Skip to main content
SpringerLink
Log in

SLC19: the folate/thiamine transporter family

  • The ABC of Solute carriers
  • Guest Editor: Matthias A. Hediger
  • Published:
Pflügers Archiv Aims and scope Submit manuscript

Abstract

The SLC19 gene family of solute carriers is a family of three transporter proteins with significant structural similarity, transporting, however, substrates with different structure and ionic charge. The three members of this gene family are expressed ubiquitously and mediate the transport of two important water-soluble vitamins, folate and thiamine. The concentrative transport of substrates mediated by the members of this gene family is energized by transcellular H+/OH− gradient. SLC19A1 is expressed at highest levels in absorptive cells where it is located in a polarized manner either in the apical or basal membrane, depending on the cell type. It mediates the transport of reduced folate and its analogs, such as methotrexate, which are anionic at physiological pH. SLC19A2 is expressed ubiquitously and mediates the transport of thiamine, a cation at physiological pH. SLC19A3 is also widely expressed and is capable of transporting thiamine. This review summarizes the current knowledge on the structural, functional, molecular and physiological aspects of the SLC19 gene family.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2A–D.

Similar content being viewed by others

References

  1. Balamurugan K, Said HM (2002) Functional role of specific amino acid residues in human thiamine transporter SLC19A2: mutational analysis. Am J Physiol 283:G37–G43

    CAS  Google Scholar 

  2. Chancy CD, Kekuda R, Huang W, Prasad PD, Kuhnel JM, Sirotnak FM, Roon P, Ganapathy V, Smith SB (2000) Expression and differential polarization of the reduced-folate transporter-1 and the folate receptor alpha in mammalian retinal pigment epithelium. J Biol Chem 275:20676–20684

    Article  CAS  PubMed  Google Scholar 

  3. Diaz GA, Banikazemi M, Oishi K, Desnick RJ, Gelb BD (1999) Mutations in a new gene encoding a thiamine transporter cause thiamine-responsive megaloblastic anaemia syndrome. Nat Genet 22:309–312

    Article  CAS  PubMed  Google Scholar 

  4. Ding BC, Whetstine JR, Witt TL, Schuetz JD, Matherly LH (2001) Repression of human reduced folate carrier gene expression by wild type p53. J Biol Chem 276:8713–8719

    Article  CAS  PubMed  Google Scholar 

  5. Dixon KH, Lampher BC, Chiu J, Kelley K, Cowan KH (1994) A novel cDNA restores reduced folate carrier activity and methotrexate sensitivity to transport deficient cells. J Biol Chem 269:17–20

    CAS  PubMed  Google Scholar 

  6. Dutta B, Huang W, Molero M, Kekuda R, Leibach FH, Devoe LD, Ganapathy V, Prasad PD (1999) Cloning of the human thiamine transporter, a member of the folate transporter family. J Biol Chem 274:31925–31929

    Article  CAS  PubMed  Google Scholar 

  7. Eudy JD, Spiegelstein O, Barber RC, Wlodarczyk BJ, Talbot J, Finnell RH (2000) Identification and characterization of the human and mouse SLC19A3 gene: a novel member of the reduced folate family of micronutrient transporter genes. Mol Genet Metab 71:581–590

    Article  CAS  PubMed  Google Scholar 

  8. Ferguson PL, Flintoff WF (1999) Topological and functional analysis of the human reduced folate carrier by hemagglutinin epitope insertion. J Biol Chem 274:16269–16278

    Article  CAS  PubMed  Google Scholar 

  9. Fleming JC, Tartaglini E, Steinkamp MP, Schorderet DF, Cohen N, Neufeld EJ (1999) The gene mutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter. Nat Genet 22:305–308

    Article  CAS  PubMed  Google Scholar 

  10. Fleming JC, Steinkamp MP, Kawatsuji R, Tartaglini E, Pinkus JL, Pinkus GS, Fleming MD, Neufeld EJ (2001) Characterization of a murine high-affinity thiamine transporter, Slc19a2. Mol Genet Metab 74:273–280

    Article  CAS  PubMed  Google Scholar 

  11. Gong M, Cowan KH, Gudas J, Moscow JA (1999) Isolation and characterization of genomic sequences involved in the regulation of the human reduced folate carrier gene (RFC1). Gene 233:21–31

    Article  CAS  PubMed  Google Scholar 

  12. Kang SS, Wong PW, Norusis M (1987) Homocysteinemia due to folate deficiency. Metabolism 36:458–462

    CAS  PubMed  Google Scholar 

  13. Labay V, Raz T, Baron D, Mandel H, Williams H, Barrett T, Szargel R, McDonald L, Shalata A, Nosaka K, Gregory S, Cohen N (1999) Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness. Nat Genet 22:300–304

    Article  CAS  PubMed  Google Scholar 

  14. Liu XY, Matherly LH (2002) Analysis of membrane topology of the human reduced folate carrier protein by hemagglutinin epitope insertion and scanning glycosylation insertion mutagenesis. Biochim Biophys Acta 1564:333–342

    Article  CAS  PubMed  Google Scholar 

  15. Liu XY, Witt TL, Matherly LH (2003) 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. Biochem J 369:31–37

    Article  CAS  PubMed  Google Scholar 

  16. Lo PK, Wang FF (2002) Identification of transcriptional start sites and splicing of mouse thiamine transporter gene THTR-1 (Slc19a2). Biochim Biophys Acta 1576:209–213

    Article  CAS  PubMed  Google Scholar 

  17. Moscow JA, Gong M, He R, Sgagias MK, Dixon KH, Anzick SL, Meltzer PS, Cowan KH (1995) 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 Res 55:3790–3794

    CAS  PubMed  Google Scholar 

  18. Naggar H, Ola MS, Moore P, Huang W, Bridges CC, Ganapathy V, Smith SB (2002) Downregulation of reduced-folate transporter by glucose in cultured RPE cells and in RPE of diabetic mice. Invest Ophthalmol Vis Sci 43:556–563

    Google Scholar 

  19. Neufeld EJ, Fleming JC, Tartaglini E, Steinkamp MP (2001) Thiamine-responsive megaloblastic anemia syndrome: a disorder of high-affinity thiamine transport. Blood Cells Mol Dis 27:135–138

    Article  CAS  PubMed  Google Scholar 

  20. Oishi K, Hirai T, Gelb BD, Diaz GA (2001) Slc19a2: cloning and characterization of the murine thiamin transporter cDNA and genomic sequence, the orthologue of the human TRMA gene. Mol Genet Metab 73:149–159

    Article  CAS  PubMed  Google Scholar 

  21. Oishi K, Hofmann S, Diaz GA, Brown T, Manwani D, Ng L, Young R, Vlassara H, Ioannou YA, Forrest D, Gelb BD (2002) Targeted disruption of Slc19a2, the gene encoding the high-affinity thiamin transporter Thtr-1, causes diabetes mellitus, sensorineural deafness and megaloblastosis in mice. Hum Mol Genet 11:2951–2960

    Article  CAS  PubMed  Google Scholar 

  22. Prasad PD, Ramamoorthy S, Leibach FH, Ganapathy V (1995) Molecular cloning of the human placental folate transporter. Biochem Biophys Res Commun 206:681–687

    Article  CAS  PubMed  Google Scholar 

  23. Rajgopal A, Edmondnson A, Goldman ID, Zhao R (2001) SLC19A3 encodes a second thiamine transporter ThTr2. Biochim Biophys Acta 1537:175–178

    Article  CAS  PubMed  Google Scholar 

  24. Rajgopal A, Sierra EE, Zhao R, Goldman ID (2001) Expression of the reduced folate carrier SLC19A1 in IEC-6 cells results in two distinct transport activities. Am J Physiol 281:C1579–C1586

    CAS  PubMed  Google Scholar 

  25. Raz T, Labay V, Baron D, Szargel R, Anbinder Y, Barrett T, Rabl W, Viana MB, Mandel H, Baruchel A, Cayuela JM, Cohen N (2000) The spectrum of mutations, including four novel ones, in the thiamine-responsive megaloblastic anemia gene SLC19A2 of eight families. Hum Mutat 16:37–42

    Article  CAS  PubMed  Google Scholar 

  26. Sadlish H, Williams FM, Flintoff WF (2002) Cytoplasmic domains of the reduced folate carrier are essential for trafficking, but not function. Biochem J 364:777–786

    Article  CAS  PubMed  Google Scholar 

  27. Said HM, Chatterjee N, Haq RU, Subramanian VS, Ortiz A, Matherly LH, Sirotnak FM, Halsted C, Rubin SA (2000) Adaptive regulation of intestinal folate uptake: effect of dietary folate deficiency. Am J Physiol 279:C1889–C1895

    CAS  Google Scholar 

  28. Schron CM, Washington C Jr, Blitzer BL (1985) The transmembrane pH gradient drives uphill folate transport in rabbit jejunum. Direct evidence for folate/hydroxyl exchange in brush border membrane vesicles. J Clin Invest 76:2030–2033

    CAS  PubMed  Google Scholar 

  29. Sharina IG, Zhao R, Wang Y, Babani S, Goldman ID (2002) Role of the C-terminus and the long cytoplasmic loop in reduced folate carrier expression and function. Biochem Pharmacol 63:1717–1724

    Article  CAS  PubMed  Google Scholar 

  30. Sierra E, Goldman ID (1999) Recent advances in the understanding of the mechanism of membrane transport of folates and antifolates. Semin Oncol 26:11–23

    CAS  Google Scholar 

  31. Smith SB, Huang W, Chancy C, Ganapathy V (1999) Regulation of the reduced-folate transporter by nitric oxide in cultured human retinal pigment epithelial cells. Biochem Biophys Res Commun 257:279–283

    Article  CAS  PubMed  Google Scholar 

  32. Stagg AR, Fleming JC, Baker MA, Sakamoto M, Cohen N, Neufeld EJ (1999) Defective high-affinity thiamine transporter leads to cell death in thiamine-responsive megaloblastic anemia syndrome fibroblasts. J Clin Invest 103:723–729

    CAS  PubMed  Google Scholar 

  33. Tolner B, Roy K, Sirotnak FM (1998) Structural analysis of the human RFC-1 gene encoding a folate transporter reveals multiple promoters and alternatively spliced transcripts with 5′ end heterogeneity. Gene 211:331–341

    Article  CAS  PubMed  Google Scholar 

  34. Trippett TM, Garcia S, Manova K, Mody R, Cohen-Gould L, Flintoff W, Bertino JR (2001) Localization of a human reduced folate carrier protein in the mitochondrial as well as the cell membrane of leukemia cells. Cancer Res 61:1941–1947

    CAS  PubMed  Google Scholar 

  35. Wang Y, Zhao R, Russell RG, Goldman ID (2001) Localization of the murine reduced folate carrier as assessed by immunohistochemical analysis. Biochim Biophys Acta 1513:49–54

    Article  CAS  PubMed  Google Scholar 

  36. Whetstine JR, Flatley RM, Matherly LH (2002) 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. Biochem J 367:629–640

    Article  CAS  PubMed  Google Scholar 

  37. Williams FM, Flintoff WF (1995) Isolation of a human cDNA that complements a mutant hamster cell defective in methotrexate uptake. J Biol Chem 270:2987–2992

    Article  CAS  PubMed  Google Scholar 

  38. Williams FM, Flintoff WF (1998) Structural organization of the human reduced folate carrier gene: evidence for 5′ heterogeneity in lymphoblast mRNA. Somat Cell Mol Genet 24:143–156

    CAS  PubMed  Google Scholar 

  39. Williams FM, Murray RC, Underhill TM, Flintoff WF (1994) Isolation of a hamster cDNA clone coding for a function involved in methotrexate uptake. J Biol Chem 269:5810–5816

    CAS  PubMed  Google Scholar 

  40. Wong SC, Proefke SA, Bhushan A, Matherly LH (1995) 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

    Article  CAS  PubMed  Google Scholar 

  41. Wong SC, Zhang L, Proefke SA, Matherly LH (1998) Effects of the loss of capacity for N-glycosylation on the transport activity and cellular localization of the human reduced folate carrier. Biochim Biophys Acta 1375:6–12

    Article  CAS  PubMed  Google Scholar 

  42. Yang-Feng TL, Ma YY, Liang R, Prasad PD, Leibach FH, Ganapathy V (1995) 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

    Article  CAS  PubMed  Google Scholar 

  43. Zhang L, Wong SC, Matherly LH (1998) Structure and organization of the human reduced folate carrier gene. Biochim Biophys Acta 1442:389–393

    Article  CAS  PubMed  Google Scholar 

  44. Zhao R, Gao F, Wang Y, Diaz GA, Gelb BD, Goldman ID (2001) Impact of the reduced folate carrier on the accumulation of active thiamin metabolites in murine leukemia cells. J Biol Chem 276:1114–1118

    Article  CAS  PubMed  Google Scholar 

  45. Zhao R, Russell RG, Wang Y, Liu L, Gao F, Kneitz B, Edelmann W, Goldman ID (2001) Rescue of embryonic lethality in reduced folate carrier-deficient mice by maternal folic acid supplementation reveals early neonatal failure of hematopoietic organs. J Biol Chem 276:10224–10228

    CAS  PubMed  Google Scholar 

  46. Zhao R, Gao F, Goldman ID (2002) Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells. Am J Physiol 282:C1512–C1517

    CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institutes of Health Grants HD37150 (PDP) and EY12830 (SBS).

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912-2100, USA

    Vadivel Ganapathy

  2. Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912, USA

    Sylvia B. Smith

  3. Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, GA 30912, USA

    Puttur D. Prasad

Authors
  1. Vadivel Ganapathy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sylvia B. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Puttur D. Prasad
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vadivel Ganapathy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ganapathy, V., Smith, S.B. & Prasad, P.D. SLC19: the folate/thiamine transporter family. Pflugers Arch - Eur J Physiol 447, 641–646 (2004). https://doi.org/10.1007/s00424-003-1068-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-003-1068-1

Keywords

Search

Navigation