Dihydrofolate reductase

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Dihydrofolate reductase
Ribbon diagram of human dihydrofolate reductase in complex with folate (blue). From PDB 1DRF.
Identifiers
Symbol(s) DHFR;
External IDs OMIM: 126060 MGI: 94890 Homologene: 56470
EC number 1.5.1.3
Orthologs
Human Mouse
Entrez 1719 13361
Ensembl na ENSMUSG00000021707
Uniprot na Q544T5
Refseq NM_000791 (mRNA)
NP_000782 (protein) 		NM_010049 (mRNA)
NP_034179 (protein)
Location na Chr 13: 93.46 - 93.49 Mb
Pubmed search [1] [2]

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Overview

Dihydrofolate reductase, or DHFR, 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.


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. Dihydrofolate reductase deficiency has been linked to megaloblastic anemia.[1]

Folic acid

Dihydrofolic acid

Tetrahydrofolic acid

Tetrahydrofolate synthesis pathway
Tetrahydrofolate synthesis pathway


Clinical significance

Because tetrahydrofolate, the product of this reaction, is the active form of folate in humans, inhibition of DHFR can cause functional folate deficiency. Because folate is needed by rapidly dividing cells to make thymine, this effect may be therapeutic. For example, methotrexate is used as cancer chemotherapy because it can prevent neoplastic cells from dividing.

A variety of drugs act on dihydrofolate reductase:

Deficiency of the enzyme may be a cause of folate deficiency, and therefore of megaloblastic anemia. Treatment is with reduced forms of folic acid.

References

Further reading

  • 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. 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. 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. 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. 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. 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. 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. 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. 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. PMID 10749676.

External links


v • d • e
CH-NH oxidoreductases (EC 1.5)
1.5.1 - NAD or NADP acceptorDihydrofolate reductase - Saccharopine dehydrogenase - Methylenetetrahydrofolate reductase
1.5.3 - oxygen acceptorDihydrobenzophenanthridine oxidase - Sarcosine oxidase
1.5.5 - quinone acceptorElectron-transferring-flavoprotein dehydrogenase

Template:Metabolism of vitamins, coenzymes, and cofactors

bg:Дихидрофолатредуктаза de:Dihydrofolatreduktase it:Diidrofolato reduttasi he:DHFR no:Dihydrofolat reduktase

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Acknowledgement and Attribution Regarding Sources of Content

Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .

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