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Reduced folate transporter

Definition:

Antiporter that mediates the import of reduced folates or a subset of cyclic dinucleotides, driven by the export of organic anions. Mechanistically, acts as a secondary active transporter, which exports intracellular organic anions down their concentration gradients to facilitate the uptake of its substrates. Has high affinity for N5-methyltetrahydrofolate, the predominant circulating form of folate. Also able to mediate the import of antifolate drug methotrexate. Also acts as an importer of immunoreactive cyclic dinucleotides, such as cyclic GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol, and its linkage isomer 3'-3'-cGAMP, thus playing a role in triggering larger immune responses. 5-amino-4-imidazolecarboxamide riboside (AICAR), when phosphorylated to AICAR monophosphate, can serve as an organic anion for antiporter activity.

References:

[1]. Teah L Witt, et al. Restoration of transport activity by co-expression of human reduced folate carrier half-molecules in transport-impaired K562 cells: localization of a substrate binding domain to transmembrane domains 7-12. J Biol Chem. 2004 Nov 5;279(45):46755-63. [Content Brief]

[2]. Rutger D Luteijn, et al. SLC19A1 transports immunoreactive cyclic dinucleotides. Nature. 2019 Sep;573(7774):434-438. [Content Brief]

[3]. Christopher Ritchie, et al. SLC19A1 Is an Importer of the Immunotransmitter cGAMP. Mol Cell. 2019 Jul 25;75(2):372-381.e5. [Content Brief]

[4]. P D Prasad, et al. Molecular cloning of the human placental folate transporter. Biochem Biophys Res Commun. 1995 Jan 17;206(2):681-7. [Content Brief]

[5]. T T Nguyen, et al. Human intestinal folate transport: cloning, expression, and distribution of complementary RNA. Gastroenterology. 1997 Mar;112(3):783-91. [Content Brief]

[6]. Michael Svaton, et al. A homozygous deletion in the SLC19A1 gene as a cause of folate-dependent recurrent megaloblastic anemia. Blood. 2020 Jun 25;135(26):2427-2431. [Content Brief]

[7]. S C Wong, et al. 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. 1998 Oct 15;1375(1-2):6-12. [Content Brief]

[8]. C D Chancy, et al. Expression and differential polarization of the reduced-folate transporter-1 and the folate receptor alpha in mammalian retinal pigment epithelium. J Biol Chem. 2000 Jul 7;275(27):20676-84. [Content Brief]

[9]. Hany Naggar, et al. Regulation of reduced-folate transporter-1 (RFT-1) by homocysteine and identity of transport systems for homocysteine uptake in retinal pigment epithelial (RPE) cells. Exp Eye Res. 2003 Dec;77(6):687-97. [Content Brief]

[10]. S C Wong, et al. Isolation of human cDNAs that restore methotrexate sensitivity and reduced folate carrier activity in methotrexate transport-defective Chinese hamster ovary cells. J Biol Chem. 1995 Jul 21;270(29):17468-75. [Content Brief]

[11]. J A Moscow, et al. 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. 1995 Sep 1;55(17):3790-4. [Content Brief]

[12]. Michele Visentin, et al. Augmentation of reduced folate carrier-mediated folate/antifolate transport through an antiport mechanism with 5-aminoimidazole-4-carboxamide riboside monophosphate. Mol Pharmacol. 2012 Aug;82(2):209-16. [Content Brief]

[13]. Zhanjun Hou, et al. Localization of a substrate binding domain of the human reduced folate carrier to transmembrane domain 11 by radioaffinity labeling and cysteine-substituted accessibility methods. J Biol Chem. 2005 Oct 28;280(43):36206-13. [Content Brief]

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