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IUBMB CommentsThe enzyme from animals and some micro-organisms also slowly reduces folate to 5,6,7,8-tetrahydrofolate.
The taxonomic range for the selected organisms is: Gallus gallus
The enzyme appears in selected viruses and cellular organisms
Synonyms
dhfr, dihydrofolate reductase, thy-1, dhfr-ts, hdhfr, dihydrofolate reductase-thymidylate synthase, ecdhfr, pcdhfr, r67 dhfr, ts-dhfr,
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7,8-dihydrofolate reductase
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dehydrogenase, tetrahydrofolate
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dihydrofolate reductase-thymidylate synthase
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dihydrofolate reductase:thymidylate synthase
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dihydrofolic acid reductase
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dihydrofolic reductase
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folic acid reductase
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NADPH-dihydrofolate reductase
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pteridine reductase:dihydrofolate reductase
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reductase, dihydrofolate
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tetrahydrofolate dehydrogenase
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thymidylate synthetase-dihydrofolate reductase
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Trimethoprim resistance protein
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
inhibitor binding mechanism
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5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase
The enzyme from animals and some micro-organisms also slowly reduces folate to 5,6,7,8-tetrahydrofolate.
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7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
water can serve as the Bronsted acid for the protonation of N5 of dihydrofolate during DHFR catalyzed reduction
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7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
8-methylpterin + NADPH
8-methyl-7,8-dihydropterin + NADP+
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subsequently reduced more slowly and incompletely to 8-methyl-5,6,7,8-tetrahydropterin
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folate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
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additional information
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equilibrium strongly favors tetrahydrofolate production
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7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
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7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
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maintainance of adequate levels of fully reduced folate in metabolism of proliferating cells
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7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
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maintainance of adequate levels of fully reduced folate in metabolism of proliferating cells
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NADH
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chicken liver: at neutral pH specific for NADPH and 7,8-dihydrofolate, at acid pH: NADH + 7,8-dihydrofolate and folate + NADPH
NADPH
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NADPH
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cofactor-enzyme interaction study from x-ray structure, structural and topological comparison with dehydrogenases
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organic mercurials
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animal enzyme: activated, bacterial enzyme: unaffected or inhibited
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2,4-diamino-5,6-dihydro-6,6-dimethyl-5-(4'-methoxyphenyl)-s-triazine
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2,4-Diamino-5-adamantylpyrimidine
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weak inhibition
2,4-Diamino-5-benzylpyrimidines
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2,4-Diamino-5-phenyl-s-triazines
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4,6-Diamino-1,2-dihydro-2,2-dimethyl-1-(phenylalkylphenyl)-s-triazines
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bearing a terminal sulfonyl fluoride
citrate
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in acid pH range: inhibitor of reduction of 7,8-dihydrofolate but not folate
methotrexate
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methotrexate
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also ornithine, lysine and dansyl analogs of methotrexate
additional information
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overview
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additional information
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overview
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additional information
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overview: design of inhibitors from X-ray crystal structures
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additional information
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stereochemistry of inhibitor binding
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additional information
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stereochemistry of inhibitor binding
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Urea
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increase in Km and kcat values for 7,8-dihydrofolate and NADPH
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0.00015
7,8-dihydrofolate
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with NADPH
0.03 - 0.2
8-Methylpterin
additional information
additional information
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0.03
8-Methylpterin
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pH 5.0
0.2
8-Methylpterin
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pH 7.4
additional information
additional information
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overview
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additional information
additional information
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overview
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additional information
additional information
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Km of enzymes with decreased binding of folate and antagonists and of drug-sensitive enzymes
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5
7,8-dihydrofolate
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pH 7.4
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0.0000037
2,4-diamino-5,6-dihydro-6,6-dimethyl-5-(4'-methoxyphenyl)-s-triazine
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additional information
additional information
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additional information
additional information
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additional information
additional information
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additional information
additional information
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folate antagonists
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additional information
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enzyme assay
additional information
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overview
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4
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7,8-dihydrofolate + NADPH, 2 optima: pH 4 and pH 7.4
5.2 - 5.5
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7,8-dihydrofolate + NADH
5.8 - 6
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8-methylpterin + NADPH
7.4
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7,8-dihydrofolate + NADPH, 2 optima: pH 4.0 and pH 7.4
additional information
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overview
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additional information
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overview
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Uniprot
brenda
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brenda
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brenda
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DYR_CHICK
189
0
21650
Swiss-Prot
other Location (Reliability: 2)
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21650
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amino acid sequence
23000
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sedimentation equilibrium studies, sucrose density gradient experiments, aminopterin titration
additional information
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overview
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monomer
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monomer
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1 * 21650, amino acid sequence
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crystal structure, complex with 2,4-diamino-5,6-dihydro-6,6-dimethyl-5-(4'-methoxyphenyl)-s-triazine
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structure of ternary complex with NADPH and trimethoprim, model development
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6 - 8
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maximal stability
392274
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N5-formyltetrahydrofolate, NADP+ and NADPH stabilize and protect against heat inactivation
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-60°C, 0.02 mM NADPH, 3 months, frequent freezing and thawing, stable
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via methotrexate-amino-ethyl starch
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medicine
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enzyme is a target of several anti-folate inhibitory drugs to combat bacteria, protozoa and cancer
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Kraut, J.; Matthews, D.A.
Dihydrofolate reductase
Biol. Macromol. and Assem. (Junak, F. , McPherson, eds. )
3
1-71
1987
Klebsiella aerogenes, Bacteria, Gallus gallus, Escherichia coli, Homo sapiens, Lacticaseibacillus casei, Mus musculus, Pigeon, protozoa, vertebrata
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brenda
Freisheim, J.H.; Matthews, D.A.
The comparative biochemistry of dihydrofolate reductase
Folate Antagonists Ther. Agents (Sirotnak, F. M. , ed. )
1
69-131
1984
Bacteria, Tequatrovirus T4, Bos taurus, Gallus gallus, Crithidia fasciculata, Streptococcus pneumoniae, Escherichia coli, Enterococcus faecium, Homo sapiens, Lacticaseibacillus casei, Mammalia, Mus musculus, protozoa, Sus scrofa, vertebrata
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brenda
Roth, B.; Bliss, E.; Beddell, C.R.
Inhibitors of dihydrofolate reductase
Top. Mol. Struct. Biol.
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363-393
1983
Bos taurus, Gallus gallus, Escherichia coli, Enterococcus faecium, Homo sapiens, Lacticaseibacillus casei, Sus scrofa
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brenda
Roth, B.
Design of dihydrofolate reductase inhibitors from X-ray crystal structures
Fed. Proc.
45
2765-2772
1986
Gallus gallus, Escherichia coli, Lacticaseibacillus casei
brenda
Kaufman, B.T.
Methotrexate-agarose in the purification of dihydrofolate reductase
Methods Enzymol.
34
272-281
1974
Tequatrovirus T4, Bos taurus, Saccharomyces cerevisiae, Gallus gallus, Cricetulus sp., Escherichia coli, Lacticaseibacillus casei, Mus musculus, Rattus norvegicus, Salmonella enterica subsp. enterica serovar Typhimurium
brenda
Huennekens, F.M.; Vitols, K.S.; Whiteley, J.M.; Neef, V.G.
Dihydrofolate reductase
Methods Cancer Res.
13
199-225
1976
Tequatrovirus T4, Bos taurus, Gallus gallus, Cricetulus sp., Escherichia coli, Enterococcus faecalis, Enterococcus faecium, Lacticaseibacillus casei, Mammalia, Mus musculus, Sus scrofa
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brenda
Thibault, V.; Koen, M.J.; Gready, J.E.
Enzymic properties of a new mechanism-based substrate for dihydrofolate reductase
Biochemistry
28
6042-6049
1989
Bos taurus, Gallus gallus, Homo sapiens
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brenda
Mell, G.P.; Whiteley, J.M.; Huennekens, F.M.
Purification of dihydrofolate reductase via amethopterin-aminoethyl starch
J. Biol. Chem.
243
6074-6075
1968
Gallus gallus
brenda
Kumar, A.A.; Blankenship, D.T.; Kaufman, B.T.; Freisheim, J.H.
Primary structure of chicken liver dihydrofolate reductase
Biochemistry
19
667-678
1980
Gallus gallus
brenda
Kaufman, B.T.; Gardiner, R.C.
Studies on dihydrofolic reductase. I. Purification and properties of dihydrofolic reductase from chicken liver
J. Biol. Chem.
241
1319-1328
1966
Gallus gallus
brenda
Shrimpton, P.; Mullaney, A.; Allemann, R.K.
Functional role for Tyr 31 in the catalytic cycle of chicken dihydrofolate reductase
Proteins
51
216-223
2003
Gallus gallus (P00378), Gallus gallus
brenda