Proton-coupled folate transporter

Details

Name
Proton-coupled folate transporter
Synonyms
  • G21
  • HCP1
  • Heme carrier protein 1
  • PCFT
  • PCFT/HCP1
  • Solute carrier family 46 member 1
Gene Name
SLC46A1
Organism
Humans
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 binding / folic acid transporter activity / hydrogen ion transmembrane transporter activity / methotrexate transporter activity
Processes
cellular iron ion homeostasis / folic acid import into cell / folic acid metabolic process / folic acid transport / heme transport / hydrogen ion transmembrane transport / intestinal folate absorption / methotrexate transport / small molecule metabolic process / transmembrane transport / vitamin metabolic process / water-soluble vitamin metabolic process
Components
apical plasma membrane / brush border membrane / cell surface / cytoplasm / integral component of membrane / plasma membrane
General Function
Methotrexate transporter activity
Specific Function
Has been shown to act both as an intestinal proton-coupled high-affinity folate transporter and as an intestinal heme transporter which mediates heme uptake from the gut lumen into duodenal epithelial cells. The iron is then released from heme and may be transported into the bloodstream. Dietary heme iron is an important nutritional source of iron. Shows a higher affinity for folate than heme.
Pfam Domain Function
Transmembrane Regions
25-48 85-107 114-137 146-168 181-203 213-236 266-288 310-328 332-356 360-381 394-412 425-449
Cellular Location
Apical 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
Not Available
External Identifiers
ResourceLink
UniProtKB IDQ96NT5
UniProtKB Entry NamePCFT_HUMAN
GenBank Protein ID16549261
GenBank Gene IDAK054669
GenAtlas IDSLC46A1
HGNC IDHGNC:30521
General References
  1. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. [Article]
  2. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [Article]
  3. Bechtel S, Rosenfelder H, Duda A, Schmidt CP, Ernst U, Wellenreuther R, Mehrle A, Schuster C, Bahr A, Blocker H, Heubner D, Hoerlein A, Michel G, Wedler H, Kohrer K, Ottenwalder B, Poustka A, Wiemann S, Schupp I: The full-ORF clone resource of the German cDNA Consortium. BMC Genomics. 2007 Oct 31;8:399. [Article]
  4. Shayeghi M, Latunde-Dada GO, Oakhill JS, Laftah AH, Takeuchi K, Halliday N, Khan Y, Warley A, McCann FE, Hider RC, Frazer DM, Anderson GJ, Vulpe CD, Simpson RJ, McKie AT: Identification of an intestinal heme transporter. Cell. 2005 Sep 9;122(5):789-801. [Article]
  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]
  9. Nakai Y, Inoue K, Abe N, Hatakeyama M, Ohta KY, Otagiri M, Hayashi Y, Yuasa H: Functional characterization of human proton-coupled folate transporter/heme carrier protein 1 heterologously expressed in mammalian cells as a folate transporter. J Pharmacol Exp Ther. 2007 Aug;322(2):469-76. Epub 2007 May 2. [Article]
  10. Daub H, Olsen JV, Bairlein M, Gnad F, Oppermann FS, Korner R, Greff Z, Keri G, Stemmann O, Mann M: Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol Cell. 2008 Aug 8;31(3):438-48. doi: 10.1016/j.molcel.2008.07.007. [Article]
  11. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP: A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7. doi: 10.1073/pnas.0805139105. Epub 2008 Jul 31. [Article]
  12. Chen R, Jiang X, Sun D, Han G, Wang F, Ye M, Wang L, Zou H: Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry. J Proteome Res. 2009 Feb;8(2):651-61. doi: 10.1021/pr8008012. [Article]
  13. Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, Brunak S, Mann M: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal. 2010 Jan 12;3(104):ra3. doi: 10.1126/scisignal.2000475. [Article]
  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]
  18. Mahadeo K, Diop-Bove N, Shin D, Unal ES, Teo J, Zhao R, Chang MH, Fulterer A, Romero MF, Goldman ID: Properties of the Arg376 residue of the proton-coupled folate transporter (PCFT-SLC46A1) and a glutamine mutant causing hereditary folate malabsorption. Am J Physiol Cell Physiol. 2010 Nov;299(5):C1153-61. doi: 10.1152/ajpcell.00113.2010. Epub 2010 Aug 4. [Article]
  19. Shin DS, Min SH, Russell L, Zhao R, Fiser A, Goldman ID: Functional roles of aspartate residues of the proton-coupled folate transporter (PCFT-SLC46A1); a D156Y mutation causing hereditary folate malabsorption. Blood. 2010 Dec 9;116(24):5162-9. doi: 10.1182/blood-2010-06-291237. Epub 2010 Aug 30. [Article]
  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]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB00158Folic acidapproved, nutraceutical, vet_approvedunknownsubstrateDetails
DB00563MethotrexateapprovedunknownsubstrateinhibitorDetails
DB00795SulfasalazineapprovedunknowninhibitorDetails
DB08878Aminopterininvestigational, withdrawnunknownDetails
DB11256Levomefolic acidapproved, investigationalunknownsubstrateDetails