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Enzyme Nomenclature
Information on EC 1.5.1.3 - dihydrofolate reductase
for references in articles please use BRENDA:EC1.5.1.3
Word Map on EC 1.5.1.3
- 1.5.1.3
- methotrexate
- antifolate
- plasmodium
- falciparum
- hamster
- malaria
- pyrimethamine
- ovary
- leukemia
-
methotrexate-resistant
- pyrimidine
-
antimalarial
- dihydropteroate
-
casey
- thymidine
- chloroquine
- tmp
- carinii
- pneumocystis
-
hydride
- polyglutamates
-
drug-resistant
-
folylpolyglutamate
- tetrahydrobiopterin
-
subline
-
folate-dependent
- leucovorin
-
ccrf-cem
- glycinamide
-
uncomplicated
- gondii
- toxoplasma
- pemetrexed
- vivax
- synthesis
-
tanzania
-
integrons
- pterins
- sepiapterin
- dihydropteridine
- bh4
-
folinic
- sulfamethoxazole
- medicine
- trimethoprim-sulfamethoxazole
- analysis
- quinazoline
- 5-methyltetrahydrofolate
-
triazine
-
nontranscribed
- drug development
- 5,10-methylenetetrahydrofolate
- artesunate
- biotechnology
- biopterins
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The enzyme appears in viruses and cellular organisms
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EC NUMBER 
COMMENTARY 
1.5.1.3
-
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RECOMMENDED NAME
GeneOntology No.
dihydrofolate reductase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
catalytic mechanism; rapid equilibrium random mechanism; substrate and cofactor binding 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
-
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
protozoa
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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+
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
-
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
-
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+
catalytic mechanism; cofactor binding mechanism, pH-dependence investigation
-
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
pteridine-binding site
-
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
kinetic mechanism; rapid random equilibrium mechanism with NADPH and reduced acetylpyridine adenine nucleotide as cofactor
-
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
bifunctional proteins with DHFR and thymidylate synthase activity
-
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
bifunctional proteins with DHFR and thymidylate synthase activity
-
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
bifunctional proteins with DHFR and thymidylate synthase activity
-
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
substrate and antifolate inhibitor methotrexate binding, modeling of three-dimensional structure
-
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
-
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
-
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+
kinetic isotope effect analysis, enzyme requires no no donor-acceptor distance fluctuations and thus no gating
-
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
analysis of higher energy conformational substates 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+
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+
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+
Ala16, Ile51, Cys59, Ser108 and Ile164 are active site residues
-
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
Ala16, Ile51, Cys59, Ser108 and Ile164 are active site residues, catalytic mechanism, overview
-
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+
-
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
reduction
-
-
-
-
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
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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.
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CAS REGISTRY NUMBER
COMMENTARY
9002-03-3
-
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
trimethoprim-susceptible strain PC 174 and trimethoprim-resistant strain PC 178
-
-
Pigeon
protozoa
chinese hamster, methotrexate-sensitive and methotrexate-resistant cells
-
-
bifunctional enzyme: dihydrofolate reductase-thymidylate synthase EC 2.1.1.45
-
-
wild carrot, enzyme complex with dihydrofolate reductase activity, thymidylate synthase activity and three other polypeptides of unknown function
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-
2 forms termed mutant type and wild-type enzyme in a single organism; amethopterin-resistant strain; var. durans
-
-
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392207, 392210, 392212, 392213, 392214, 392217, 392218, 392220, 392222, 392226, 392241, 392277, 654970, 655867, 671581, 674153, 674351, 676824, 687305, 687933, 688397, 689954, 693567, 705044, 712320, 724168, 724382, 724390
-
-
-
654202, 654738, 671846, 672009, 674549, 675312, 676788, 676936, 677124, 685285, 685386, 685625, 687680, 688349, 688388, 689903, 701696, 703803, 711480, 724416, 725204, 742438, 742491, 743678
Uniprot
extremely halophilic archaebacterium; isozyme hDHFR-1 from gene hdrA and isozyme hDHFR-2 from gene hdrB
-
-
-
655633, 671040, 671315, 672523, 684271, 684287, 685519, 685955, 686360, 687287, 687840, 688238, 689753, 702155, 702500, 702667, 702999, 703158, 705018, 705451, 705800
-
-
-
675293, 686154, 688285, 688294, 688381, 689773, 689962, 693567, 701531, 702275, 703803, 705044, 710914, 711459, 741536, 741613, 741615, 742518, 743213, 743758
UniProt
c.86 + 60_78 insertion/deletion polymorphism is associated with serum and red blood cell folate concentrations in women
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methotrexate-resistant WIL-2 lymphoblastoid cells
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methotrexate-resistant WIL-2 lymphoblastoid cells; methotrexate-sensitive cell line HeLa BU-25, methotrexate-insensitive cell line VA2-B
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mothers of a spina bifida affected child, spina biWda patients, and controls
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bifunctional enzyme dihydrofolate reductase-thymidylate synthase; methotrexate-resistant strain with altered enzyme
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-
methotrexate resistant bifunctional enzyme: thymidylate synthase-dihydrofolate reductase
-
-
bifunctional enzyme: dihydrofolate reductase-thymidylate synthase EC 2.1.1.45
-
-
-
-
-
bifunctional thymidylate synthase-dihydrofolate reductase
Uniprot
isolated from Sudanese patients treated with sulphadoxine/pyrimethamine or sulphadoxine/pyrimethamine plus chloroquine
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-
fragment; bifunctional dihydrofolate reductase-thymidylate synthase
UniProt
phage type 179, R-plasmid enzyme, isozyme type III
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green algae, thymidylate synthase and dihydrofolate reductase cannot be dissociated from each other
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bifuntional enzyme with dihydrofolate reductase and thymidylate synthase activity; trimethoprim-resistant strain
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-
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
alignment analysis shows several substitutions between Schistosoma mansoni and human DHFR at both the folate- and NADP+-binding sites. The folate-binding site exhibits two differences at three residues (human DHFR numbering): E30D and N64F. The NADP+-binding site exhibits six substitutions at 11 residues: D21G,K54R, K55V, R76S, E77T and S118Y
evolution
Leishmania braziliensis subsp. viannia
dihydrofolate reductase (DHFR) and thymidylate synthase (TS) have undergone a fusion event generating a single polypeptide but conserving the two functions in trypanosomatids
evolution
dihydrofolate reductase (DHFR) and thymidylate synthase (TS) have undergone a fusion event generating a single polypeptide but conserving the two functions in trypanosomatids
evolution
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dihydrofolate reductase (DHFR) and thymidylate synthase (TS) have undergone a fusion event generating a single polypeptide but conserving the two functions in trypanosomatids
evolution
identification of a second functional dihydrofolate reductase enzyme in humans, DHFRL1. RNA-mediated DHFR duplication events occur across the mammal tree. Dihydrofolate reductase activity is also a feature of the mitochondria in both rat and mouse but this is not due to a second enzyme. Humans have evolved the need for two separate enzymes, while laboratory rats and mice have just one. RNA-mediated DHFR duplicates in brown rat and mouse are likely to be processed pseudogenes; identification of a second functional dihydrofolate reductase enzyme in humans, DHFRL1. RNA-mediated DHFR duplication events occur across the mammal tree. Dihydrofolate reductase activity is also a feature of the mitochondria in both rat and mouse but this is not due to a second enzyme. Humans have evolved the need for two separate enzymes, while laboratory rats and mice have just one. RNA-mediated DHFR duplicates in brown rat and mouse are likely to be processed pseudogenes
evolution
-
identification of a second functional dihydrofolate reductase enzyme in humans, DHFRL1. RNA-mediated DHFR duplication events occur across the mammal tree. Dihydrofolate reductase activity is also a feature of the mitochondria in both rat and mouse but this is not due to a second enzyme. Humans have evolved the need for two separate enzymes, while laboratory rats and mice have just one. RNA-mediated DHFR duplicates in brown rat and mouse are likely to be processed pseudogenes
evolution
-
identification of a second functional dihydrofolate reductase enzyme in humans, DHFRL1. RNA-mediated DHFR duplication events occur across the mammal tree. Dihydrofolate reductase activity is also a feature of the mitochondria in both rat and mouse but this is not due to a second enzyme. Humans have evolved the need for two separate enzymes, while laboratory rats and mice have just one. RNA-mediated DHFR duplicates in brown rat and mouse are likely to be processed pseudogenes
malfunction
-
inhibition of the enzyme activity leads to arrest of DNA synthesis and hence cell death
malfunction
inhibition of DHFR leads to the depletion of tetrahydrofolate and eventual cell death; inhibitor trimethoprim shows loss potency and NADPH synergy on binding S1 mutant DHFR. Mutation of residues Y98F/A43G in S1 mutant restores trimethoprim sensitivity and NADPH synergy
malfunction
-
enzyme knockdown results in the abnormal developments of zebrafish embryos in the early stages. Obvious malformations in heart and outflow tract are also observed in knockdown embryos. Enzyme knockdown causes reduced cell proliferation and increased apoptosis
metabolism
DHFR is a critical enzyme in the maintenance of reduced folate pools used in the biosynthetic pathways of purines, thymidylate, methionine, glycine, pantothenic acid, and N-formyl-methionyl tRNA
metabolism
dihydrofolate reductase (DHFR) is involved in the thymidylate and is essential for nucleotide metabolism
metabolism
-
enzyme DHFR is a pivotal enzyme in the thymidine and purine synthesis pathway
physiological function
-
dihydrofolate reductase is an enzyme with a pivotal role in the synthesis of intracellular tetrahydrofolic acid, which is essential in the synthesis of purines, some amino acids, and thymidine. DHFR is the sole source of tetrahydrofolic acid
physiological function
-
dihydrofolate reductase is an enzyme with a pivotal role in the synthesis of intracellular tetrahydrofolic acid, which is essential in the synthesis of purines, some amino acids, and thymidine. DHFR is the sole source of tetrahydrofolic acid
physiological function
-
dihydrofolate reductase is an enzyme with a pivotal role in the synthesis of intracellular tetrahydrofolic acid, which is essential in the synthesis of purines, some amino acids, and thymidine. DHFR is the sole source of tetrahydrofolic acid
physiological function
-
DHFR is essential for the survival and pathogenesis of anthrax. DHFR is required for de novo DNA synthesis and amino acid synthesis
physiological function
-
tetrahydrofolate is a precursor of cofactors necessary for the synthesis of thymidylate, purine nucleotides,methionine, serine, and glycine required for DNA, RNA, and protein synthesis
physiological function
DHFR is the enzyme responsible for the NADPH-dependent reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate, an essential cofactor in the synthesis of purines, thymidylate, methionine, and other key metabolites. DHFR is a critical enzyme in the maintenance of reduced folate pools used in the biosynthetic pathways of purines, thymidylate, methionine, glycine, pantothenic acid, and N-formyl-methionyl tRNA
physiological function
-
dihydrofolate reductase is required for the development of heart and outflow tract in zebrafish. Enzyme overexpression promotes cell proliferation and inhibited apoptosis
physiological function
-
several parasitic protozoa, including Toxoplasma gondii, contain a unique bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) having the catalytic activities contained on a single polypeptide chain in contrast to the human enzyme. Three-dimensional structures of Toxoplasma gondii enzyme TS-DHFR and of a loop truncated TS-DHFR enzyme, removing several flexible surface loops in the DHFR domain, shows that the TS-DHFR homodimer includes a junctional region containing a linked crossover helix between the DHFR domains of the two adjacent monomers, a long linker connecting the TS and DHFR domains, and a DHFR domain that is positively charged. The crystal structure suggests that the positively charged DHFR domain governs this electrostatically mediated movement of dihydrofolate, preventing release from the enzyme. Importance of this region not only in DHFR catalysis but also in modulating the distal TS activity suggests a role for TS-DHFR interdomain interactions
physiological function
Leishmania braziliensis subsp. viannia
dihydrofolate reductase is an essential enzyme in the tetrahydrofolate pathway which catalyzes the NADPH-dependent reduction of 7,8-dihydrofolate (H2F) to the 5,6,7,8-tetrahydrofolate needed to maintain intracellular pools of tetrahydrofolate and its derivatives. These are essential cofactors in the biosynthesis of purines, pyrimidines and several amino acids
physiological function
dihydrofolate reductase is an essential enzyme in the tetrahydrofolate pathway which catalyzes the NADPH-dependent reduction of 7,8-dihydrofolate (H2F) to the 5,6,7,8-tetrahydrofolate needed to maintain intracellular pools of tetrahydrofolate and its derivatives. These are essential cofactors in the biosynthesis of purines, pyrimidines and several amino acids
physiological function
-
dihydrofolate reductase is an essential enzyme in the tetrahydrofolate pathway which catalyzes the NADPH-dependent reduction of 7,8-dihydrofolate (H2F) to the 5,6,7,8-tetrahydrofolate needed to maintain intracellular pools of tetrahydrofolate and its derivatives. These are essential cofactors in the biosynthesis of purines, pyrimidines and several amino acids
physiological function
dihydrofolate reductase (DHFR) is an enzyme from the folate one-carbon metabolism pathway that plays a role in drug resistance and in reducing the synthetic supplement folic acid and 7,8-dihydrofolate to the active form, tetrahydrofolate; dihydrofolate reductase (DHFR) is an enzyme from the folate one-carbon metabolism pathway that plays a role in drug resistance and in reducing the synthetic supplement folic acid and 7,8-dihydrofolate to the active form, tetrahydrofolate
physiological function
-
dihydrofolate reductase (DHFR) is an enzyme from the folate one-carbon metabolism pathway that plays a role in drug resistance and in reducing the synthetic supplement folic acid and 7,8-dihydrofolate to the active form, tetrahydrofolate
physiological function
-
dihydrofolate reductase (DHFR) is an enzyme from the folate one-carbon metabolism pathway that plays a role in drug resistance and in reducing the synthetic supplement folic acid and 7,8-dihydrofolate to the active form, tetrahydrofolate
physiological function
DHFR-TS is essential for cell survival of Trypanosoma brucei
physiological function
-
the human thymidylate synthase and dihydrofolate reductase catalyse two consecutive reactions in the folate metabolism pathway and are very likely to bind in the same multi-enzyme complex in vivo, substrate channeling occurs between the human thymidylate synthase and dihydrofolate reductase, analysis by protein-protein docking, electrostatics calculations, and Brownian dynamics, overview. The non-covalently non-covalently bound human thymidylate synthase and dihydrofolate reductase are capable of substrate channeling and the formation of the surface electrostatic highway. The substrate channeling efficiency between the two can be reasonably high and comparable to that of the bifunctional protozoan enzyme
physiological function
-
DHFR-TS is essential for cell survival of Trypanosoma brucei
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additional information
the DHFR enzyme structure exhibits the canonical DHFR fold
additional information
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the DHFR enzyme structure exhibits the canonical DHFR fold
additional information
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homology model of enzyme pjDHFR in ternary complex with NADPH and inhibitor 2,4-diamino-6-[(2',5'-dichloro anilino)methyl]pyrido[2,3-d]pyrimidine
additional information
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DHFR domain structure analysis, the domain consists of 252 residues from the N-terminus to the start of the junctional region, overview
additional information
role for water in stabilizing the DHFR substrate pocket and of Cys52, overview
additional information
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analysis of the orientation of residues Y100, D27, M20, and the ligands in the active site of ecDHFR, PDB ID 1rx2
additional information
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the predicted specificity determining positions in BmDHFR for ligand binding are Val5, Gly12, Met27, Asn44, Ala45, Lys51, Phe60, Val84, Phe89 Leu95, Leu96, Gly133, Ala137, Val139, Phe140, Phe141 and Glu169
additional information
-
in vitro, one human thymidylate synthase dimer binds to up to six human dihydrofolate reductase monomers, protein-protein docking process, overview. Existence of bound-state conformations of the human DHFR and TS proteins where a continuous positive surface potential region, connecting the TS and DHFR active sites, is formed
additional information
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role for water in stabilizing the DHFR substrate pocket and of Cys52, overview
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
6-hydroxymethylpterin + NADPH
6-hydroxymethyl-7,8-dihydropterin + NADP+
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-
-
-
?
7,8-dihydrofolate + acetylpyridine adenine nucleotide, reduced
5,6,7,8-tetrahydrofolate + acetylpyridine adenine nucleotide, oxidized
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-
-
?
7,8-dihydrofolate + NADH + H+
5,6,7,8-tetrahydrofolate + NAD+
-
-
-
-
?
dihydrobiopterin + NADPH
? + NADP+
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10% of the activity with 7,8-dihydrofolate
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-
?
7,8-dihydrofolate + NADP + H+
5,6,7,8-tetrahydrofolate + NADP+
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assay at 37°C
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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+
-
equilibrium strongly favors tetrahydrofolate production
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?, r
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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directly correlated with thymidylate synthesis
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-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
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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key enzyme in biosynthesis of purines, pyrimidines and several amino acids
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-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
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enzyme plays important role in nucleotide biosynthesis
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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
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
r
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
reverse reaction at only one tenth of forward reaction
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r
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
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clear evidence against dihydrofolate substrate channeling in the bifunctional thymidylate synthase-dihydrofolate reductase
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-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
strongly specific for
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
equilibrium strongly favors tetrahydrofolate production
-
r
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
Enterococcus faecalis R / ATCC 8043
-
-
-
-
ir
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
equilibrium strongly favors tetrahydrofolate production
-
?, r
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
kinetic mechanism
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
equilibrium strongly favors tetrahydrofolate production
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
equilibrium strongly favors tetrahydrofolate production
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
equilibrium strongly favors tetrahydrofolate production
-
r
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
equilibrium strongly favors tetrahydrofolate production
-
r
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
cannot use NADH as reducing agent
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
maintainance of adequate levels of fully reduced folate in metabolism of proliferating cells
-
-
?
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
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
strongly specific for
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
enzyme content of methotrexate-insensitive cell line VA2-B is 200fold higher than that of sensitive cell line HeLa BU-25 due to production of alternate enzyme type
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
key role in thymidylate biosynthesis
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
r
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
equilibrium strongly favors tetrahydrofolate production
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
equilibrium strongly favors tetrahydrofolate production
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
equilibrium strongly favors tetrahydrofolate production
-
r
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
equilibrium strongly favors tetrahydrofolate production
-
r
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
ir
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
bifunctional enzyme DHFR-thymidylate synthase
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
equilibrium strongly favors tetrahydrofolate production
-
?, r
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
r
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
DHFR activity is not essential for virus replication
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
at neutral pH the forward reaction is favored
-
-
r
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
equilibrium strongly favors tetrahydrofolate production
-
-
r
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
equilibrium constant: 320000000000
-
r
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
maintainance of adequate levels of fully reduced folate in metabolism of proliferating cells
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
r
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
at pH 7 hydride transfer is at least partially rate limiting for temperatures below 50°C, at higher temperatures hydride transfer is faster than the steady state
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
DHFR catalyzes hydride transfer from the cofactor NADPH to 7,8-dihydrofolate to produce tetrahydrofolate requiring electrostatic complementarity between the enzyme and the transition state
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
Leishmania braziliensis subsp. viannia
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
the reaction is essential in DNA synthesis
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
Q2YY41
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
the conserved residues Leu28, Val31, Ile50 and Leu54 forming a hydrophobic pocket in the enzyme are the binding site for the p-aminobenzamide moiety of the substrate dihydrofolate
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
8-methylpterin + NADPH
8-methyl-7,8-dihydropterin + NADP+
-
-
subsequently reduced more slowly and incompletely to 8-methyl-5,6,7,8-tetrahydropterin
?
8-methylpterin + NADPH
8-methyl-7,8-dihydropterin + NADP+
-
-
subsequently reduced more slowly and incompletely to 8-methyl-5,6,7,8-tetrahydropterin
?
8-methylpterin + NADPH
8-methyl-7,8-dihydropterin + NADP+
-
-
subsequently reduced more slowly and incompletely to 8-methyl-5,6,7,8-tetrahydropterin
?
folate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
no activity
-
-
-
folate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
Escherichia coli MB 1428 / B / ATCC 11303
-
no activity
-
-
-
folate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
bifunctional enzyme DHFR-thymidylate synthase
-
-
?
folate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
at a slow rate, reaction not catalyzed by all dihydrofolate reductases
-
?
folate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
activity only at acidic pH around 4.5
-
?
additional information
?
-
a bifunctional enzyme with dihydrofolate reductase and thymidylate synthase activities, overview
-
-
-
additional information
?
-
-
a bifunctional enzyme with dihydrofolate reductase and thymidylate synthase activities, overview
-
-
-
additional information
?
-
-
equilibrium strongly favors tetrahydrofolate production
-
-
-
additional information
?
-
-
key enzyme in the biosynthesis of purines, pyrimidines and several amino acids
-
-
-
additional information
?
-
-
key enzyme in the biosynthesis of purines, pyrimidines and several amino acids
-
-
-
additional information
?
-
-
equilibrium strongly favors tetrahydrofolate production
-
-
-
additional information
?
-
-
no activity with 7,8-dihydrobiopterin and biopterin
-
-
-
additional information
?
-
-
no activity with folate, sepiapterin, isoxanthopterin, leucopterin
-
-
-
additional information
?
-
-
in Cryptosporidium, DHFR and thymidylate synthase are present as a bifunctional enzyme, DHFR-TS
-
-
-
additional information
?
-
-
3-acetylpyridine adenine dinucleotide + dihydrofolate: rapid equilibrium random mechanism
-
-
-
additional information
?
-
-
NADPH + dihydrofolate: steady-state random mechanism
-
-
-
additional information
?
-
-
enzyme activity decreases with increasing pressure. The Km values for dihydrofolate and NADPH are slightly higher at 200 MPa than at atmospheric pressure. The hydride transfer step is insensitive to pressure, while the dissociation constants of substrates and cofactors increase with pressure
-
-
-
additional information
?
-
-
free energy perturbation with molecular dynamics simulations of dihydrofolate reductase in complex with dihydrofolate. In the Michaelis complex the pKa is modulated by the Met20 loop fluctuations, providing the largest pKa shift in substates with a tightly closed loop conformation, in the partially closed/open substates, the pKa is similar to that in the occluded complex. Conducive to the protonation, tightly closing the Met20 loop enhances the interactions of the cofactor and the substrate with the Met20 side chain and aligns the nicotinamide ring of the cofactor coplanar with the pterin ring of the substrate
-
-
-
additional information
?
-
-
equilibrium strongly favors tetrahydrofolate production
-
-
-
additional information
?
-
-
both dihydrolfolate reductase and thymidylate synthase are substrates for UBC9-catalyzed modification with small ubiquitin-like modifier-1
-
-
-
additional information
?
-
-
dihydrofolate reductase is a substrate of ubiquitin ligase MDM2. MDM2 binds directly to dihydrofolate reductase and catalyzes its monoubiquitination. It reduces dihydrofolate reductase activity in a p53-independent manner, but has no effect on the steady-state level of expression. the ability of MDM2 to inhibit dihydrofolate reductase deoends on an active MDM2 RING-finger domain
-
-
-
additional information
?
-
-
dihydrofolate reductase deficient mutant needs thymidine for growth, pathway overview
-
-
-
additional information
?
-
-
knockout mutants with either no pteridine reductase or dihydrofolate reductase activity revealed in comparison to wild-type that 90% of the cellular dihydrofolate reduction activity belongs to DHFR and 10% of the cellular dihydrofolate reductase activity belongs to pteridine reductase
-
-
-
additional information
?
-
substrate binding site analysis, overview
-
-
-
additional information
?
-
-
substrate binding site analysis, overview
-
-
-
additional information
?
-
-
no activity with 7,8-dihydrobiopterin and biopterin
-
-
-
additional information
?
-
-
equilibrium strongly favors tetrahydrofolate production
-
-
-
additional information
?
-
-
molecular mechanism of the distinct differences in substrate channeling behavior between Toxoplasma gondii TS-DHFR and Cryptosporidium hominis TS-DHFR, overview
-
-
-
additional information
?
-
the bifunctional folate and pyrimidine-metabolising enzyme dihydrofolate reductase-thymidylate synthase dihydrofolate reductase-thymidylate synthase is expressed from a single gene as a homodimer comprising of an N-terminal DHFR domain fused via a linker peptide to a thymidylate synthase domain at the C-terminus
-
-
-
additional information
?
-
no activity with folic acid and the structurally related pterins (biopterin, dihydrobiopterin, sepiapterin and neopterin) as substrates by enzyme DHFR-TS
-
-
-
additional information
?
-
the bifunctional folate and pyrimidine-metabolising enzyme dihydrofolate reductase-thymidylate synthase dihydrofolate reductase-thymidylate synthase is expressed from a single gene as a homodimer comprising of an N-terminal DHFR domain fused via a linker peptide to a thymidylate synthase domain at the C-terminus
-
-
-
additional information
?
-
no activity with folic acid and the structurally related pterins (biopterin, dihydrobiopterin, sepiapterin and neopterin) as substrates by enzyme DHFR-TS
-
-
-
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
7,8-dihydrofolate + NADH + H+
5,6,7,8-tetrahydrofolate + NAD+
-
-
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
maintainance of adequate levels of fully reduced folate in metabolism of proliferating cells
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
directly correlated with thymidylate synthesis
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
maintainance of adequate levels of fully reduced folate in metabolism of proliferating cells
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
key enzyme in biosynthesis of purines, pyrimidines and several amino acids
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
maintainance of adequate levels of fully reduced folate in metabolism of proliferating cells
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
maintainance of adequate levels of fully reduced folate in metabolism of proliferating cells
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
key role in thymidylate biosynthesis
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
DHFR activity is not essential for virus replication
-
-
?
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
maintainance of adequate levels of fully reduced folate in metabolism of proliferating cells
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
B5U9U8
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
Q6FPH0
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
Q27552
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
Q834R2
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
Q834R2
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
P00383
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
Q7BPB0
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
Leishmania braziliensis subsp. viannia
A4H4P8
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
S5M3K7
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
the reaction is essential in DNA synthesis
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
Q9UUP5
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
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-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
G4VJD6
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-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
Q2YY41
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-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
P13955
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-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
Q27783
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-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
Q27783
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-
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r
additional information
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key enzyme in the biosynthesis of purines, pyrimidines and several amino acids
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additional information
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key enzyme in the biosynthesis of purines, pyrimidines and several amino acids
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-
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additional information
?
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in Cryptosporidium, DHFR and thymidylate synthase are present as a bifunctional enzyme, DHFR-TS
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-
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additional information
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dihydrofolate reductase deficient mutant needs thymidine for growth, pathway overview
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-
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additional information
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knockout mutants with either no pteridine reductase or dihydrofolate reductase activity revealed in comparison to wild-type that 90% of the cellular dihydrofolate reduction activity belongs to DHFR and 10% of the cellular dihydrofolate reductase activity belongs to pteridine reductase
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additional information
?
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Q27783
the bifunctional folate and pyrimidine-metabolising enzyme dihydrofolate reductase-thymidylate synthase dihydrofolate reductase-thymidylate synthase is expressed from a single gene as a homodimer comprising of an N-terminal DHFR domain fused via a linker peptide to a thymidylate synthase domain at the C-terminus
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additional information
?
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Q27783
the bifunctional folate and pyrimidine-metabolising enzyme dihydrofolate reductase-thymidylate synthase dihydrofolate reductase-thymidylate synthase is expressed from a single gene as a homodimer comprising of an N-terminal DHFR domain fused via a linker peptide to a thymidylate synthase domain at the C-terminus
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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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cofactor-enzyme interaction study from x-ray structure, structural and topological comparison with dehydrogenases
NADPH
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cofactor-enzyme interaction study from x-ray structure, structural and topological comparison with dehydrogenases
NADPH
-
cofactor-enzyme interaction study from x-ray structure, structural and topological comparison with dehydrogenases
NADPH
Q2YY41
binding structure and comformation of wild-type and mutant enzyme
NADPH
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binding strutcure and conformation, the adenine moiety adopts an off-plane tilt of nearly 90° and this orientation is stabilized by hydrogen bonds to functionally conserved Arg residues, hydrid transfer and structural role in catalytic mechanism, overview
NADPH
; the presence of NADPH greatly enhances binding of trimethoprim to DHFR
NADPH
-
binding structure analysis, residues interacting with the substrate NADPH include the conserved residues A10, I17, R81, T83, S103, and G153 and the nonconserved residue A154
NADPH
NADPH binds in an extended form making several hydrophobic and hydrogen bond interactions with the protein residues. The hydrophobic pocket consists of residues V9, A11, L25, I62 and T134 interacting with the pyrrolo[2,3-d]pyrimidine scaffold whereas T40 and F36 interact with the phenyl ring of inhibitor 2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidine-methyl-phenyl-L-glutamic acid
NADPH
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effects of 1,3,5-triazine-2,4-diamine derivatives on the cofactor NADPH binding, overview
NADPH
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-
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Cs+
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activation of mutant type enzyme at 0.2 mM, decrease of wild type enzyme activity above 0.1 mM
K+
KCl
Li+
-
activation of mutant type enzyme at 0.2 mM, decrease of wild type enzyme activity above 0.1 mM
Na+
Organic mercurials
Ru+
-
activation of mutant type enzyme at 0.2 mM, decrease of wild type enzyme activity above 0.1 mM
K+
-
activation of mutant type enzyme activity at 0.2 mM, decrease of wild type enzyme activity above 0.1 mM
KCl
-
dihydrofolate reductase hvDHFR1 and hvDHFR2 unfold at KCl concentrations below 0.5 M. Above 1 M, the KCl dependence of the dihydrofolate reductase activities can be attributed to the effect of salt on substrate affinity
KCl
the optimal ionic strength for both enzymes requires 100 mM KCl, with DHFR displaying 2.5fold activation and TS 4.5fold activation
Na+
-
activation of mutant type enzyme 0.2 mM, decrease of wild type enzyme activity above 0.1 mM
Organic mercurials
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animal enzyme: activated, bacterial enzyme: unaffected or inhibited
Organic mercurials
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animal enzyme: activated, bacterial enzyme: unaffected or inhibited
Organic mercurials
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animal enzyme: activated, bacterial enzyme: unaffected or inhibited
Organic mercurials
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animal enzyme: activated, bacterial enzyme: unaffected or inhibited
Organic mercurials
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animal enzyme: activated, bacterial enzyme: unaffected or inhibited
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(-)-epicatechin gallate
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competitive to 7,8-dihydrofolate, formation of a slow dissociation ternary complex by the reaction of NADPH with the enzyme-inhibitor complex. Ionization state of E30 is critical for inhibitory activity
(-)-epigallocatechin gallate
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competitive to 7,8-dihydrofolate, formation of a slow dissociation ternary complex by the reaction of NADPH with the enzyme-inhibitor complex. Ionization state of E30 is critical for inhibitory activity
(1E)-1-[4-[(3,5-dichloropyridin-4-yl)oxy]phenyl]ethanone thiosemicarbazone
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-
(2,5-dimethyl-1,4-phenylene)bis(methylene) bis(N-[amino(imino)methyl](imidothiocarbamate))
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50% inhibition at 0.000075 mM
(2E)-1-(1-cyclohexylphthalazin-2(1H)-yl)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]prop-2-en-1-one
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(2E)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]-1-(1-phenoxyphthalazin-2(1H)-yl)prop-2-en-1-one
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(2E)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]-1-(1-phenylphthalazin-2(1H)-yl)prop-2-en-1-one
-
(2E)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]-1-(1-propylphthalazin-2(1H)-yl)prop-2-en-1-one
-
(2E)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]-1-[1-(2-methylphenyl)phthalazin-2(1H)-yl]prop-2-en-1-one
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(2E)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]-1-[1-(3,3,3-trifluoropropyl)phthalazin-2(1H)-yl]prop-2-en-1-one
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(2E)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]-1-[1-(3,5-dimethylphenyl)phthalazin-2(1H)-yl]prop-2-en-1-one
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(2E)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]-1-[1-(3-fluorophenyl)phthalazin-2(1H)-yl]prop-2-en-1-one
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(2E)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]-1-[1-(3-methylbut-2-en-1-yl)phthalazin-2(1H)-yl]prop-2-en-1-one
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(2E)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]-1-[1-(3-methylbutyl)phthalazin-2(1H)-yl]prop-2-en-1-one
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(2E)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]-1-[1-(4-fluorophenyl)phthalazin-2(1H)-yl]prop-2-en-1-one
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(2E)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]-1-[1-(4-methoxyphenoxy)phthalazin-2(1H)-yl]prop-2-en-1-one
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(2E)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]-1-[1-(4-methylphenoxy)phthalazin-2(1H)-yl]prop-2-en-1-one
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(2E)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]-1-[1-(4-methylphenyl)phthalazin-2(1H)-yl]prop-2-en-1-one
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(2E)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]-1-[1-(hexan-3-yl)phthalazin-2(1H)-yl]prop-2-en-1-one
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(2E)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]-1-[1-(propan-2-yl)phthalazin-2(1H)-yl]prop-2-en-1-one
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(2E)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]-1-[1-[4-(trifluoromethoxy)phenoxy]phthalazin-2(1H)-yl]prop-2-en-1-one
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(2S)-2-((4-[(2-amino-6-ethyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)thio]benzoyl)amino)pentanedioic acid
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50% inhibition at 0.00042 mM, additionally inhibitory on thymidylate synthase
(2S)-2-((4-[(2-amino-6-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)thio]benzoyl)amino)pentanedioic acid
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50% inhibition at 0.0021 mM, additionally inhibitory on thymidylate synthase
(2S)-2-[(4-([(2,4-diaminopteridin-6-yl)methyl](methyl)amino)phenyl)formamido]pentanedioic acid
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i.e, methotrexate, A DHFR inhibitor, binds at the DHFR active site
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(2S)-2-[(5-{methyl[(2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl]amino}thiophen-2-yl)formamido]pentanedioic acid
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in low-folate medium, up to 300-fold increase of inhibitory activity
1,1'-{6-[(4-nitrophenyl)amino]-1,3,5-triazine-2,4-diyl}bis(4-benzylpyrazinediium)
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minimal inhibitory concentration: 0.003536 mM
1,1'-{6-[(4-nitrophenyl)amino]-1,3,5-triazine-2,4-diyl}bis(4-methylpyrazinediium)
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minimal inhibitory concentration: 0.002418 mM
1,1'-{6-[(4-nitrophenyl)amino]-1,3,5-triazine-2,4-diyl}bis(4-phenylpyrazinediium)
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minimal inhibitory concentration: 0.018 mM
1,3-phenylenebis(methylene) bis(N-[amino(imino)methyl](imidothiocarbamate))
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50% inhibition at 0.000075 mM
1,4-bis-([N-(1-imino-1-guanidino-methyl)]sulfanylmethyl)-3,6-dimethyl-benzene
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binding of the inhibitor has both a favorable entropy and enthalpy of binding. Positive binding cooperativity between inhibitor and the cofactor NADPH. Binding of inhibitor to DHFR is 285fold tighter in the presence of the NADPH cofactor than in its absence
1,4-phenylenebis(methylene) bis(N-[amino(imino)methyl](imidothiocarbamate))
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1,6-bis-(4-fluoro-phenyl)-[1,3,5]triazine-2,4-diamine
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IC50: 0.011 nM, 0.03 mM 7,8-dihydrofolate
1-(4-nitrophenyl)-3-[4-[4-[(4-nitrophenyl)carbamoylamino]phenoxy]phenyl]urea
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NSC80735, complete inhibition at 1 mM
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1-([N-(1-imino-guanidino-methyl)]sulfanylmethyl)-3-trifluoromethyl-benzene
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binding of the inhibitor has both a favorable entropy and enthalpy of binding. Positive binding cooperativity between inhibitor and the cofactor NADPH. Binding of inhibitor to DHFR in the absence of NADPH is not observed
1-N,4-N-bis(4-aminophenyl)benzene-1,4-dicarboxamide
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NSC55152, complete inhibition at 1 mM
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1-[3-(aminomethyl)phenyl]-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
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1-[3-chloro-4-(5-phenylpentyl)phenyl]-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
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uncompetitive versus NADPH, competitive versus 7,8-dihydrofolate
1-[4-(aminomethyl)phenyl]-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
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1-[4-(dimethylamino)phenyl]-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
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1-[4-[4-(2,4-dichlorophenyl)butyl]phenyl]-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
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2,2'-({6-[(4-nitrophenyl)amino]-1,3,5-triazine-2,4-diyl}diimino)diethanol
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minimal inhibitory concentration: 0.149 mM
2,4-diamino-5-(3-(2,5-dimethoxyphenyl)prop-1-ynyl)-6-ethylpyrimidine
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i.e. UCP120B, potent enzyme inhibitor of DHFR and bacterial growth, three-dimensional solution structure of the ternary complex with enzyme and NADPH cofactor determined by NMR from 20 mM TES, 50 mM KCl, 10 mM DTT, and 0.5 mM EDTA solution containing 2 mM of each ligand, comparison to the crystal structure of the ternary complex, overview. Analysis of structure and dynamics of the binary inhibitor-enzyme complex
2,4-diamino-5-methyl-6-(2',3',5',6'-tetrafluoro-4'-trifluoromethylphenylsulfanyl)-furo[2,3-d]pyrimidine
2,4-diamino-5-propyl-6-(1'-naphthylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine
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2,4-diamino-5-[(R)-3-(3-methoxy-5-phenylphenyl)but-1-ynyl]-6-methylpyrimidine
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2,4-diamino-5-[(S)-3-(3-methoxy-5-phenylphenyl)but-1-ynyl]-6-methylpyrimidine
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2,4-diamino-5-[3-(2-methoxy-5-phenylphenyl)prop-1-ynyl]-6-ethylpyrimidine
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2,4-diamino-5-[3-(2-phenyl-5-methoxyphenyl)prop-1-ynyl]-6-ethylpyrimidine
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2,4-diamino-5-[3-(3-methoxy-4-(2,6-diisopropylphenyl)phenyl)-but-1-ynyl]-6-methylpyrimidine
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2,4-diamino-5-[3-(3-methoxy-4-(2,6-dimethylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
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2,4-diamino-5-[3-(3-methoxy-4-(2-methylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
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2,4-diamino-5-[3-(3-methoxy-4-phenylphenyl)but-1-ynyl]-6-methylpyrimidine
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2,4-diamino-5-[3-(3-methoxy-5-(2,6-diisopropylphenyl)phenyl)-but-1-ynyl]-6-methylpyrimidine
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2,4-diamino-5-[3-(3-methoxy-5-phenylphenyl)but-1-ynyl]-6-methylpyrimidine
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2,4-diamino-6-(2-hydroxydibenz[b,f]azepin-5-yl)methylpteridine
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crystallization data
2-(2-((5,7-diaminopyrimido[4,5-d]pyrimidin-2-yl)(1-(naphthalen-1-yl)ethyl)amino)ethoxy)ethanol
2-(2-((5,7-diaminopyrimido[4,5-d]pyrimidin-2-yl)[1-(naphthalen-1-yl)ethyl]amino)ethoxy)ethanol
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2-(3-(2-(hydroxyimino)-2-(pyridine-4-yl)-6,7-dimethylquinoxalin-2-yl)-1-(pyridine-4-yl)ethanone) oxime
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i.e. 373265, a dual-site inhibitor, that targets both the substrate and cofactor binding site, docking modelling, overview