Proton-coupled folate transporter

Details

Name
Proton-coupled folate transporter
Kind
protein
Synonyms
  • G21
  • HCP1
  • Heme carrier protein 1
  • hPCFT
  • HsPCFT
  • PCFT
  • PCFT/HCP1
  • Solute carrier family 46 member 1
Gene Name
SLC46A1
UniProtKB Entry
Q96NT5Swiss-Prot
Organism
Humans
NCBI Taxonomy ID
9606
Amino acid sequence
>lcl|BSEQ0002087|Proton-coupled folate transporter
MEGSASPPEKPRARPAAAVLCRGPVEPLVFLANFALVLQGPLTTQYLWHRFSADLGYNGT
RQRGGCSNRSADPTMQEVETLTSHWTLYMNVGGFLVGLFSSTLLGAWSDSVGRRPLLVLA
SLGLLLQALVSVFVVQLQLHVGYFVLGRILCALLGDFGGLLAASFASVADVSSSRSRTFR
MALLEASIGVAGMLASLLGGHWLRAQGYANPFWLALALLIAMTLYAAFCFGETLKEPKST
RLFTFRHHRSIVQLYVAPAPEKSRKHLALYSLAIFVVITVHFGAQDILTLYELSTPLCWD
SKLIGYGSAAQHLPYLTSLLALKLLQYCLADAWVAEIGLAFNILGMVVFAFATITPLMFT
GYGLLFLSLVITPVIRAKLSKLVRETEQGALFSAVACVNSLAMLTASGIFNSLYPATLNF
MKGFPFLLGAGLLLIPAVLIGMLEKADPHLEFQQFPQSP
Number of residues
459
Molecular Weight
49770.04
Theoretical pI
8.97
GO Classification
Functions
folic acid / folic acid transmembrane transporter activity / heme transmembrane transporter activity / methotrexate transmembrane transporter activity / proton transmembrane transporter activity / symporter activity / transmembrane transporter activity
Processes
folate import across plasma membrane / folate transmembrane transport / heme metabolic process / intracellular iron ion homeostasis / proton transmembrane transport
Components
basolateral plasma membrane / endosome / endosome membrane
General 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)
Specific Function
Folic acid binding
Pfam Domain Function
Signal Regions
Not Available
Transmembrane Regions
26-44 83-108 113-135 141-154 178-203 209-227 267-289 303-325 332-351 356-376 389-414 423-441
Cellular Location
Cell membrane
Gene sequence
>lcl|BSEQ0016294|Proton-coupled folate transporter (SLC46A1)
ATGGAGGGGAGCGCGAGCCCCCCGGAAAAGCCCCGCGCCCGCCCTGCGGCTGCCGTGCTG
TGCCGGGGCCCGGTAGAGCCGCTGGTCTTCCTGGCCAACTTTGCCTTGGTCCTGCAGGGC
CCGCTCACCACGCAGTATCTGTGGCACCGCTTCAGCGCCGACCTCGGCTACAATGGCACC
CGCCAAAGGGGGGGCTGCAGCAACCGCAGCGCGGACCCCACCATGCAGGAAGTGGAGACC
CTTACCTCCCACTGGACCCTCTACATGAACGTGGGCGGCTTCCTGGTGGGGCTCTTCTCG
TCCACCCTGCTGGGAGCTTGGAGCGACAGTGTGGGCCGCCGCCCGCTGCTAGTGCTGGCC
TCGCTGGGCCTGCTGCTCCAGGCCCTAGTGTCCGTTTTTGTGGTGCAGCTGCAGCTCCAC
GTCGGCTACTTCGTGCTGGGTCGCATCCTTTGTGCCCTCCTCGGCGACTTCGGTGGCCTT
CTGGCTGCTAGCTTTGCGTCCGTGGCAGATGTCAGCTCCAGTCGCAGCCGCACCTTCCGG
ATGGCCCTGCTGGAAGCCAGCATCGGGGTGGCTGGGATGCTGGCAAGCCTCCTCGGGGGC
CACTGGCTCCGGGCCCAGGGTTATGCCAACCCCTTCTGGCTGGCCTTGGCCTTGCTGATA
GCCATGACTCTCTATGCAGCTTTCTGCTTTGGTGAGACCTTAAAGGAGCCAAAGTCCACC
CGGCTCTTCACGTTCCGTCACCACCGATCCATTGTCCAGCTCTATGTGGCTCCCGCCCCA
GAGAAGTCCAGGAAACATTTAGCCCTCTACTCACTGGCCATCTTCGTGGTGATCACTGTG
CACTTTGGGGCCCAGGACATCTTAACCCTTTATGAACTAAGCACACCCCTCTGCTGGGAC
TCCAAACTAATCGGCTATGGTTCTGCAGCTCAGCATCTCCCCTACCTCACCAGCCTGCTG
GCCCTGAAGCTCCTGCAGTACTGCCTGGCCGATGCCTGGGTAGCTGAGATCGGCCTGGCC
TTCAACATCCTGGGGATGGTGGTCTTTGCCTTTGCCACTATCACGCCTCTCATGTTCACA
GGTGCTCTCTTTTCTGCTGTGGCCTGTGTGAATAGCCTGGCCATGCTGACGGCCTCCGGC
ATCTTCAACTCACTCTACCCAGCCACTCTGAACTTTATGAAGGGGTTCCCCTTCCTCCTG
GGAGCTGGCCTCCTGCTCATCCCGGCTGTTCTGATTGGGATGCTGGAAAAGGCTGATCCT
CACCTCGAGTTCCAGCAGTTTCCCCAGAGCCCCTGA
Chromosome Location
17
Locus
17q11.2
External Identifiers
ResourceLink
UniProtKB IDQ96NT5
UniProtKB Entry NamePCFT_HUMAN
GenBank Protein ID16549261
GenBank Gene IDAK054669
GeneCard IDSLC46A1
GenAtlas IDSLC46A1
HGNC IDHGNC:30521
KEGG IDhsa:113235
IUPHAR/Guide To Pharmacology ID1213
NCBI Gene ID113235
General References
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  5. Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, Sandoval C, Zhao R, Akabas MH, Goldman ID: Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell. 2006 Dec 1;127(5):917-28. [Article]
  6. Latunde-Dada GO, Takeuchi K, Simpson RJ, McKie AT: Haem carrier protein 1 (HCP1): Expression and functional studies in cultured cells. FEBS Lett. 2006 Dec 22;580(30):6865-70. Epub 2006 Nov 29. [Article]
  7. Zhao R, Min SH, Qiu A, Sakaris A, Goldberg GL, Sandoval C, Malatack JJ, Rosenblatt DS, Goldman ID: The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption. Blood. 2007 Aug 15;110(4):1147-52. Epub 2007 Apr 19. [Article]
  8. Sharma S, Dimasi D, Broer S, Kumar R, Della NG: Heme carrier protein 1 (HCP1) expression and functional analysis in the retina and retinal pigment epithelium. Exp Cell Res. 2007 Apr 1;313(6):1251-9. Epub 2007 Feb 6. [Article]
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  14. Van Damme P, Lasa M, Polevoda B, Gazquez C, Elosegui-Artola A, Kim DS, De Juan-Pardo E, Demeyer K, Hole K, Larrea E, Timmerman E, Prieto J, Arnesen T, Sherman F, Gevaert K, Aldabe R: N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12449-54. doi: 10.1073/pnas.1210303109. Epub 2012 Jul 18. [Article]
  15. Duddempudi PK, Nakashe P, Blanton MP, Jansen M: The monomeric state of the proton-coupled folate transporter represents the functional unit in the plasma membrane. FEBS J. 2013 Jun;280(12):2900-15. doi: 10.1111/febs.12293. Epub 2013 May 28. [Article]
  16. Wilson MR, Hou Z, Matherly LH: Substituted cysteine accessibility reveals a novel transmembrane 2-3 reentrant loop and functional role for transmembrane domain 2 in the human proton-coupled folate transporter. J Biol Chem. 2014 Sep 5;289(36):25287-95. doi: 10.1074/jbc.M114.578252. Epub 2014 Jul 22. [Article]
  17. Lasry I, Berman B, Straussberg R, Sofer Y, Bessler H, Sharkia M, Glaser F, Jansen G, Drori S, Assaraf YG: A novel loss-of-function mutation in the proton-coupled folate transporter from a patient with hereditary folate malabsorption reveals that Arg 113 is crucial for function. Blood. 2008 Sep 1;112(5):2055-61. doi: 10.1182/blood-2008-04-150276. Epub 2008 Jun 17. [Article]
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  20. Shin DS, Mahadeo K, Min SH, Diop-Bove N, Clayton P, Zhao R, Goldman ID: Identification of novel mutations in the proton-coupled folate transporter (PCFT-SLC46A1) associated with hereditary folate malabsorption. Mol Genet Metab. 2011 May;103(1):33-7. doi: 10.1016/j.ymgme.2011.01.008. Epub 2011 Jan 25. [Article]

Associated Data

Drug Relations
DrugDrug groupPharmacological action?TypeActionsDetails
Folic acidapproved, nutraceutical, vet_approvedunknowntransportersubstrateDetails
MethotrexateapprovedunknowntransportersubstrateinhibitorDetails
SulfasalazineapprovednotransporterinhibitorDetails
Aminopterininvestigational, withdrawnunknowntransporterDetails
Levomefolic acidapproved, investigationalunknowntransportersubstrateDetails
Pralatrexateapproved, investigationalnotransportersubstrateDetails
Pemetrexedapproved, investigationalnotransportersubstrateDetails
LeucovorinapprovedyestargetmodulatorDetails
Folic acidapproved, nutraceutical, vet_approvedyestargetmodulatorDetails
MethotrexateapprovedyestargetmodulatorDetails