SLC46A1
entrez
113235
canonical
uniprot
Q96NT5
canonical
ensembl
ENSG00000076351
resolver
ensp
ENSP00000480703
resolver
ensp
ENSP00000483652
resolver
genesymbol
SLC46A1
resolver
genesymbol_syn
G21
resolver
genesymbol_syn
HCP1
resolver
genesymbol_syn
PCFT
resolver
hgnc
HGNC:30521
resolver
uniprot
Q1HE20
resolver
uniprot
Q86T92
resolver
uniprot
Q8TEG3
resolver
uniprot
Q96FL0
resolver
uniprot_entry
PCFT_HUMAN
resolver
uniprot_sec
Q1HE20
resolver
uniprot_sec
Q86T92
resolver
uniprot_sec
Q8TEG3
resolver
uniprot_sec
Q96FL0
resolver
activity_regulation
ACTIVITY REGULATION: Inhibited by myricetin. {ECO:0000269|PubMed:31792273}.
uniprot
proteins
amino_acid_sequence
MEGSASPPEKPRARPAAAVLCRGPVEPLVFLANFALVLQGPLTTQYLWHRFSADLGYNGTRQRGGCSNRSADPTMQEVETLTSHWTLYMNVGGFLVGLFSSTLLGAWSDSVGRRPLLVLASLGLLLQALVSVFVVQLQLHVGYFVLGRILCALLGDFGGLLAASFASVADVSSSRSRTFRMALLEASIGVAGMLASLLGGHWLRAQGYANPFWLALALLIAMTLYAAFCFGETLKEPKSTRLFTFRHHRSIVQLYVAPAPEKSRKHLALYSLAIFVVITVHFGAQDILTLYELSTPLCWDSKLIGYGSAAQHLPYLTSLLALKLLQYCLADAWVAEIGLAFNILGMVVFAFATITPLMFTGYGLLFLSLVITPVIRAKLSKLVRETEQGALFSAVACVNSLAMLTASGIFNSLYPATLNFMKGFPFLLGAGLLLIPAVLIGMLEKADPHLEFQQFPQSP
uniprot
proteins
disease_involvement
DISEASE: Hereditary folate malabsorption (HFM) [MIM:229050]: Rare autosomal recessive disorder characterized by impaired intestinal folate absorption with folate deficiency resulting in anemia, hypoimmunoglobulinemia with recurrent infections, and recurrent or chronic diarrhea. In many patients, neurological abnormalities such as seizures or intellectual disability become apparent during early childhood, attributed to impaired transport of folates into the central nervous system. When diagnosed early, the disorder can be treated by administration of folate. If untreated, it can be fatal and, if treatment is delayed, the neurological defects can become permanent. {ECO:0000269|PubMed:17129779, ECO:0000269|PubMed:17446347, ECO:0000269|PubMed:18559978, ECO:0000269|PubMed:20686069, ECO:0000269|PubMed:20805364, ECO:0000269|PubMed:21333572, ECO:0000269|PubMed:22345511, ECO:0000269|PubMed:23816405, ECO:0000269|PubMed:29344585, ECO:0000269|PubMed:29390264, ECO:0000269|PubMed:31494288, ECO:0000269|PubMed:32893190}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
function
FUNCTION: Proton-coupled folate symporter that mediates folate absorption using an H(+) gradient as a driving force (PubMed:17129779, PubMed:17446347, PubMed:17475902, PubMed:19389703, PubMed:19762432, PubMed:25504888, PubMed:29344585, PubMed:30858177, PubMed:31494288, PubMed:31792273, PubMed:32893190, PubMed:34619546). Involved in the intestinal absorption of folates at the brush-border membrane of the proximal jejunum, and the transport from blood to cerebrospinal fluid across the choroid plexus (PubMed:17129779, PubMed:17446347, PubMed:17475902, PubMed:19389703, PubMed:25504888, PubMed:29344585, PubMed:30858177, PubMed:31494288, PubMed:32893190). Functions at acidic pH via alternate outward- and inward-open conformation states (PubMed:32893190, PubMed:34040256). Protonation of residues in the outward open state primes the protein for transport (PubMed:34040256). Binding of folate promotes breaking of salt bridge network and subsequent closure of the extracellular gate, leading to the inward-open state and release of protons and folate (PubMed:34040256). Also able to transport antifolate drugs, such as methotrexate and pemetrexed, which are established treatments for cancer and autoimmune diseases (PubMed:18524888, PubMed:19762432, PubMed:22345511, PubMed:25608532, PubMed:28802835, PubMed:29326243, PubMed:34040256, PubMed:34619546). Involved in FOLR1-mediated endocytosis by serving as a route of export of folates from acidified endosomes (PubMed:19074442). Also acts as a lower-affinity, pH-independent heme carrier protein and constitutes the main importer of heme in the intestine (PubMed:17156779). Imports heme in the retina and retinal pigment epithelium, in neurons of the hippocampus, in hepatocytes and in the renal epithelial cells (PubMed:32621820). Hence, participates in the trafficking of heme and increases intracellular iron content (PubMed:32621820). {ECO:0000269|PubMed:17129779, ECO:0000269|PubMed:17156779, ECO:0000269|PubMed:17446347, ECO:0000269|PubMed:17475902, ECO:0000269|PubMed:18524888, ECO:0000269|PubMed:19074442, ECO:0000269|PubMed:19389703, ECO:0000269|PubMed:19762432, ECO:0000269|PubMed:22345511, ECO:0000269|PubMed:25504888, ECO:0000269|PubMed:25608532, ECO:0000269|PubMed:28802835, ECO:0000269|PubMed:29326243, ECO:0000269|PubMed:29344585, ECO:0000269|PubMed:30858177, ECO:0000269|PubMed:31494288, ECO:0000269|PubMed:31792273, ECO:0000269|PubMed:32621820, ECO:0000269|PubMed:32893190, ECO:0000269|PubMed:34040256, ECO:0000269|PubMed:34619546}.; FUNCTION: [Isoform 2]: Inactive isoform which is not able to mediate proton-coupled folate transport. {ECO:0000269|PubMed:17129779}.
uniprot
proteins
mass_dalton
49771
uniprot
proteins
mutagenesis
MUTAGEN 58; /note="N->Q: Abolished N-glycosylation without affecting localization to the cell membrane; when associated with Q-68."; /evidence="ECO:0000269|PubMed:18405659"; MUTAGEN 68; /note="N->Q: Abolished N-glycosylation without affecting localization to the cell membrane; when associated with Q-58."; /evidence="ECO:0000269|PubMed:18405659"; MUTAGEN 109; /note="D->A,G,E,K,N,S: Loss of methotrexate uptake."; /evidence="ECO:0000269|PubMed:20805364"; MUTAGEN 109; /note="D->A: Complete loss of transport function."; /evidence="ECO:0000269|PubMed:25504888"; MUTAGEN 156; /note="D->E: Does not affect methotrexate uptake."; /evidence="ECO:0000269|PubMed:20805364"; MUTAGEN 156; /note="D->F,K,N,V,W: Loss of methotrexate uptake."; /evidence="ECO:0000269|PubMed:20805364"; MUTAGEN 156; /note="D->G: 2-fold reduction of methotrexate uptake."; /evidence="ECO:0000269|PubMed:20805364"; MUTAGEN 156; /note="D->S: 8-fold reduction of methotrexate uptake."; /evidence="ECO:0000269|PubMed:20805364"; MUTAGEN 158; /note="G->N: Abolished sensitivity to myricetin inhibitor."; /evidence="ECO:0000269|PubMed:31792273"; MUTAGEN 172; /note="S->A: Decreased proton-coupled folate transport."; /evidence="ECO:0000269|PubMed:19389703"; MUTAGEN 185; /note="E->A: Abolished proton-coupled folate transport at pH 5.5 and pH 7.5."; /evidence="ECO:0000269|PubMed:34040256"; MUTAGEN 185; /note="E->N: Abolished proton-coupled folate transport at pH 5.5, while it displays strong proton-coupled folate transporter activity at pH 7.5."; /evidence="ECO:0000269|PubMed:34040256"; MUTAGEN 247; /note="H->A: Decreased proton-coupled folate transport."; /evidence="ECO:0000269|PubMed:19389703"; MUTAGEN 281; /note="H->A: Abolished proton-coupled folate transport."; /evidence="ECO:0000269|PubMed:19389703"; MUTAGEN 299; /note="W->C: About 90% loss of transport function."; /evidence="ECO:0000269|PubMed:25504888"; MUTAGEN 314; /note="P->C: Displays a lower affinity for folate substrate associated with a higher rate of conformational change."; /evidence="ECO:0000269|PubMed:28802835"; MUTAGEN 315; /note="Y->A,P: Displays a lower affinity for folate substrate associated with a higher rate of conformational change."; /evidence="ECO:0000269|PubMed:25608532, ECO:0000269|PubMed:28802835"; MUTAGEN 318; /note="S->A,C: Slightly decreased proton-coupled folate transport."; /evidence="ECO:0000269|PubMed:34619546"; MUTAGEN 318; /note="S->R,K: Abolished proton-coupled folate transport."; /evidence="ECO:0000269|PubMed:34619546"; MUTAGEN 376; /note="R->A,C,E,H,Q,W: Abolishes folate uptake."; /evidence="ECO:0000269|PubMed:20686069"; MUTAGEN 392; /note="F->A,H,W,Y: Decreased methotrexate uptake at low concentration."; /evidence="ECO:0000269|PubMed:32893190"; MUTAGEN 392; /note="F->E,D,K,L,I,Q,T: Abolished methotrexate uptake."; /evidence="ECO:0000269|PubMed:32893190"; MUTAGEN 392; /note="F->M: Does not affect methotrexate uptake at low concentration."; /evidence="ECO:0000269|PubMed:32893190"; MUTAGEN 411; /note="N->A,D,L,Q: Does not affect folate uptake."; /evidence="ECO:0000269|PubMed:29344585"; MUTAGEN 411; /note="N->E,H,K,R: Abolished folate uptake."; /evidence="ECO:0000269|PubMed:29344585"; MUTAGEN 411; /note="N->T: Decreased folate uptake at low folate concentration, while folate uptake is not affected at high folate concentration."; /evidence="ECO:0000269|PubMed:29344585"; MUTAGEN 425; /note="P->K: Strongly decreased folate and methotrexate uptake, while it still binds pemetrexed."; /evidence="ECO:0000269|PubMed:22345511
uniprot
proteins
protein_family
Major facilitator superfamily
uniprot
proteins
protein_family
SLC46A family
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16143108
uniprot
proteins
pubmed
17129779
uniprot
proteins
pubmed
17156779
uniprot
proteins
pubmed
17335806
uniprot
proteins
pubmed
17446347
uniprot
proteins
pubmed
17475902
uniprot
proteins
pubmed
17974005
uniprot
proteins
pubmed
18405659
uniprot
proteins
pubmed
18524888
uniprot
proteins
pubmed
18559978
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
18691976
uniprot
proteins
pubmed
19074442
uniprot
proteins
pubmed
19159218
uniprot
proteins
pubmed
19389703
uniprot
proteins
pubmed
19762432
uniprot
proteins
pubmed
20068231
uniprot
proteins
pubmed
20686069
uniprot
proteins
pubmed
20805364
uniprot
proteins
pubmed
21333572
uniprot
proteins
pubmed
22345511
uniprot
proteins
pubmed
22814378
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
23601781
uniprot
proteins
pubmed
23816405
uniprot
proteins
pubmed
25053408
uniprot
proteins
pubmed
25504888
uniprot
proteins
pubmed
25608532
uniprot
proteins
pubmed
28802835
uniprot
proteins
pubmed
29326243
uniprot
proteins
pubmed
29344585
uniprot
proteins
pubmed
29390264
uniprot
proteins
pubmed
30858177
uniprot
proteins
pubmed
31494288
uniprot
proteins
pubmed
31792273
uniprot
proteins
pubmed
32621820
uniprot
proteins
pubmed
32893190
uniprot
proteins
pubmed
34040256
uniprot
proteins
pubmed
34619546
uniprot
proteins
sequence_length
459
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:17156779, ECO:0000269|PubMed:17446347, ECO:0000269|PubMed:18405659, ECO:0000269|PubMed:23601781, ECO:0000269|PubMed:25053408, ECO:0000269|PubMed:25504888, ECO:0000269|PubMed:29344585, ECO:0000269|PubMed:30858177, ECO:0000269|PubMed:34619546}; Multi-pass membrane protein {ECO:0000269|PubMed:25053408}. Apical cell membrane {ECO:0000269|PubMed:16143108, ECO:0000269|PubMed:17129779, ECO:0000269|PubMed:17475902}; Multi-pass membrane protein {ECO:0000269|PubMed:25053408}. Basolateral cell membrane {ECO:0000269|PubMed:19074442}; Multi-pass membrane protein {ECO:0000269|PubMed:25053408}. Endosome membrane {ECO:0000305|PubMed:19074442}; Multi-pass membrane protein {ECO:0000269|PubMed:25053408}. Cytoplasm {ECO:0000250|UniProtKB:Q6PEM8}. Note=Localizes to the apical membrane of intestinal cells in iron-deficient cells, while it resides in the cytoplasm in iron-replete cells (By similarity). Localizes to the basolateral membrane of choroid plexus (PubMed:19074442). {ECO:0000250|UniProtKB:Q6PEM8, ECO:0000269|PubMed:19074442}.
uniprot
proteins
transmembrane_region
TRANSMEM 26..44; /note="Helical; Name=TM1"; /evidence="ECO:0000250|UniProtKB:F1NJ67"; TRANSMEM 83..108; /note="Helical; Name=TM2"; /evidence="ECO:0000250|UniProtKB:F1NJ67"; TRANSMEM 113..135; /note="Helical; Name=TM3"; /evidence="ECO:0000250|UniProtKB:F1NJ67"; TRANSMEM 141..154; /note="Helical; Name=TM4"; /evidence="ECO:0000250|UniProtKB:F1NJ67"; TRANSMEM 178..203; /note="Helical; Name=TM5"; /evidence="ECO:0000250|UniProtKB:F1NJ67"; TRANSMEM 209..227; /note="Helical; Name=TM6"; /evidence="ECO:0000250|UniProtKB:F1NJ67"; TRANSMEM 267..289; /note="Helical; Name=TM7"; /evidence="ECO:0000250|UniProtKB:F1NJ67"; TRANSMEM 303..325; /note="Helical; Name=TM8"; /evidence="ECO:0000250|UniProtKB:F1NJ67"; TRANSMEM 332..351; /note="Helical; Name=TM9"; /evidence="ECO:0000250|UniProtKB:F1NJ67"; TRANSMEM 356..376; /note="Helical; Name=TM10"; /evidence="ECO:0000250|UniProtKB:F1NJ67"; TRANSMEM 389..414; /note="Helical; Name=TM11"; /evidence="ECO:0000250|UniProtKB:F1NJ67"; TRANSMEM 423..441; /note="Helical; Name=TM12"; /evidence="ECO:0000250|UniProtKB:F1NJ67
uniprot
proteins