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Information on EC 1.5.1.3 - dihydrofolate reductase and Organism(s) Gallus gallus and UniProt Accession P00378

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EC Tree
     1 Oxidoreductases
         1.5 Acting on the CH-NH group of donors
             1.5.1 With NAD+ or NADP+ as acceptor
                1.5.1.3 dihydrofolate reductase
IUBMB Comments
The enzyme from animals and some micro-organisms also slowly reduces folate to 5,6,7,8-tetrahydrofolate.
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This record set is specific for:
Gallus gallus
UNIPROT: P00378
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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, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7,8-dihydrofolate reductase
-
-
-
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dehydrogenase, tetrahydrofolate
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-
-
-
DHFR
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-
-
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DHFR type IIIC
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-
-
-
dihydrofolate reductase-thymidylate synthase
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-
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dihydrofolate reductase:thymidylate synthase
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-
-
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dihydrofolic acid reductase
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-
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dihydrofolic reductase
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-
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folic acid reductase
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-
-
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folic reductase
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-
-
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NADPH-dihydrofolate reductase
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-
-
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pteridine reductase:dihydrofolate reductase
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-
-
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reductase, dihydrofolate
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-
-
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tetrahydrofolate dehydrogenase
-
-
-
-
thymidylate synthetase-dihydrofolate reductase
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-
-
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Trimethoprim resistance protein
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-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
show the reaction diagram
inhibitor binding mechanism
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
redox reaction
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-
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oxidation
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reduction
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PATHWAY SOURCE
PATHWAYS
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-, -, -, -
SYSTEMATIC NAME
IUBMB Comments
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.
CAS REGISTRY NUMBER
COMMENTARY hide
9002-03-3
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
show the reaction diagram
water can serve as the Bronsted acid for the protonation of N5 of dihydrofolate during DHFR catalyzed reduction
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
show the reaction diagram
8-methylpterin + NADPH
8-methyl-7,8-dihydropterin + NADP+
show the reaction diagram
-
-
subsequently reduced more slowly and incompletely to 8-methyl-5,6,7,8-tetrahydropterin
?
folate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
show the reaction diagram
-
-
-
-
?
additional information
?
-
-
equilibrium strongly favors tetrahydrofolate production
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
show the reaction diagram
-
maintainance of adequate levels of fully reduced folate in metabolism of proliferating cells
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-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NADH
-
chicken liver: at neutral pH specific for NADPH and 7,8-dihydrofolate, at acid pH: NADH + 7,8-dihydrofolate and folate + NADPH
NADPH
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
organic mercurials
-
animal enzyme: activated, bacterial enzyme: unaffected or inhibited
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
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
aminopterin
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-
citrate
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in acid pH range: inhibitor of reduction of 7,8-dihydrofolate but not folate
methotrexate
NADP+
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-
pyrimethamine
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trimethoprim
-
-
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
Urea
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increase in Km and kcat values for 7,8-dihydrofolate and NADPH
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00015
7,8-dihydrofolate
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with NADPH
0.03 - 0.2
8-Methylpterin
0.0067
folate
-
-
additional information
additional information
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
5
7,8-dihydrofolate
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pH 7.4
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0000037
2,4-diamino-5,6-dihydro-6,6-dimethyl-5-(4'-methoxyphenyl)-s-triazine
-
-
additional information
additional information
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
14
-
chicken liver, 28°C
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
3.8
-
folate + NADPH
4
-
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
-
overview
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
-
overview
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
Uniprot
Manually annotated by BRENDA team
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
DYR_CHICK
189
0
21650
Swiss-Prot
other Location (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
21650
-
amino acid sequence
23000
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sedimentation equilibrium studies, sucrose density gradient experiments, aminopterin titration
additional information
-
overview
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
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
-
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6 - 8
-
maximal stability
392274
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
60
-
half-life: 2 min
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
N5-formyltetrahydrofolate, NADP+ and NADPH stabilize and protect against heat inactivation
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-60°C, 0.02 mM NADPH, 3 months, frequent freezing and thawing, stable
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
via methotrexate-amino-ethyl starch
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
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enzyme is a target of several anti-folate inhibitory drugs to combat bacteria, protozoa and cancer
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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
-
Manually annotated by BRENDA team
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
-
Manually annotated by BRENDA team
Roth, B.; Bliss, E.; Beddell, C.R.
Inhibitors of dihydrofolate reductase
Top. Mol. Struct. Biol.
3
363-393
1983
Bos taurus, Gallus gallus, Escherichia coli, Enterococcus faecium, Homo sapiens, Lacticaseibacillus casei, Sus scrofa
-
Manually annotated by BRENDA team
Roth, B.
Design of dihydrofolate reductase inhibitors from X-ray crystal structures
Fed. Proc.
45
2765-2772
1986
Gallus gallus, Escherichia coli, Lacticaseibacillus casei
Manually annotated by BRENDA team
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
Manually annotated by BRENDA team
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
-
Manually annotated by BRENDA team
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
-
Manually annotated by BRENDA team
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
Manually annotated by BRENDA team
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
Manually annotated by BRENDA team
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
Manually annotated by BRENDA team
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
Manually annotated by BRENDA team