Reduced folate carrier family

The Reduced Folate Carrier (RFC) Family (TC# 2.A.48) is a group of transport proteins that is part of the major facilitator superfamily. RFCs take up folate, reduced folate, derivatives of reduced folate and the drug, methotrexate.

Structure and Homology

These proteins are usually 500-600 amino acyl residues long and possess 12 putative transmembrane α-helical segments (TMSs). Residues in the first TMS and in the region between TMSs 1 and 2, and in TMS 11 appear to play roles in substrate recognition.[1][2] The large cytoplasmic loop between TMSs 6 and 7 is required for stability and efficient transport.

Proteins of the RFC family have been characterized only from animals, but homologues can also be found in other eukaryotes such as slime molds and Giardia. They have been sequenced from several mammals and from the worm, Caenorhabditis elegans, as well as the fly, Drosophila melanogaster. Humans have at least two RFC family paralogues, and C. elegans has three. All homologues exhibit a high degree of sequence similarity with each other.

Proposed Mechanisms

The RFC members appear to transport reduced folate by an energy-dependent, pH-dependent, Na+-independent mechanism. Folate:H+ symport, folate:OH−antiport and folate:anion antiport mechanisms have been proposed. Intracellular anions are able to promote folate derivative uptake. A bidirectional anion antiport mechanism for RFC family members is favored. In support of this notion, RFC1 has been shown to catalyze efflux of thiamin pyrophosphate (TPP).[3][4]

Transport Reactions

The generalized transport reactions catalyzed by the proteins of the RFC family are:

Folate derivative (out) + anion (in) ⇌ folate derivative (in) + anion (out)
Thiamine (out) + H+ (out) ⇌ thiamine (in) + H+ (in)
TPP (in) + H+ (in) ⇌ TPP (out) + H+ (out)

Medical relevance

Several human RFCs have been linked to chronic kidney disease. In particular, RFC1, ThTr-1, and ThTr-2 have been shown to be downregulated in heart, liver and brain, causing malabsorption.[5]

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See also

References
  1. Flintoff, Wayne F.; Williams, Frederick M. R.; Sadlish, Heather (2003-10-17). "The region between transmembrane domains 1 and 2 of the reduced folate carrier forms part of the substrate-binding pocket". The Journal of Biological Chemistry. 278 (42): 40867–40876. doi:10.1074/jbc.M302102200. ISSN 0021-9258. PMID 12909642.
  2. Hou, Zhanjun; Stapels, Sarah E.; Haska, Christina L.; Matherly, Larry H. (2005-10-28). "Localization of a substrate binding domain of the human reduced folate carrier to transmembrane domain 11 by radioaffinity labeling and cysteine-substituted accessibility methods". The Journal of Biological Chemistry. 280 (43): 36206–36213. doi:10.1074/jbc.M507295200. ISSN 0021-9258. PMID 16115875.
  3. Zhao, R.; Gao, F.; Wang, Y.; Diaz, G. A.; Gelb, B. D.; Goldman, I. D. (2001-01-12). "Impact of the reduced folate carrier on the accumulation of active thiamin metabolites in murine leukemia cells". The Journal of Biological Chemistry. 276 (2): 1114–1118. doi:10.1074/jbc.M007919200. ISSN 0021-9258. PMID 11038362.
  4. Visentin, Michele; Zhao, Rongbao; Goldman, I. David (2012-08-01). "Augmentation of reduced folate carrier-mediated folate/antifolate transport through an antiport mechanism with 5-aminoimidazole-4-carboxamide riboside monophosphate". Molecular Pharmacology. 82 (2): 209–216. doi:10.1124/mol.112.078642. ISSN 1521-0111. PMC 3400841. PMID 22554803.
  5. Bukhari, Farhan J.; Moradi, Hamid; Gollapudi, Pavan; Ju Kim, Hyun; Vaziri, Nosratola D.; Said, Hamid M. (2011-07-01). "Effect of chronic kidney disease on the expression of thiamin and folic acid transporters". Nephrology, Dialysis, Transplantation. 26 (7): 2137–2144. doi:10.1093/ndt/gfq675. ISSN 1460-2385. PMC 3164444. PMID 21149507.

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