7xq0

Structural highlights

Disease

S19A1_HUMAN Methotrexate dose selection. The disease is caused by variants affecting the gene represented in this entry.

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]}

References

1. ↑ 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:http://dx.doi.org/10.1074/jbc.M002328200
2. ↑ 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:http://dx.doi.org/10.1016/j.exer.2003.08.013
3. ↑ 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:http://dx.doi.org/10.1074/jbc.M408696200
4. ↑ 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:http://dx.doi.org/10.1074/jbc.M507295200
5. ↑ 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:http://dx.doi.org/10.1124/mol.112.078642
6. ↑ 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:http://dx.doi.org/10.1016/j.molcel.2019.05.006
7. ↑ 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:http://dx.doi.org/10.1038/s41586-019-1553-0
8. ↑ 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:http://dx.doi.org/10.1182/blood.2019003178
9. ↑ 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:http://dx.doi.org/10.1074/jbc.270.29.17468
10. ↑ 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
11. ↑ 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:http://dx.doi.org/10.1006/bbrc.1995.1096
12. ↑ 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:http://dx.doi.org/10.1053/gast.1997.v112.pm9041240
13. ↑ 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:http://dx.doi.org/10.1016/s0005-2736(98)00118-7