| Structural highlights
Disease
[S19A1_HUMAN] Methotrexate dose selection. The disease is caused by variants affecting the gene represented in this entry.
Function
[C562_ECOLX] Electron-transport protein of unknown function.[S19A1_HUMAN] Antiporter that mediates the import of reduced folates or a subset of cyclic dinucleotides, driven by the export of organic anions (PubMed:7826387, PubMed:9041240, PubMed:10787414, PubMed:15337749, PubMed:16115875, PubMed:22554803, PubMed:31511694, PubMed:31126740, PubMed:32276275). Mechanistically, acts as a secondary active transporter, which exports intracellular organic anions down their concentration gradients to facilitate the uptake of its substrates (PubMed:22554803, PubMed:31511694, PubMed:31126740). Has high affinity for N5-methyltetrahydrofolate, the predominant circulating form of folate (PubMed:10787414, PubMed:14609557, PubMed:22554803). Also able to mediate the import of antifolate drug methotrexate (PubMed:7615551, PubMed:7641195, PubMed:9767079, PubMed:22554803). 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 (PubMed:31511694, PubMed:31126740). 5-amino-4-imidazolecarboxamide riboside (AICAR), when phosphorylated to AICAR monophosphate, can serve as an organic anion for antiporter activity (PubMed:22554803).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Publication Abstract from PubMed
Folates are essential nutrients with important roles as cofactors in one-carbon transfer reactions, being heavily utilized in the synthesis of nucleic acids and the metabolism of amino acids during cell division(1,2). Mammals lack de novo folate synthesis pathways and thus rely on folate uptake from the extracellular milieu(3). The human reduced folate carrier (hRFC, also known as SLC19A1) is the major importer of folates into the cell(1,3), as well as chemotherapeutic agents such as methotrexate(4-6). As an anion exchanger, RFC couples the import of folates and antifolates to anion export across the cell membrane and it is a major determinant in methotrexate (antifolate) sensitivity, as genetic variants and its depletion result in drug resistance(4-8). Despite its importance, the molecular basis of substrate specificity by hRFC remains unclear. Here we present cryo-electron microscopy structures of hRFC in the apo state and captured in complex with methotrexate. Combined with molecular dynamics simulations and functional experiments, our study uncovers key determinants of hRFC transport selectivity among folates and antifolate drugs while shedding light on important features of anion recognition by hRFC.
Methotrexate recognition by the human reduced folate carrier SLC19A1.,Wright NJ, Fedor JG, Zhang H, Jeong P, Suo Y, Yoo J, Hong J, Im W, Lee SY Nature. 2022 Sep 7. pii: 10.1038/s41586-022-05168-0. doi:, 10.1038/s41586-022-05168-0. PMID:36071163[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Chancy CD, Kekuda R, Huang W, Prasad PD, Kuhnel JM, Sirotnak FM, Roon P, Ganapathy V, Smith SB. 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. doi: 10.1074/jbc.M002328200. PMID:10787414 doi:https://dx.doi.org/10.1074/jbc.M002328200
- ↑ Naggar H, Fei YJ, Ganapathy V, Smith SB. 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. doi: 10.1016/j.exer.2003.08.013. PMID:14609557 doi:https://dx.doi.org/10.1016/j.exer.2003.08.013
- ↑ Witt TL, Stapels SE, Matherly LH. 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. doi: 10.1074/jbc.M408696200. Epub 2004 , Aug 26. PMID:15337749 doi:https://dx.doi.org/10.1074/jbc.M408696200
- ↑ Hou Z, Stapels SE, Haska CL, Matherly LH. 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. doi: 10.1074/jbc.M507295200. Epub 2005, Aug 22. PMID:16115875 doi:https://dx.doi.org/10.1074/jbc.M507295200
- ↑ Visentin M, Zhao R, Goldman ID. 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. doi: 10.1124/mol.112.078642. Epub 2012 May , 3. PMID:22554803 doi:https://dx.doi.org/10.1124/mol.112.078642
- ↑ Ritchie C, Cordova AF, Hess GT, Bassik MC, Li L. SLC19A1 Is an Importer of the Immunotransmitter cGAMP. Mol Cell. 2019 Jul 25;75(2):372-381.e5. doi: 10.1016/j.molcel.2019.05.006. Epub, 2019 May 21. PMID:31126740 doi:https://dx.doi.org/10.1016/j.molcel.2019.05.006
- ↑ Luteijn RD, Zaver SA, Gowen BG, Wyman SK, Garelis NE, Onia L, McWhirter SM, Katibah GE, Corn JE, Woodward JJ, Raulet DH. SLC19A1 transports immunoreactive cyclic dinucleotides. Nature. 2019 Sep;573(7774):434-438. doi: 10.1038/s41586-019-1553-0. Epub 2019 Sep, 11. PMID:31511694 doi:https://dx.doi.org/10.1038/s41586-019-1553-0
- ↑ Svaton M, Skvarova Kramarzova K, Kanderova V, Mancikova A, Smisek P, Jesina P, Krijt J, Stiburkova B, Dobrovolny R, Sokolova J, Bakardjieva-Mihaylova V, Vodickova E, Rackova M, Stuchly J, Kalina T, Stary J, Trka J, Fronkova E, Kozich V. A homozygous deletion in the SLC19A1 gene as a cause of folate-dependent recurrent megaloblastic anemia. Blood. 2020 Jun 25;135(26):2427-2431. doi: 10.1182/blood.2019003178. PMID:32276275 doi:https://dx.doi.org/10.1182/blood.2019003178
- ↑ 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. J Biol Chem. 1995 Jul 21;270(29):17468-75. doi: 10.1074/jbc.270.29.17468. PMID:7615551 doi:https://dx.doi.org/10.1074/jbc.270.29.17468
- ↑ 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 Res. 1995 Sep 1;55(17):3790-4. PMID:7641195
- ↑ Prasad PD, Ramamoorthy S, Leibach FH, Ganapathy V. Molecular cloning of the human placental folate transporter. Biochem Biophys Res Commun. 1995 Jan 17;206(2):681-7. doi:, 10.1006/bbrc.1995.1096. PMID:7826387 doi:https://dx.doi.org/10.1006/bbrc.1995.1096
- ↑ Nguyen TT, Dyer DL, Dunning DD, Rubin SA, Grant KE, Said HM. Human intestinal folate transport: cloning, expression, and distribution of complementary RNA. Gastroenterology. 1997 Mar;112(3):783-91. doi: 10.1053/gast.1997.v112.pm9041240. PMID:9041240 doi:https://dx.doi.org/10.1053/gast.1997.v112.pm9041240
- ↑ Wong SC, Zhang L, Proefke SA, Matherly LH. 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. doi:, 10.1016/s0005-2736(98)00118-7. PMID:9767079 doi:https://dx.doi.org/10.1016/s0005-2736(98)00118-7
- ↑ Wright NJ, Fedor JG, Zhang H, Jeong P, Suo Y, Yoo J, Hong J, Im W, Lee SY. Methotrexate recognition by the human reduced folate carrier SLC19A1. Nature. 2022 Sep 7. pii: 10.1038/s41586-022-05168-0. doi:, 10.1038/s41586-022-05168-0. PMID:36071163 doi:https://dx.doi.org/10.1038/s41586-022-05168-0
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