon K.H., Anzick S.L.,
RA Meltzer P.S., Cowan K.H.;
RT "Isolation of a gene encoding a human reduced folate carrier (RFC1)
RT and analysis of its expression in transport-deficient, methotrexate-
RT resistant human breast cancer cells.";
RL Cancer Res. 55:3790-3794(1995).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Lymphoma;
RX PubMed=7852378; DOI=10.1074/jbc.270.7.2987;
RA Williams F.M., Flintoff W.F.;
RT "Isolation of a human cDNA that complements a mutant hamster cell
RT defective in methotrexate uptake.";
RL J. Biol. Chem. 270:2987-2992(1995).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ARG-27.
RC TISSUE=Liver;
RA Tolner B.M., Roy K., Sirotnak F.M.;
RT "Structural analysis of the human RFC1 gene encoding a folate
RT transporter and alternatively spliced transcripts with 5' end
RT heterogeneity.";
RL Submitted (MAR-1997) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Small intestine;
RX PubMed=9041240; DOI=10.1053/gast.1997.v112.pm9041240;
RA Nguyen T.T., Dyer D.L., Dunning D.D., Rubin S.A., Grant K.E.,
RA Said H.M.;
RT "Human intestinal folate transport: cloning, expression, and
RT distribution of complementary RNA.";
RL Gastroenterology 112:783-791(1997).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Thymus, and Tongue;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10830953; DOI=10.1038/35012518;
RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T.,
RA Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y.,
RA Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K.,
RA Polley A., Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D.,
RA Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W.,
RA Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S.,
RA Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E.,
RA Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P.,
RA Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H.,
RA Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E.,
RA Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F.,
RA Lehrach H., Reinhardt R., Yaspo M.-L.;
RT "The DNA sequence of human chromosome 21.";
RL Nature 405:311-319(2000).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND VARIANT
RP ARG-27.
RC TISSUE=Brain;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [12]
RP TOPOLOGY.
RX PubMed=10347183; DOI=10.1074/jbc.274.23.16269;
RA Ferguson P.L., Flintoff W.F.;
RT "Topological and functional analysis of the human reduced folate
RT carrier by hemagglutinin epitope insertion.";
RL J. Biol. Chem. 274:16269-16278(1999).
RN [13]
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 [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-499 AND SER-503, AND
RP MASS SPECTROMETRY.
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.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [16]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
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.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
CC -!- FUNCTION: Transporter for the intake of folate. Uptake of folate
CC in human placental choriocarcinoma cells occurs by a novel
CC mechanism called potocytosis which functionally couples three
CC components, namely the folate receptor, the folate transporter,
CC and a V-type H(+)-pump.
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P41440-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P41440-2; Sequence=VSP_042891;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=P41440-3; Sequence=VSP_044497;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Placenta, liver, and to a much smaller extent,
CC in lung.
CC -!- PTM: Heavily glycosylated.
CC -!- SIMILARITY: Belongs to the reduced folate carrier (RFC)
CC transporter (TC 2.A.48) family.
CC -----------------------------------------------------------------------
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DR EMBL; U15939; AAA98442.1; -; mRNA.
DR EMBL; U19720; AAC50180.1; -; mRNA.
DR EMBL; S78996; AAB35058.1; -; mRNA.
DR EMBL; U17566; AAA74914.1; -; mRNA.
DR EMBL; U92873; AAC26162.1; -; Genomic_DNA.
DR EMBL; U92869; AAC26162.1; JOINED; Genomic_DNA.
DR EMBL; U92870; AAC26162.1; JOINED; Genomic_DNA.
DR EMBL; U92871; AAC26162.1; JOINED; Genomic_DNA.
DR EMBL; U92872; AAC26162.1; JOINED; Genomic_DNA.
DR EMBL; AF004354; AAB61417.1; -; mRNA.
DR EMBL; AK303168; BAH13909.1; -; mRNA.
DR EMBL; AK313125; BAG35945.1; -; mRNA.
DR EMBL; AL163302; CAB90483.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BX322561; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471079; EAX09331.1; -; Genomic_DNA.
DR EMBL; BC003068; AAH03068.1; -; mRNA.
DR PIR; I38924; I38924.
DR PIR; I52728; I52728.
DR RefSeq; NP_001192135.1; NM_001205206.1.
DR RefSeq; NP_001192136.1; NM_001205207.1.
DR RefSeq; NP_919231.1; NM_194255.2.
DR RefSeq; XP_005261220.1; XM_005261163.1.
DR UniGene; Hs.736903; -.
DR UniGene; Hs.84190; -.
DR ProteinModelPortal; P41440; -.
DR STRING; 9606.ENSP00000308895; -.
DR BindingDB; P41440; -.
DR ChEMBL; CHEMBL4833; -.
DR GuidetoPHARMACOLOGY; 1014; -.
DR TCDB; 2.A.48.1.1; the reduced folate carrier (rfc) family.
DR PhosphoSite; P41440; -.
DR DMDM; 12643280; -.
DR PaxDb; P41440; -.
DR PRIDE; P41440; -.
DR DNASU; 6573; -.
DR Ensembl; ENST00000311124; ENSP00000308895; ENSG00000173638.
DR Ensembl; ENST00000380010; ENSP00000369347; ENSG00000173638.
DR Ensembl; ENST00000485649; ENSP00000441772; ENSG00000173638.
DR GeneID; 6573; -.
DR KEGG; hsa:6573; -.
DR UCSC; uc002zhl.2; human.
DR CTD; 6573; -.
DR GeneCards; GC21M046913; -.
DR HGNC; HGNC:10937; SLC19A1.
DR HPA; HPA024802; -.
DR MIM; 600424; gene.
DR neXtProt; NX_P41440; -.
DR Orphanet; 306574; Methotrexate dose selection.
DR PharmGKB; PA327; -.
DR eggNOG; NOG241030; -.
DR HOVERGEN; HBG054198; -.
DR InParanoid; P41440; -.
DR KO; K14609; -.
DR OMA; HILWNVV; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR GeneWiki; SLC19A1; -.
DR GenomeRNAi; 6573; -.
DR NextBio; 25575; -.
DR PRO; PR:P41440; -.
DR ArrayExpress; P41440; -.
DR Bgee; P41440; -.
DR CleanEx; HS_FLOT1; -.
DR CleanEx; HS_RFC1; -.
DR CleanEx; HS_SLC19A1; -.
DR Genevestigator; P41440; -.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0005542; F:folic acid binding; IEA:UniProtKB-KW.
DR GO; GO:0008517; F:folic acid transporter activity; TAS:ProtInc.
DR GO; GO:0015350; F:methotrexate transporter activity; TAS:ProtInc.
DR GO; GO:0046655; P:folic acid metabolic process; TAS:Reactome.
DR InterPro; IPR002666; Folate_carrier.
DR InterPro; IPR016196; MFS_dom_general_subst_transpt.
DR InterPro; IPR028339; RFC.
DR PANTHER; PTHR10686; PTHR10686; 1.
DR Pfam; PF01770; Folate_carrier; 1.
DR PIRSF; PIRSF028739; Folate_carrier; 1.
DR PIRSF; PIRSF500793; Folate_transporter_1; 1.
DR SUPFAM; SSF103473; SSF103473; 2.
DR TIGRFAMs; TIGR00806; rfc; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Complete proteome; Folate-binding;
KW Glycoprotein; Membrane; Phosphoprotein; Polymorphism;
KW Reference proteome; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 591 Folate transporter 1.
FT /FTId=PRO_0000178660.
FT TOPO_DOM 1 23 Cytoplasmic (Probable).
FT TRANSMEM 24 44 Helical; (Probable).
FT TOPO_DOM 45 70 Extracellular (Probable).
FT TRANSMEM 71 89 Helical; (Probable).
FT TOPO_DOM 90 95 Cytoplasmic (Probable).
FT TRANSMEM 96 116 Helical; (Probable).
FT TOPO_DOM 117 123 Extracellular (Probable).
FT TRANSMEM 124 144 Helical; (Probable).
FT TOPO_DOM 145 159 Cytoplasmic (Probable).
FT TRANSMEM 160 177 Helical; (Probable).
FT TOPO_DOM 178 186 Extracellular (Probable).
FT TRANSMEM 187 203 Helical; (Probable).
FT TOPO_DOM 204 259 Cytoplasmic (Probable).
FT TRANSMEM 260 287 Helical; (Probable).
FT TOPO_DOM 288 309 Extracellular (Probable).
FT TRANSMEM 310 327 Helical; (Probable).
FT TOPO_DOM 328 333 Cytoplasmic (Probable).
FT TRANSMEM 334 354 Helical; (Probable).
FT TOPO_DOM 355 360 Extracellular (Probable).
FT TRANSMEM 361 378 Helical; (Probable).
FT TOPO_DOM 379 394 Cytoplasmic (Probable).
FT TRANSMEM 395 419 Helical; (Probable).
FT TOPO_DOM 420 433 Extracellular (Probable).
FT TRANSMEM 434 454 Helical; (Probable).
FT TOPO_DOM 455 591 Cytoplasmic (Probable).
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 474 474 Phosphoserine (By similarity).
FT MOD_RES 485 485 Phosphoserine (By similarity).
FT MOD_RES 499 499 Phosphoserine.
FT MOD_RES 503 503 Phosphoserine.
FT CARBOHYD 58 58 N-linked (GlcNAc...) (Potential).
FT VAR_SEQ 1 63 MVPSSPAVEKQVPVEPGPDPELRSWRHLVCYLCFYGFMAQI
FT RPGESFITPYLLGPDKNFTREQ -> MRPQPAEPAPGGRGN
FT EACSIHSE (in isoform 2).
FT /FTId=VSP_042891.
FT VAR_SEQ 432 591 FQLYSVYFLILSIIYFLGAMLDGLRHCQRGHHPRQPPAQGL
FT RSAAEEKAAQALSVQDKGLGGLQPAQSPPLSPEDSLGAVGP
FT ASLEQRQSDPYLAQAPAPQAAEFLSPVTTPSPCTLCSAQAS
FT GPEAADETCPQLAVHPPGVSKLGLQCLPSDGVQNVNQ ->
FT NEELHVASLSLWKSHLRLAADTLSSEGSSGSGPRSWFLSPT
FT LRAALHGPVCPSEVCPS (in isoform 3).
FT /FTId=VSP_044497.
FT VARIANT 27 27 H -> R (in dbSNP:rs1051266).
FT /FTId=VAR_020210.
FT VARIANT 558 558 A -> V (in dbSNP:rs35786590).
FT /FTId=VAR_052404.
FT CONFLICT 62 63 EQ -> DE (in Ref. 1 and 4).
FT CONFLICT 268 268 R -> P (in Ref. 1; AAA98442).
FT CONFLICT 457 457 H -> D (in Ref. 4; AAB35058).
FT CONFLICT 483 483 A -> R (in Ref. 4; AAB35058).
FT CONFLICT 549 549 C -> S (in Ref. 1, 4, 5 and 6).
SQ SEQUENCE 591 AA; 64868 MW; 0437B1615F5517EB CRC64;
MVPSSPAVEK QVPVEPGPDP ELRSWRHLVC YLCFYGFMAQ IRPGESFITP YLLGPDKNFT
REQVTNEITP VLSYSYLAVL VPVFLLTDYL RYTPVLLLQG LSFVSVWLLL LLGHSVAHMQ
LMELFYSVTM AARIAYSSYI FSLVRPARYQ RVAGYSRAAV LLGVFTSSVL GQLLVTVGRV
SFSTLNYISL AFLTFSVVLA LFLKRPKRSL FFNRDDRGRC ETSASELERM NPGPGGKLGH
ALRVACGDSV LARMLRELGD SLRRPQLRLW SLWWVFNSAG YYLVVYYVHI LWNEVDPTTN
SARVYNGAAD AASTLLGAIT SFAAGFVKIR WARWSKLLIA GVTATQAGLV FLLAHTRHPS
SIWLCYAAFV LFRGSYQFLV PIATFQIASS LSKELCALVF GVNTFFATIV KTIITFIVSD
VRGLGLPVRK QFQLYSVYFL ILSIIYFLGA MLDGLRHCQR GHHPRQPPAQ GLRSAAEEKA
AQALSVQDKG LGGLQPAQSP PLSPEDSLGA VGPASLEQRQ SDPYLAQAPA PQAAEFLSPV
TTPSPCTLCS AQASGPEAAD ETCPQLAVHP PGVSKLGLQC LPSDGVQNVN Q
//
MIM
600424
*RECORD*
*FIELD* NO
600424
*FIELD* TI
*600424 SOLUTE CARRIER FAMILY 19 (FOLATE TRANSPORTER), MEMBER 1; SLC19A1
;;FOLATE TRANSPORTER; FOLT;;
read moreREDUCED FOLATE CARRIER 1; RFC1;;
INTESTINAL FOLATE CARRIER 1; IFC1
*FIELD* TX
DESCRIPTION
Transport of folate compounds into mammalian cells can occur via
receptor-mediated (see 136430) or carrier-mediated mechanisms. A
functional coordination between these 2 mechanisms has been proposed to
be the method of folate uptake in certain cell types. Methotrexate (MTX)
is an antifolate chemotherapeutic agent that is actively transported by
the carrier-mediated uptake system. RFC1 plays a role in maintaining
intracellular concentrations of folate.
CLONING
Several groups independently cloned cDNAs encoding the 591-amino acid
human folate transporter. Using a mouse reduced folate carrier (RFC)
partial cDNA as a probe, Wong et al. (1995) cloned a human RFC cDNA from
a library prepared from MTX transport-upregulated erythroleukemia cells.
Using homologous murine cDNAs as probes, Williams and Flintoff (1995),
Prasad et al. (1995), and Nguyen et al. (1997) independently isolated
human folate transporter cDNAs from lymphoblast, placenta, and small
intestine libraries, respectively.
Prasad et al. (1995) reported that the human folate transporter, which
they symbolized FOLT, had 65% amino acid sequence identity to mouse and
hamster folate transporters. When transfected into COS-1 and HeLa cells,
the human FOLT cDNA caused a significant increase in the uptake of
5-methyltetrahydrofolate. By Northern blot analysis, mRNA transcripts
hybridizing to the human FOLT cDNA were detected in placenta and liver
and also in several cell lines of human origin. The principal transcript
was approximately 2.7 kb.
Williams and Flintoff (1995) and Wong et al. (1995) observed that human
folate transport cDNAs expressed in MTX transport-deficient Chinese
hamster ovary cells restored MTX transport and sensitivity.
Nguyen et al. (1997) injected human intestinal folate carrier-1 (IFC1)
cRNA into Xenopus oocytes and observed increased uptake of
methyltetrahydrofolic acid. Northern blot analysis revealed that the
IFC1 gene was expressed as a 3.3-kb mRNA at a high level in placenta and
at lower levels in a variety of other tissues, including the small
intestine. In situ hybridization of thin sections of intestinal
epithelia demonstrated IFC1 expression localized to the villus and crypt
cells, particularly the upper half of the villi.
GENE FUNCTION
In luminal epithelial cells isolated from mouse small intestine, Chiao
et al. (1997) found increased PH-dependent folate influx associated with
RFC1 gene expression in the form of a 2.5-kb transcript and a 58-kD
brush border membrane protein detected by folate-based affinity labeling
and with antibodies against the transporter. The authors concluded that
RFC1 mediates intestinal folate transport.
GENE STRUCTURE
Point mutations in the reduced folate carrier-1 gene and alterations
resulting in the downregulation of its message are major factors in the
resistance to antifolate chemotherapeutic agents. As a framework for
understanding the significance of such changes in relation to gene
expression and function, Williams and Flintoff (1998) described the
organization of the RFC1 gene from human lymphoblasts. They found that
the gene contains 5 exons (2 to 6) coding for protein. At least 4
5-prime exons, used in a mutually exclusive manner in the production of
RFC1 message from lymphoblast cells, are spliced to exon 2, which
contains the translational start site. Semiquantitative PCR indicated
that exon 1 is preferentially used. The major transcriptional start site
was mapped by RACE and RNase protection to a region 109 to 135 bp
5-prime to the start of exon 1.
MAPPING
Yang-Feng et al. (1995) used the human folate transporter cDNA and a
human genomic clone hybridizing to the cDNA to perform chromosomal
mapping of the FOLT gene. Human/rodent somatic cell hybrid analysis
using the cDNA as the probe demonstrated perfect segregation with
chromosome 21. Isotopic in situ hybridization with the cDNA probe mapped
the gene to 21q22.3. Fluorescence in situ hybridization using the
genomic clone confirmed this chromosomal localization.
GENETIC VARIABILITY
Tolner et al. (1998) identified 3 splice variants of RFC1, incorporating
3 alternatives of exon 1 and 5 additional exons. By functional deletion
analysis, they identified 2 TATA-less promoters that show substantial
differences in the efficiency with which they drive transcription.
L1210/D3 mouse leukemia cells are resistant to
5,10-dideazatetrahydrofolate due to expansion of cellular folate pools
which block polyglutamation of the drug. These cells were found to have
2 point mutations in the RFC, resulting in the replacement of
isoleucine-48 by phenylalanine (I48F) and of tryptophan-105 by glycine
(W105G). Each mutation contributes to the resistance phenotype. Genomic
DNA from resistant cells contained both the wildtype and mutant alleles,
but wildtype message was not detected. Folic acid was a much better
substrate, and 5-formyltetrahydrofolate was a poorer substrate, for
transport in L1210/D3 cells relative to L1210 cells. Enhanced transport
of folic acid was due to a marked, approximately 20-fold, decrease in
the influx K(m). Influx of methotrexate and 5,10-dideazatetrahydrofolate
were minimally altered. Tse et al. (1998) concluded that the I48F and
W105G mutations in RFC caused resistance to
5,10-dideazatetrahydrofolate, that the region of the RFC protein near
these 2 positions defines the substrate-binding site, that the wildtype
allele was silenced during the multistep development of resistance, and
that this mutant phenotype represents a genetically dominant trait.
Using data from a California population-based case-control interview
study, Shaw et al. (2002) investigated whether spina bifida risk was
influenced by an interaction between a polymorphism of infant RFC1 at
nucleotide 80 (A80G) and maternal periconceptional use of vitamins
containing folic acid. Although the study did not find an increased
spina bifida risk for infants who were heterozygous or homozygous for
RFC1 A80G, it did reveal modest evidence for a gene-nutrient interaction
between infant homozygosity for the G80/G80 genotype and maternal
periconceptional intake of vitamins containing folic acid on the risk of
spina bifida.
*FIELD* RF
1. Chiao, J. H.; Roy, K.; Tolner, B.; Yang, C.-H.; Sirotnak, F. M.
: RFC-1 gene expression regulates folate absorption in mouse small
intestine. J. Biol. Chem. 272: 11165-11170, 1997.
2. Nguyen, T. T.; Dyer, D. L.; Dunning, D. D.; Rubin, S. A.; Grant,
K. E.; Said, H. M.: Human intestinal folate transport: cloning, expression,
and distribution of complementary RNA. Gastroenterology 112: 783-791,
1997.
3. Prasad, P. D.; Ramamoorthy, S.; Leibach, F. H.; Ganapathy, V.:
Molecular cloning of the human placental folate transporter. Biochem.
Biophys. Res. Commun. 206: 681-687, 1995.
4. Shaw, G. M.; Lammer, E. J.; Zhu, H.; Baker, M. W.; Neri, E.; Finnell,
R. H.: Maternal periconceptional vitamin use, genetic variation of
infant reduced folate carrier (A80G), and risk of spina bifida. Am.
J. Med. Genet. 108: 1-6, 2002. Note: Erratum: Am. J. Med. Genet.
113: 392 only, 2002.
5. Tolner, B.; Roy, K.; Sirotnak, F. M.: Structural analysis of the
human RFC-1 gene encoding a folate transporter reveals multiple promoters
and alternatively spliced transcripts with 5-prime end heterogeneity. Gene 211:
331-341, 1998.
6. Tse, A.; Brigle, K.; Taylor, S. M.; Moran, R. G.: Mutations in
the reduced folate carrier gene which confer dominant resistance to
5,10-dideazatetrahydrofolate. J. Biol. Chem. 273: 25953-25960, 1998.
7. Williams, F. M. R.; Flintoff, W. F.: Structural organization of
the human reduced folate carrier gene: evidence for 5-prime heterogeneity
in lymphoblast mRNA. Somat. Cell Molec. Genet. 24: 143-156, 1998.
8. Williams, F. M. R.; Flintoff, W. F.: Isolation of a human cDNA
that complements a mutant hamster cell defective in methotrexate uptake. J.
Biol. Chem. 270: 2987-2992, 1995.
9. Wong, S. C.; Proefke, S. A.; Bhushan, A.; Matherly, L. H.: Isolation
of human cDNAs that restore methotrexate sensitivity and reduced folate
carrier activity in methotrexate transport-defective Chinese hamster
ovary cells. J. Biol. Chem. 270: 17468-17475, 1995.
10. Yang-Feng, T. L.; Ma, Y.-Y.; Liang, R.; Prasad, P. D.; Leibach,
F. H.; Ganapathy, V.: Assignment of the human folate transporter
gene to chromosome 21q22.3 by somatic cell hybrid analysis and in
situ hybridization. Biochem. Biophys. Res. Commun. 210: 874-879,
1995.
*FIELD* CN
Victor A. McKusick - updated: 2/8/2002
Carol A. Bocchini - updated: 6/14/2001
Ada Hamosh - updated: 7/28/2000
Victor A. McKusick - updated: 6/8/1999
Jennifer P. Macke - updated: 5/22/1998
*FIELD* CD
Victor A. McKusick: 2/20/1995
*FIELD* ED
carol: 04/18/2013
terry: 5/21/2004
cwells: 11/12/2003
alopez: 2/18/2002
terry: 2/8/2002
carol: 6/14/2001
alopez: 8/1/2000
terry: 7/28/2000
jlewis: 6/17/1999
terry: 6/8/1999
alopez: 5/22/1998
jenny: 4/4/1997
mark: 9/17/1995
carol: 2/20/1995
*RECORD*
*FIELD* NO
600424
*FIELD* TI
*600424 SOLUTE CARRIER FAMILY 19 (FOLATE TRANSPORTER), MEMBER 1; SLC19A1
;;FOLATE TRANSPORTER; FOLT;;
read moreREDUCED FOLATE CARRIER 1; RFC1;;
INTESTINAL FOLATE CARRIER 1; IFC1
*FIELD* TX
DESCRIPTION
Transport of folate compounds into mammalian cells can occur via
receptor-mediated (see 136430) or carrier-mediated mechanisms. A
functional coordination between these 2 mechanisms has been proposed to
be the method of folate uptake in certain cell types. Methotrexate (MTX)
is an antifolate chemotherapeutic agent that is actively transported by
the carrier-mediated uptake system. RFC1 plays a role in maintaining
intracellular concentrations of folate.
CLONING
Several groups independently cloned cDNAs encoding the 591-amino acid
human folate transporter. Using a mouse reduced folate carrier (RFC)
partial cDNA as a probe, Wong et al. (1995) cloned a human RFC cDNA from
a library prepared from MTX transport-upregulated erythroleukemia cells.
Using homologous murine cDNAs as probes, Williams and Flintoff (1995),
Prasad et al. (1995), and Nguyen et al. (1997) independently isolated
human folate transporter cDNAs from lymphoblast, placenta, and small
intestine libraries, respectively.
Prasad et al. (1995) reported that the human folate transporter, which
they symbolized FOLT, had 65% amino acid sequence identity to mouse and
hamster folate transporters. When transfected into COS-1 and HeLa cells,
the human FOLT cDNA caused a significant increase in the uptake of
5-methyltetrahydrofolate. By Northern blot analysis, mRNA transcripts
hybridizing to the human FOLT cDNA were detected in placenta and liver
and also in several cell lines of human origin. The principal transcript
was approximately 2.7 kb.
Williams and Flintoff (1995) and Wong et al. (1995) observed that human
folate transport cDNAs expressed in MTX transport-deficient Chinese
hamster ovary cells restored MTX transport and sensitivity.
Nguyen et al. (1997) injected human intestinal folate carrier-1 (IFC1)
cRNA into Xenopus oocytes and observed increased uptake of
methyltetrahydrofolic acid. Northern blot analysis revealed that the
IFC1 gene was expressed as a 3.3-kb mRNA at a high level in placenta and
at lower levels in a variety of other tissues, including the small
intestine. In situ hybridization of thin sections of intestinal
epithelia demonstrated IFC1 expression localized to the villus and crypt
cells, particularly the upper half of the villi.
GENE FUNCTION
In luminal epithelial cells isolated from mouse small intestine, Chiao
et al. (1997) found increased PH-dependent folate influx associated with
RFC1 gene expression in the form of a 2.5-kb transcript and a 58-kD
brush border membrane protein detected by folate-based affinity labeling
and with antibodies against the transporter. The authors concluded that
RFC1 mediates intestinal folate transport.
GENE STRUCTURE
Point mutations in the reduced folate carrier-1 gene and alterations
resulting in the downregulation of its message are major factors in the
resistance to antifolate chemotherapeutic agents. As a framework for
understanding the significance of such changes in relation to gene
expression and function, Williams and Flintoff (1998) described the
organization of the RFC1 gene from human lymphoblasts. They found that
the gene contains 5 exons (2 to 6) coding for protein. At least 4
5-prime exons, used in a mutually exclusive manner in the production of
RFC1 message from lymphoblast cells, are spliced to exon 2, which
contains the translational start site. Semiquantitative PCR indicated
that exon 1 is preferentially used. The major transcriptional start site
was mapped by RACE and RNase protection to a region 109 to 135 bp
5-prime to the start of exon 1.
MAPPING
Yang-Feng et al. (1995) used the human folate transporter cDNA and a
human genomic clone hybridizing to the cDNA to perform chromosomal
mapping of the FOLT gene. Human/rodent somatic cell hybrid analysis
using the cDNA as the probe demonstrated perfect segregation with
chromosome 21. Isotopic in situ hybridization with the cDNA probe mapped
the gene to 21q22.3. Fluorescence in situ hybridization using the
genomic clone confirmed this chromosomal localization.
GENETIC VARIABILITY
Tolner et al. (1998) identified 3 splice variants of RFC1, incorporating
3 alternatives of exon 1 and 5 additional exons. By functional deletion
analysis, they identified 2 TATA-less promoters that show substantial
differences in the efficiency with which they drive transcription.
L1210/D3 mouse leukemia cells are resistant to
5,10-dideazatetrahydrofolate due to expansion of cellular folate pools
which block polyglutamation of the drug. These cells were found to have
2 point mutations in the RFC, resulting in the replacement of
isoleucine-48 by phenylalanine (I48F) and of tryptophan-105 by glycine
(W105G). Each mutation contributes to the resistance phenotype. Genomic
DNA from resistant cells contained both the wildtype and mutant alleles,
but wildtype message was not detected. Folic acid was a much better
substrate, and 5-formyltetrahydrofolate was a poorer substrate, for
transport in L1210/D3 cells relative to L1210 cells. Enhanced transport
of folic acid was due to a marked, approximately 20-fold, decrease in
the influx K(m). Influx of methotrexate and 5,10-dideazatetrahydrofolate
were minimally altered. Tse et al. (1998) concluded that the I48F and
W105G mutations in RFC caused resistance to
5,10-dideazatetrahydrofolate, that the region of the RFC protein near
these 2 positions defines the substrate-binding site, that the wildtype
allele was silenced during the multistep development of resistance, and
that this mutant phenotype represents a genetically dominant trait.
Using data from a California population-based case-control interview
study, Shaw et al. (2002) investigated whether spina bifida risk was
influenced by an interaction between a polymorphism of infant RFC1 at
nucleotide 80 (A80G) and maternal periconceptional use of vitamins
containing folic acid. Although the study did not find an increased
spina bifida risk for infants who were heterozygous or homozygous for
RFC1 A80G, it did reveal modest evidence for a gene-nutrient interaction
between infant homozygosity for the G80/G80 genotype and maternal
periconceptional intake of vitamins containing folic acid on the risk of
spina bifida.
*FIELD* RF
1. Chiao, J. H.; Roy, K.; Tolner, B.; Yang, C.-H.; Sirotnak, F. M.
: RFC-1 gene expression regulates folate absorption in mouse small
intestine. J. Biol. Chem. 272: 11165-11170, 1997.
2. Nguyen, T. T.; Dyer, D. L.; Dunning, D. D.; Rubin, S. A.; Grant,
K. E.; Said, H. M.: Human intestinal folate transport: cloning, expression,
and distribution of complementary RNA. Gastroenterology 112: 783-791,
1997.
3. Prasad, P. D.; Ramamoorthy, S.; Leibach, F. H.; Ganapathy, V.:
Molecular cloning of the human placental folate transporter. Biochem.
Biophys. Res. Commun. 206: 681-687, 1995.
4. Shaw, G. M.; Lammer, E. J.; Zhu, H.; Baker, M. W.; Neri, E.; Finnell,
R. H.: Maternal periconceptional vitamin use, genetic variation of
infant reduced folate carrier (A80G), and risk of spina bifida. Am.
J. Med. Genet. 108: 1-6, 2002. Note: Erratum: Am. J. Med. Genet.
113: 392 only, 2002.
5. Tolner, B.; Roy, K.; Sirotnak, F. M.: Structural analysis of the
human RFC-1 gene encoding a folate transporter reveals multiple promoters
and alternatively spliced transcripts with 5-prime end heterogeneity. Gene 211:
331-341, 1998.
6. Tse, A.; Brigle, K.; Taylor, S. M.; Moran, R. G.: Mutations in
the reduced folate carrier gene which confer dominant resistance to
5,10-dideazatetrahydrofolate. J. Biol. Chem. 273: 25953-25960, 1998.
7. Williams, F. M. R.; Flintoff, W. F.: Structural organization of
the human reduced folate carrier gene: evidence for 5-prime heterogeneity
in lymphoblast mRNA. Somat. Cell Molec. Genet. 24: 143-156, 1998.
8. Williams, F. M. R.; Flintoff, W. F.: Isolation of a human cDNA
that complements a mutant hamster cell defective in methotrexate uptake. J.
Biol. Chem. 270: 2987-2992, 1995.
9. Wong, S. C.; Proefke, S. A.; Bhushan, A.; Matherly, L. H.: Isolation
of human cDNAs that restore methotrexate sensitivity and reduced folate
carrier activity in methotrexate transport-defective Chinese hamster
ovary cells. J. Biol. Chem. 270: 17468-17475, 1995.
10. Yang-Feng, T. L.; Ma, Y.-Y.; Liang, R.; Prasad, P. D.; Leibach,
F. H.; Ganapathy, V.: Assignment of the human folate transporter
gene to chromosome 21q22.3 by somatic cell hybrid analysis and in
situ hybridization. Biochem. Biophys. Res. Commun. 210: 874-879,
1995.
*FIELD* CN
Victor A. McKusick - updated: 2/8/2002
Carol A. Bocchini - updated: 6/14/2001
Ada Hamosh - updated: 7/28/2000
Victor A. McKusick - updated: 6/8/1999
Jennifer P. Macke - updated: 5/22/1998
*FIELD* CD
Victor A. McKusick: 2/20/1995
*FIELD* ED
carol: 04/18/2013
terry: 5/21/2004
cwells: 11/12/2003
alopez: 2/18/2002
terry: 2/8/2002
carol: 6/14/2001
alopez: 8/1/2000
terry: 7/28/2000
jlewis: 6/17/1999
terry: 6/8/1999
alopez: 5/22/1998
jenny: 4/4/1997
mark: 9/17/1995
carol: 2/20/1995