From Wikipedia, the free encyclopedia
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Dihydrofolate reductase
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| Ribbon diagram of human dihydrofolate reductase in complex with folate (blue). From PDB 1DRF. |
| Available structures: 1boz, 1dhf, 1dlr, 1dls, 1drf, 1hfp, 1hfq, 1hfr, 1kms, 1kmv, 1mvs, 1mvt, 1ohj, 1ohk, 1pd8, 1pd9, 1pdb, 1s3u, 1s3v, 1s3w, 1u71, 1u72, 1yho, 2c2s, 2c2t, 2dhf |
| Identifiers |
| Symbols |
DHFR; |
| External IDs |
OMIM: 126060 MGI: 94890 HomoloGene: 56470 |
| EC number |
1.5.1.3 |
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| Orthologs |
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Human |
Mouse |
| Entrez |
1719 |
13361 |
| Ensembl |
ENSG00000188985 |
ENSMUSG00000021707 |
| Uniprot |
P00374 |
Q544T5 |
| Refseq |
NM_000791 (mRNA)
NP_000782 (protein) |
NM_010049 (mRNA)
NP_034179 (protein) |
| Location |
Chr 5: 79.96 - 79.99 Mb |
Chr 13: 93.46 - 93.49 Mb |
| Pubmed search |
[1] |
[2] |
Dihydrofolate reductase, or DHFR, is an enzyme which reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry. In humans, the DHFR enzyme is encoded by the DHFR gene.[1][2]
[edit] Function
Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids. While the functional dihydrofolate reductase gene has been mapped to chromosome 5, multiple intronless processed pseudogenes or dihydrofolate reductase-like genes have been identified on separate chromosomes.[3]
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Reaction catalyzed by DHFR.
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Tetrahydrofolate synthesis pathway.
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[edit] Clinical significance
Dihydrofolate reductase deficiency has been linked to megaloblastic anemia.[3] Treatment is with reduced forms of folic acid. Because tetrahydrofolate, the product of this reaction, is the active form of folate in humans, inhibition of DHFR can cause functional folate deficiency.
[edit] Therapeutic application
Since folate is needed by rapidly dividing cells to make thymine, this effect may be used to therapeutic advantage.
[edit] References
- ^ Chen MJ, Shimada T, Moulton AD, Harrison M, Nienhuis AW (December 1982). "Intronless human dihydrofolate reductase genes are derived from processed RNA molecules". Proc. Natl. Acad. Sci. U.S.A. 79 (23): 7435–9. doi:10.1073/pnas.79.23.7435. PMID 6961421.
- ^ Chen MJ, Shimada T, Moulton AD, Cline A, Humphries RK, Maizel J, Nienhuis AW (March 1984). "The functional human dihydrofolate reductase gene". J. Biol. Chem. 259 (6): 3933–43. PMID 6323448. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=6323448.
- ^ a b "Entrez Gene: DHFR dihydrofolate reductase". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1719.
[edit] Further reading
- Joska TM, Anderson AC (October 2006). "Structure-activity relationships of Bacillus cereus and Bacillus anthracis dihydrofolate reductase: toward the identification of new potent drug leads". Antimicrob. Agents Chemother. 50 (10): 3435–43. doi:10.1128/AAC.00386-06. PMID 17005826.
- Chan DC, Fu H, Forsch RA, Queener SF, Rosowsky A (June 2005). "Design, synthesis, and antifolate activity of new analogues of piritrexim and other diaminopyrimidine dihydrofolate reductase inhibitors with omega-carboxyalkoxy or omega-carboxy-1-alkynyl substitution in the side chain". J. Med. Chem. 48 (13): 4420–31. doi:10.1021/jm0581718. PMID 15974594.
- Banerjee D, Mayer-Kuckuk P, Capiaux G, et al. (2002). "Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase.". Biochim. Biophys. Acta 1587 (2-3): 164–73. PMID 12084458.
- Stockman BJ, Nirmala NR, Wagner G, et al. (1992). "Sequence-specific 1H and 15N resonance assignments for human dihydrofolate reductase in solution.". Biochemistry 31 (1): 218–29. doi:10.1021/bi00116a031. PMID 1731871.
- Beltzer JP, Spiess M (1991). "In vitro binding of the asialoglycoprotein receptor to the beta adaptin of plasma membrane coated vesicles.". Embo J. 10 (12): 3735–42. PMID 1935897.
- Davies JF, Delcamp TJ, Prendergast NJ, et al. (1991). "Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate.". Biochemistry 29 (40): 9467–79. doi:10.1021/bi00492a021. PMID 2248959.
- Will CL, Dolnick BJ (1990). "5-Fluorouracil inhibits dihydrofolate reductase precursor mRNA processing and/or nuclear mRNA stability in methotrexate-resistant KB cells.". J. Biol. Chem. 264 (35): 21413–21. PMID 2592384.
- Masters JN, Attardi G (1985). "Discrete human dihydrofolate reductase gene transcripts present in polysomal RNA map with their 5' ends several hundred nucleotides upstream of the main mRNA start site.". Mol. Cell. Biol. 5 (3): 493–500. PMID 2859520.
- Miszta H, Dabrowski Z, Lanotte M (1988). "In vitro patterns of enzymic tetrahydrofolate dehydrogenase (EC 1.5.1.3) expression in bone marrow stromal cells.". Leukemia 2 (11): 754–9. PMID 3185016.
- Oefner C, D'Arcy A, Winkler FK (1988). "Crystal structure of human dihydrofolate reductase complexed with folate.". Eur. J. Biochem. 174 (2): 377–85. doi:10.1111/j.1432-1033.1988.tb14108.x. PMID 3383852.
- Yang JK, Masters JN, Attardi G (1984). "Human dihydrofolate reductase gene organization. Extensive conservation of the G + C-rich 5' non-coding sequence and strong intron size divergence from homologous mammalian genes.". J. Mol. Biol. 176 (2): 169–87. doi:10.1016/0022-2836(84)90419-4. PMID 6235374.
- Masters JN, Yang JK, Cellini A, Attardi G (1983). "A human dihydrofolate reductase pseudogene and its relationship to the multiple forms of specific messenger RNA.". J. Mol. Biol. 167 (1): 23–36. doi:10.1016/S0022-2836(83)80032-1. PMID 6306253.
- Chen MJ, Shimada T, Moulton AD, et al. (1984). "The functional human dihydrofolate reductase gene.". J. Biol. Chem. 259 (6): 3933–43. PMID 6323448.
- Funanage VL, Myoda TT, Moses PA, Cowell HR (1985). "Assignment of the human dihydrofolate reductase gene to the q11----q22 region of chromosome 5.". Mol. Cell. Biol. 4 (10): 2010–6. PMID 6504041.
- Masters JN, Attardi G (1983). "The nucleotide sequence of the cDNA coding for the human dihydrofolic acid reductase.". Gene 21 (1-2): 59–63. doi:10.1016/0378-1119(83)90147-6. PMID 6687716.
- Morandi C, Masters JN, Mottes M, Attardi G (1982). "Multiple forms of human dihydrofolate reductase messenger RNA. Cloning and expression in Escherichia coli of their DNA coding sequence.". J. Mol. Biol. 156 (3): 583–607. doi:10.1016/0022-2836(82)90268-6. PMID 6750132.
- Bonifaci N, Sitia R, Rubartelli A (1996). "Nuclear translocation of an exogenous fusion protein containing HIV Tat requires unfolding.". AIDS 9 (9): 995–1000. PMID 8527095.
- Mayhew M, da Silva AC, Martin J, et al. (1996). "Protein folding in the central cavity of the GroEL-GroES chaperonin complex.". Nature 379 (6564): 420–6. doi:10.1038/379420a0. PMID 8559246.
- Gross M, Robinson CV, Mayhew M, et al. (1997). "Significant hydrogen exchange protection in GroEL-bound DHFR is maintained during iterative rounds of substrate cycling.". Protein Sci. 5 (12): 2506–13. PMID 8976559.
- Schleiff E, Shore GC, Goping IS (1997). "Human mitochondrial import receptor, Tom20p. Use of glutathione to reveal specific interactions between Tom20-glutathione S-transferase and mitochondrial precursor proteins.". FEBS Lett. 404 (2-3): 314–8. doi:10.1016/S0014-5793(97)00145-2. PMID 9119086.
- Cody V, Galitsky N, Luft JR, et al. (1997). "Comparison of two independent crystal structures of human dihydrofolate reductase ternary complexes reduced with nicotinamide adenine dinucleotide phosphate and the very tight-binding inhibitor PT523.". Biochemistry 36 (45): 13897–903. doi:10.1021/bi971711l. PMID 9374868.
- Vanguri VK, Wang S, Godyna S, et al. (2001). "Thrombospondin-1 binds to polyhistidine with high affinity and specificity.". Biochem. J. 347 (Pt 2): 469–73. doi:10.1042/0264-6021:3470469. PMID 10749676.
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