| Structural highlights
Disease
[DYR_HUMAN] Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:613839]. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.[1] [2]
Function
[DYR_HUMAN] Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.[3] [4]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The results of the crystal structure determination of human dihydrofolate reductase (hDHFR) as a binary complex with the potent N9-C10 reversed-bridge antifolate inhibitor 2,4-diamino-6-[N-(3',4',5'-trimethoxybenzyl)-N-methylamino]pyrido[2,3-d]py rimidine (1) are reported for two independent polymorphic rhombohedral R3 lattices [R3(1) and R3(2)]. Data from these two crystal forms were refined to 1.90 A resolution for complex R3(1), with R = 0.186 for 9689 data, and to 1.80 A resolution for complex R3(2), with R = 0.194 for 13 305 data. Changes in the loop geometry between the two structures reflects contact differences in the packing environments in the two R3 lattices. The largest changes (between 0.5 and 1.7 A) are observed for the loop regions encompassing residues 16-25, 40-48, 81-89, 99-108, 143-148 and 161-169. Comparison of the intermolecular contacts of these loops reveals that the R3(2) lattice is more tightly packed, as reflected in its smaller V(M) value and smaller solvent content. The conformation of inhibitor (1) is similar in both structures and the N9-C10 bridge geometry is more similar to that observed for the normal C9-N10 bridge of trimetrexate (TMQ) than to the other N9-C10 reversed-bridge antifolates previously reported. The effect of the N9-C10 reversed-bridge geometry is to distort the bridge from coplanarity with the pyrido[2,3-d]pyrimidine ring system and to twist the C10 methylene conformation towards a gauche conformation. This also influences the conformation of the methoxybenzyl ring, moving it away from a trans position and placing the 5'-methoxy group deeper within the hydrophobic pocket made by Leu60, Pro61 and Asn64 of the hDHFR active site.
Analysis of two polymorphic forms of a pyrido[2,3-d]pyrimidine N9-C10 reversed-bridge antifolate binary complex with human dihydrofolate reductase.,Cody V, Galitsky N, Luft JR, Pangborn W, Gangjee A Acta Crystallogr D Biol Crystallogr. 2003 Apr;59(Pt 4):654-61. Epub 2003, Mar 25. PMID:12657784[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Banka S, Blom HJ, Walter J, Aziz M, Urquhart J, Clouthier CM, Rice GI, de Brouwer AP, Hilton E, Vassallo G, Will A, Smith DE, Smulders YM, Wevers RA, Steinfeld R, Heales S, Crow YJ, Pelletier JN, Jones S, Newman WG. Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency. Am J Hum Genet. 2011 Feb 11;88(2):216-25. doi: 10.1016/j.ajhg.2011.01.004. PMID:21310276 doi:10.1016/j.ajhg.2011.01.004
- ↑ Cario H, Smith DE, Blom H, Blau N, Bode H, Holzmann K, Pannicke U, Hopfner KP, Rump EM, Ayric Z, Kohne E, Debatin KM, Smulders Y, Schwarz K. Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease. Am J Hum Genet. 2011 Feb 11;88(2):226-31. doi: 10.1016/j.ajhg.2011.01.007. PMID:21310277 doi:10.1016/j.ajhg.2011.01.007
- ↑ Anderson DD, Quintero CM, Stover PJ. Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15163-8. doi:, 10.1073/pnas.1103623108. Epub 2011 Aug 26. PMID:21876188 doi:10.1073/pnas.1103623108
- ↑ Klon AE, Heroux A, Ross LJ, Pathak V, Johnson CA, Piper JR, Borhani DW. Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1.09 a and 1.05 a resolution. J Mol Biol. 2002 Jul 12;320(3):677-93. PMID:12096917
- ↑ Cody V, Galitsky N, Luft JR, Pangborn W, Gangjee A. Analysis of two polymorphic forms of a pyrido[2,3-d]pyrimidine N9-C10 reversed-bridge antifolate binary complex with human dihydrofolate reductase. Acta Crystallogr D Biol Crystallogr. 2003 Apr;59(Pt 4):654-61. Epub 2003, Mar 25. PMID:12657784
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