Folate transporter 1 explained

Folate transporter 1 is a protein which in humans is encoded by the SLC19A1 gene.^[1]

Function

Transport of folate compounds into mammalian cells can occur via receptor-mediated (see folate receptor 1) 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.^[2] SLC19A1 has also been shown to transport the immune second messenger 2'3'-cGAMP.^[3]

Clinical significance

Individuals carrying a specific polymorphism of SLC19A1 (c.80GG) have lower levels of folate.^[4] Other studies have also shown that individuals carrying the c.80AA polymorphism who are treated with methotrexate have higher levels of this anti-folate chemotherapeutic agent. Personalized dosing of the drug depending on the patient's genotype may therefore be required.

Alternative names

• Reduced folate carrier 1
• Intestinal folate carrier 1

See also

• Solute carrier family
• Folate-binding protein
• Reduced folate carrier family

Further reading

• Matherly LH, Hou Z, Deng Y . Human reduced folate carrier: translation of basic biology to cancer etiology and therapy . Cancer and Metastasis Reviews . 26 . 1 . 111–28 . March 2007 . 17334909 . 10.1007/s10555-007-9046-2 . 26489607 .
• Wong SC, Proefke SA, Bhushan A, Matherly LH . Isolation of human cDNAs that restore methotrexate sensitivity and reduced folate carrier activity in methotrexate transport-defective Chinese hamster ovary cells . The Journal of Biological Chemistry . 270 . 29 . 17468–75 . July 1995 . 7615551 . 10.1074/jbc.270.29.17468 . free .
• Moscow JA, Gong M, He R, Sgagias MK, Dixon KH, Anzick SL, Meltzer PS, Cowan KH . Isolation of a gene encoding a human reduced folate carrier (RFC1) and analysis of its expression in transport-deficient, methotrexate-resistant human breast cancer cells . Cancer Research . 55 . 17 . 3790–4 . September 1995 . 7641195 .
• Yang-Feng TL, Ma YY, Liang R, Prasad PD, Leibach FH, Ganapathy V . Assignment of the human folate transporter gene to chromosome 21q22.3 by somatic cell hybrid analysis and in situ hybridization . Biochemical and Biophysical Research Communications . 210 . 3 . 874–9 . May 1995 . 7763259 . 10.1006/bbrc.1995.1739 . free .
• Prasad PD, Ramamoorthy S, Leibach FH, Ganapathy V . Molecular cloning of the human placental folate transporter . Biochemical and Biophysical Research Communications . 206 . 2 . 681–7 . January 1995 . 7826387 . 10.1006/bbrc.1995.1096 .
• Williams FM, Flintoff WF . Isolation of a human cDNA that complements a mutant hamster cell defective in methotrexate uptake . The Journal of Biological Chemistry . 270 . 7 . 2987–92 . February 1995 . 7852378 . 10.1074/jbc.270.7.2987 . free .
• Dixon KH, Lanpher BC, Chiu J, Kelley K, Cowan KH . A novel cDNA restores reduced folate carrier activity and methotrexate sensitivity to transport deficient cells . The Journal of Biological Chemistry . 269 . 1 . 17–20 . January 1994 . 10.1016/S0021-9258(17)42301-5 . 8276792 . free .
• Nguyen TT, Dyer DL, Dunning DD, Rubin SA, Grant KE, Said HM . Human intestinal folate transport: cloning, expression, and distribution of complementary RNA . Gastroenterology . 112 . 3 . 783–91 . March 1997 . 9041240 . 10.1053/gast.1997.v112.pm9041240 .
• Lapenta V, Sossi V, Gosset P, Vayssettes C, Vitali T, Rabatel N, Tassone F, Blouin JL, Scott HS, Antonarakis SE, Créau N, Brahe C . Construction of a 2.5-Mb integrated physical and gene map of distal 21q22.3 . Genomics . 49 . 1 . 1–13 . April 1998 . 9570943 . 10.1006/geno.1997.5185 .
• Tolner B, Roy K, Sirotnak FM . Structural analysis of the human RFC-1 gene encoding a folate transporter reveals multiple promoters and alternatively spliced transcripts with 5' end heterogeneity . Gene . 211 . 2 . 331–41 . May 1998 . 9602167 . 10.1016/S0378-1119(98)00123-1 . free .
• Zhang L, Wong SC, Matherly LH . Structure and organization of the human reduced folate carrier gene . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1442 . 2–3 . 389–93 . November 1998 . 9804996 . 10.1016/s0167-4781(98)00168-7 .
• Ferguson PL, Flintoff WF . Topological and functional analysis of the human reduced folate carrier by hemagglutinin epitope insertion . The Journal of Biological Chemistry . 274 . 23 . 16269–78 . June 1999 . 10347183 . 10.1074/jbc.274.23.16269 . free .
• Hattori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park HS, Toyoda A, Ishii K, Totoki Y, Choi DK, Groner Y, Soeda E, Ohki M, Takagi T, Sakaki Y, Taudien S, Blechschmidt K, Polley A, Menzel U, Delabar J, Kumpf K, Lehmann R, Patterson D, Reichwald K, Rump A, Schillhabel M, Schudy A, Zimmermann W, Rosenthal A, Kudoh J, Schibuya K, Kawasaki K, Asakawa S, Shintani A, Sasaki T, Nagamine K, Mitsuyama S, Antonarakis SE, Minoshima S, Shimizu N, Nordsiek G, Hornischer K, Brant P, Scharfe M, Schon O, Desario A, Reichelt J, Kauer G, Blocker H, Ramser J, Beck A, Klages S, Hennig S, Riesselmann L, Dagand E, Haaf T, Wehrmeyer S, Borzym K, Gardiner K, Nizetic D, Francis F, Lehrach H, Reinhardt R, Yaspo ML . The DNA sequence of human chromosome 21 . Nature . 405 . 6784 . 311–9 . May 2000 . 10830953 . 10.1038/35012518 . 2000Natur.405..311H . free .
• Whetstine JR, Gifford AJ, Witt T, Liu XY, Flatley RM, Norris M, Haber M, Taub JW, Ravindranath Y, Matherly LH . Single nucleotide polymorphisms in the human reduced folate carrier: characterization of a high-frequency G/A variant at position 80 and transport properties of the His(27) and Arg(27) carriers . Clinical Cancer Research . 7 . 11 . 3416–22 . November 2001 . 11705857 .
• Shaw GM, Lammer EJ, Zhu H, Baker MW, Neri E, Finnell RH . Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spina bifida . American Journal of Medical Genetics . 108 . 1 . 1–6 . February 2002 . 11857541 . 10.1002/ajmg.10195 . free .
• Marchant JS, Subramanian VS, Parker I, Said HM . Intracellular trafficking and membrane targeting mechanisms of the human reduced folate carrier in Mammalian epithelial cells . The Journal of Biological Chemistry . 277 . 36 . 33325–33 . September 2002 . 12087110 . 10.1074/jbc.M205955200 . free .
• Rothem L, Ifergan I, Kaufman Y, Priest DG, Jansen G, Assaraf YG . Resistance to multiple novel antifolates is mediated via defective drug transport resulting from clustered mutations in the reduced folate carrier gene in human leukaemia cell lines . The Biochemical Journal . 367 . Pt 3 . 741–50 . November 2002 . 12139489 . 1222927 . 10.1042/BJ20020801 .
• Whetstine JR, Flatley RM, Matherly LH . The human reduced folate carrier gene is ubiquitously and differentially expressed in normal human tissues: identification of seven non-coding exons and characterization of a novel promoter . The Biochemical Journal . 367 . Pt 3 . 629–40 . November 2002 . 12144527 . 1222932 . 10.1042/BJ20020512 .
• Liu XY, Matherly LH . Analysis of membrane topology of the human reduced folate carrier protein by hemagglutinin epitope insertion and scanning glycosylation insertion mutagenesis . Biochimica et Biophysica Acta (BBA) - Biomembranes . 1564 . 2 . 333–42 . August 2002 . 12175915 . 10.1016/S0005-2736(02)00467-4 .
• Liu XY, Witt TL, Matherly LH . Restoration of high-level transport activity by human reduced folate carrier/ThTr1 thiamine transporter chimaeras: role of the transmembrane domain 6/7 linker region in reduced folate carrier function . The Biochemical Journal . 369 . Pt 1 . 31–7 . January 2003 . 12227830 . 1223057 . 10.1042/BJ20020419 .

Notes and References

1. Lapenta V, Sossi V, Gosset P, Vayssettes C, Vitali T, Rabatel N, Tassone F, Blouin JL, Scott HS, Antonarakis SE, Créau N, Brahe C . Construction of a 2.5-Mb integrated physical and gene map of distal 21q22.3 . Genomics . 49 . 1 . 1–13 . April 1998 . 9570943 . 10.1006/geno.1997.5185 .
2. Web site: Entrez Gene: SLC19A1 solute carrier family 19 (folate transporter), member 1.
3. Ritchie . C . Cordova . AF . Hess . GT . Bassik . MC . Li . L . SLC19A1 Is an Importer of the Immunotransmitter cGAMP. . Molecular Cell . 25 July 2019 . 75 . 2 . 372–381.e5 . 10.1016/j.molcel.2019.05.006 . 31126740. 6711396 .
4. Stanisławska-Sachadyn A, Mitchell LE, Woodside JV, Buckley PT, Kealey C, Young IS, Scott JM, Murray L, Boreham CA, McNulty H, Strain JJ, Whitehead AS . The reduced folate carrier (SLC19A1) c.80G>A polymorphism is associated with red cell folate concentrations among women . Annals of Human Genetics . 73 . Pt 5 . 484–91 . September 2009 . 19650776 . 2812009 . 10.1111/j.1469-1809.2009.00529.x.
   • Web site: Kelly France . 22 August 2009 . Polymorphisms Affecting Red Cell Folate Concentrations in Women could Identify Increased Risk for certain Birth Defects . PGxNews . https://web.archive.org/web/20090922073604/http://www.pgxnews.org/web/pgx-pharmacogenomics-articles-reviews/40-pgx-pharmacogenomics-article-review/113-polymorphisms-affecting-red-cell-folate-concentrations-in-women-could-identify-increased-risk-for-certain-birth-defects . 2009-09-22.