Dihydrofolate reductase: Definition from Answers.com

Dihydrofolate reductase

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

Gene ontology
Molecular function	• dihydrofolate reductase activity • oxidoreductase activity • NADP binding
Cellular component	• cellular_component
Biological process	• glycine biosynthetic process • one-carbon compound metabolic process • nucleotide biosynthetic process

Orthologs

Species

Human

Mouse

RefSeq

NM_000791 (mRNA)

NM_010049 (mRNA)

NP_000782 (protein)

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 that 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]

1 Function
2 Clinical significance
3 Therapeutic application
4 Interactions
5 References
6 Further reading
7 External links

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]

Reaction catalyzed by DHFR.

Tetrahydrofolate synthesis pathway.

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.

Therapeutic application

Main article: Dihydrofolate reductase inhibitor

Since folate is needed by rapidly dividing cells to make thymine, this effect may be used to therapeutic advantage.

Interactions

Dihydrofolate reductase has been shown to interact with GroEL^[4] and Mdm2.^[5]

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.
^ Mayhew, M; da Silva A C, Martin J, Erdjument-Bromage H, Tempst P, Hartl F U (Feb. 1996). "Protein folding in the central cavity of the GroEL-GroES chaperonin complex". Nature (ENGLAND) 379 (6564): 420-6. doi:10.1038/379420a0. ISSN 0028-0836. PMID 8559246.
^ Maguire, Maria; Nield Paul C, Devling Timothy, Jenkins Rosalind E, Park B Kevin, Polański Radoslaw, Vlatković Nikolina, Boyd Mark T (May. 2008). "MDM2 regulates dihydrofolate reductase activity through monoubiquitination". Cancer Res. (United States) 68 (9): 3232-42. doi:10.1158/0008-5472.CAN-07-5271. PMID 18451149.

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.

PDB Gallery

1boz: STRUCTURE-BASED DESIGN AND SYNTHESIS OF LIPOPHILIC 2,4-DIAMINO-6-SUBSTITUTED QUINAZOLINES AND THEIR EVALUATION AS INHIBITORS OF DIHYDROFOLATE REDUCTASE AND POTENTIAL ANTITUMOR AGENTS

1dhf: CRYSTAL STRUCTURES OF RECOMBINANT HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH FOLATE AND 5-DEAZOFOLATE

1dlr: METHOTREXATE-RESISTANT VARIANTS OF HUMAN DIHYDROFOLATE REDUCTASE WITH SUBSTITUTION OF LEUCINE 22: KINETICS, CRYSTALLOGRAPHY AND POTENTIAL AS SELECTABLE MARKERS

1dls: METHOTREXATE-RESISTANT VARIANTS OF HUMAN DIHYDROFOLATE REDUCTASE WITH SUBSTITUTION OF LEUCINE 22: KINETICS, CRYSTALLOGRAPHY AND POTENTIAL AS SELECTABLE MARKERS

1drf: CRYSTAL STRUCTURE OF HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH FOLATE

1hfp: COMPARISON OF TERNARY CRYSTAL COMPLEXES OF HUMAN DIHYDROFOLATE REDUCTASE WITH NADPH AND A CLASSICAL ANTITUMOR FUROPYRIMDINE

1hfq: COMPARISON OF TERNARY CRYSTAL COMPLEXES OF HUMAN DIHYDROFOLATE REDUCTASE WITH NADPH AND A CLASSICAL ANTITUMOR FUROPYRIMDINE

1hfr: COMPARISON OF TERNARY CRYSTAL COMPLEXES OF HUMAN DIHYDROFOLATE REDUCTASE WITH NADPH AND A CLASSICAL ANTITUMOR FUROPYRIMDINE

1kms: HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND 6-([5-QUINOLYLAMINO]METHYL)-2,4-DIAMINO-5-METHYLPYRIDO[2,3-D]PYRIMIDINE (SRI-9439), A LIPOPHILIC ANTIFOLATE

1kmv: HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND (Z)-6-(2-[2,5-DIMETHOXYPHENYL]ETHEN-1-YL)-2,4-DIAMINO-5-METHYLPYRIDO[2,3-D]PYRIMIDINE (SRI-9662), A LIPOPHILIC ANTIFOLATE

1mvs: Analysis of Two Polymorphic Forms of a Pyrido[2,3-d]pyrimidine N9-C10 Reverse-Bridge Antifolate Binary Complex with Human Dihydrofolate Reductase

1mvt: Analysis of Two Polymorphic Forms of a Pyrido[2,3-d]pyrimidine N9-C10 Reverse-Bridge Antifolate Binary Complex with Human Dihydrofolate Reductase

1ohj: HUMAN DIHYDROFOLATE REDUCTASE, MONOCLINIC (P21) CRYSTAL FORM

1ohk: HUMAN DIHYDROFOLATE REDUCTASE, ORTHORHOMBIC (P21 21 21) CRYSTAL FORM

1pd8: Analysis of Three Crystal Structure Determinations of a 5-Methyl-6-N-Methylanilino Pyridopyrimidine Antifolate Complex with Human Dihydrofolate Reductase

1pd9: Analysis of Three Crystal Structure Determinations of a 5-Methyl-6-N-Methylanilino Pyridopyrimidine antifolate Complex with Human Dihydrofolate Reductase

1pdb: Analysis of Three Crystal Structure Determinations of a 5-Methyl-6-N-Methylanilino Pyridopyrimidine Antifolate Complex with Human Dihydrofolate Reductase

1s3u: Structure Determination of Tetrahydroquinazoline Antifolates in Complex with Human and Pneumocystis carinii Dihydrofolate Reductase: Correlations of Enzyme Selectivity and Stereochemistry

1s3v: Structure Determination of Tetrahydroquinazoline Antifolates in Complex with Human and Pneumocystis carinii Dihydrofolate Reductase: Correlations of Enzyme Selectivity and Stereochemistry

1s3w: Structure Determination of Tetrahydroquinazoline Antifoaltes in Complex with Human and Pneumocystis carinii Dihydrofolate Reductase: Correlations of Enzyme Selectivity and Stereochemistry

1u71: Understanding the Role of Leu22 Variants in Methotrexate Resistance: Comparison of Wild-type and Leu22Arg Variant Mouse and Human Dihydrofolate Reductase Ternary Crystal Complexes with Methotrexate and NADPH

1u72: Understanding the Role of Leu22 Variants in Methotrexate Resistance: Comparison of Wild-type and Leu22Arg Variant Mouse and Human Dihydrfolate Reductase Ternary Crystal Complexes with Methotrexate and NADPH

1yho: Solution structure of human dihydrofolate reductase complexed with trimethoprim and nadph, 25 structures

2c2s: HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND 2,4-DIAMINO-5-(1-O-CARBORANYLMETHYL)-6-METHYLPYRIMIDINE, A NOVEL BORON CONTAINING, NONCLASSICAL ANTIFOLATE

2c2t: HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND 2,4-DIAMINO-5-((7,8-DICARBAUNDECABORAN-7-YL)METHYL)-6-METHYLPYRIMIDINE, A NOVEL BORON CONTAINING, NONCLASSICAL ANTIFOLATE

2dhf: CRYSTAL STRUCTURES OF RECOMBINANT HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH FOLATE AND 5-DEAZOFOLATE

External links

This EC 1.5 enzyme-related article is a stub. You can help Wikipedia by expanding it.

v • d • e Oxidoreductases: CH-NH (EC 1.5)

1.5.1: NAD or NADP acceptor	Dihydrofolate reductase - Saccharopine dehydrogenase - Methylenetetrahydrofolate reductase

1.5.3: oxygen acceptor	Dihydrobenzophenanthridine oxidase - Sarcosine oxidase - Proline oxidase

1.5.5: quinone acceptor	Electron-transferring-flavoprotein dehydrogenase

Metabolism of vitamins, coenzymes, and cofactors

Fat soluble

Vitamin A	Retinol binding protein

Vitamin D	liver (Sterol 27-hydroxylase or CYP27A1) · renal (25-Hydroxyvitamin D3 1-alpha-hydroxylase or CYP27B1) · degradation (1,25-Dihydroxyvitamin D3 24-hydroxylase or CYP24A1)

Vitamin K	Vitamin K epoxide reductase

Water soluble

Thiamine (B1)	Thiamine pyrophosphokinase

Niacin (B3)	Indoleamine 2,3-dioxygenase · Formamidase

Pantothenic acid (B5)	Pantothenate kinase

Folic acid (B9)	Dihydropteroate synthetase · Dihydrofolate reductase · Serine hydroxymethyltransferase Methylenetetrahydrofolate reductase

Vitamin B12	MMAA · MMAB · MMACHC · MMADHC

Vitamin C	L-gulonolactone oxidase

Tetrahydrobiopterin

GTP cyclohydrolase I · 6-pyruvoyltetrahydropterin synthase · Sepiapterin reductase
PCBD1 · PTS · QDPR

see also vitamins, disorders

Metabolism: amino acid metabolism - nucleotide enzymes

Purine metabolism

Pyrimidine metabolism

Anabolism	CAD (Carbamoyl phosphate synthase II, Aspartate carbamoyltransferase, Dihydroorotase) Dihydroorotate dehydrogenase - Orotidine 5'-phosphate decarboxylase/Uridine monophosphate synthetase CTP synthase

Catabolism	Dihydropyrimidine dehydrogenase - Dihydropyrimidinase/DPYS - Beta-ureidopropionase/UPB1

Deoxyribonucleotides

Ribonucleotide reductase - Nucleoside-diphosphate kinase - DCMP deaminase - Thymidylate synthase - Dihydrofolate reductase

see also disorders, intermediates

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