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Information on EC 1.5.1.3 - dihydrofolate reductase
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1.5.1.3 dihydrofolate reductaseIUBMB Comments
The enzyme from animals and some micro-organisms also slowly reduces folate to 5,6,7,8-tetrahydrofolate.
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Word Map
- 1.5.1.3
- methotrexate
- antifolate
- plasmodium
- falciparum
- hamster
- malaria
- pyrimethamine
- ovary
-
antimalarial
- leukemia
- dihydropteroate
- thymidine
- pyrimidine
- carinii
- polyglutamates
- pneumocystis
-
hydride
- chloroquine
-
casey
-
drug-resistant
- tmp
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ccrf-cem
- vivax
- glycinamide
- toxoplasma
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uncomplicated
-
folate-dependent
- mthfr
- folylpolyglutamate
- pemetrexed
-
sublines
- leucovorin
- tetrahydrobiopterin
-
polyglutamylation
- gondii
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nontranscribed
- sulfamethoxazole
- trimethoprim-sulfamethoxazole
- quinazoline
- 5-methyltetrahydrofolate
- sepiapterin
- integrons
- dihydropteridine
- analysis
- medicine
- artesunate
- synthesis
-
triazine
-
folinic
- 5,10-methylenetetrahydrofolate
- bh4
- biotechnology
- biopterins
- drug development
- pterins
The enzyme appears in 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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topREACTION 
REACTION DIAGRAM
COMMENTARY 
ORGANISM
UNIPROT
LITERATURE
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
kinetic mechanism
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
rapid equilibrium random mechanism
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
catalytic mechanism
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
catalytic mechanism
-
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
catalytic mechanism
-
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
catalytic mechanism
-
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
catalytic mechanism
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
catalytic mechanism
protozoa
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
bifunctional proteins with DHFR and thymidylate synthase activity
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
bifunctional proteins with DHFR and thymidylate synthase activity
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
bifunctional proteins with DHFR and thymidylate synthase activity
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
pteridine-binding site
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
rapid random equilibrium mechanism with NADPH and reduced acetylpyridine adenine nucleotide as cofactor
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
cofactor binding mechanism, pH-dependence investigation
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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+ = 7,8-dihydrofolate + NADPH + H+
inhibitor binding mechanism
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
inhibitor binding mechanism
-
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
inhibitor binding mechanism
-
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
inhibitor binding mechanism
-
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
inhibitor binding mechanism
-
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
inhibitor binding mechanism
-
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
inhibitor binding mechanism
Pigeon
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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+ = 7,8-dihydrofolate + NADPH + H+
inhibitor binding mechanism
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
substrate and cofactor binding mechanism
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
substrate and antifolate inhibitor methotrexate binding, modeling of three-dimensional structure
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
analysis of higher energy conformational substrates by NMR relaxation dispersion. The maximum hydride transfer and steady-state turnover rates are governed by the dynamics of transitions between ground and excited states of the intermediates. Model of conformational changes during the catalytic cycle
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
donor carbon at the hydride transfer transition state resembles the reactant state more than the product state, whereas the acceptor carbon is more productlike, a symptom of transition state imbalance
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
kinetic isotope effect analysis, enzyme requires no no donor-acceptor distance fluctuations and thus no gating
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
model for hydrogen transfer includes contributions from quantum mechanical tunnelling coupled with protein motions that actively modulate the tunnelling distance
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
ordered kinetic mechanism at elevated temperature around 60°C, with NADPH binding first. More random mechanism at temperatures around 20°C with greatly reduced Km-value for 7,8-dihydrofolate. Rate-limiting hydride-transfer with a moderate enthalpy of activiation
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
study on enzyme ternary complex with substrate analogue folates and oxidized NADP+ cofactor using NMR relaxation methods. Conformational exchanges of protein between a ground state with closed conformation of active site loops and an excited state with loops in occluded conformation. Fluctuations include motions of the nicotinamide ring of the cofactor into and out of the active site
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
binding of NADPH is accompanied by release of 38 water molecules, while binding of dihydrofolate is accompanied by the net uptake of water
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
in Plasmodium bifunctional thymidylate synthase-dihydrofolate reductase, the overall rate-limiting step is thymidylate synthase catalysis.If thymidylate synthase is in an activated liganded conformation, the dihydrofolate reductase is 2-fold activated. The thymidylate synthase rate is also reciprocally activated by 1.5-fold if dihydrolfolate reductase is in an activated, ligand-bound conformation
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
the active-site loop dynamics access a closed conformation, and the accompanying closed to occluded rate constant is comparable to the maximum pH-independent hydride transfer rate constant. The closed to occluded conformational transition in the product ternary complex is a prerequisite for progression through the catalytic cycle. The rate of this process places an effective limit on the maximum rate of the hydride transfer step. The dynamics of the C-terminally associated region is pH-dependent, but the dynamics of the active-site loops and cofactor binding cleft are pH-independent
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
Ala16, Ile51, Cys59, Ser108 and Ile164 are active site residues
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
Ala16, Ile51, Cys59, Ser108 and Ile164 are active site residues, catalytic mechanism, overview
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
the product (tetrahydrofolate) dissociation step that is the rate-limiting step in Escherichia coli DHFR is significantly accelerated in spDHFR so that hydride transfer or a preceding step is rate-limiting
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
transfer of a proR hydride from the C4 atom of NADPH to the C6 position of the dihydropterin ring of DHF, mechanism of the proton and hydride transfer reaction, active site residues D27 and Y100 play a synergistic role in facilitating both the proton transfer and subsequent hydride transfer steps. Residue D27 appears to have a greater effect on the overall rate of conversion of DHF to tetrahydrofolate, Y100 plays an important electrostatic role in modulating the pKa of the N5 of DHF to enable the preprotonation of DHF by an active site water molecule. The D27 and Y100 residues function synergistically to provide an active site environment for the solvent-assisted protonation of N5 and to position the reacting substrates, NADPH and DHF, properly
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
in Plasmodium bifunctional thymidylate synthase-dihydrofolate reductase, the overall rate-limiting step is thymidylate synthase catalysis.If thymidylate synthase is in an activated liganded conformation, the dihydrofolate reductase is 2-fold activated. The thymidylate synthase rate is also reciprocally activated by 1.5-fold if dihydrolfolate reductase is in an activated, ligand-bound conformation
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
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