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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
- leukemia
- pyrimidine
- thymidine
- dihydropteroate
-
antimalarial
- tmp
-
casey
- pneumocystis
- chloroquine
-
hydride
-
drug-resistant
- carinii
- polyglutamates
- leucovorin
-
folate-dependent
- folylpolyglutamate
- vivax
-
ccrf-cem
-
uncomplicated
- glycinamide
- mthfr
-
subline
- gondii
- tetrahydrobiopterin
- toxoplasma
- pemetrexed
- pterins
-
folinic
- analysis
- biopterins
-
cyclobutane
- medicine
- 5,10-methylenetetrahydrofolate
- drug development
-
nontranscribed
-
integrons
- sulfamethoxazole
- 5-methyltetrahydrofolate
- quinazoline
- trimethoprim-sulfamethoxazole
- bh4
- sepiapterin
-
triazine
- biotechnology
- dihydropteridine
- synthesis
- artesunate
The enzyme appears in viruses and cellular organisms
Synonyms
5,6,7,8-tetrahydrofolate: NADP+ oxidoreductase, 7,8-dihydrofolate reductase, bifunctional TS-DHFR, BmDHFR, dehydrogenase, tetrahydrofolate, DFR-TS, DHFR, DHFR type IIIC, DHFR-TS, DHFR2, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
7,8-dihydrofolate reductase
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-
-
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dehydrogenase, tetrahydrofolate
-
-
-
-
DHFR
DHFR type IIIC
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-
-
-
DHFR-TS
dihydrofolate reductase
dihydrofolate reductase-thymidylate synthase
dihydrofolate reductase:thymidylate synthase
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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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EC 1.5.1.4
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-
formerly
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ecDHFR
folA3
folic acid reductase
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-
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-
folic reductase
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-
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HjDHFR
NADPH-dihydrofolate reductase
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pcDHFR
pteridine reductase:dihydrofolate reductase
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reductase, dihydrofolate
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S3DHFR
tetrahydrofolate dehydrogenase
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-
-
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thymidylate synthase-dihydrofolate reductase
thymidylate synthetase-dihydrofolate reductase
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-
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Trimethoprim resistance protein
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-
-
-
TS-DHFR
additional information
DHFR
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-
-
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DHFR
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dihydrofolate reductase-thymidylate synthase
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-
-
-
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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
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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
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
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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+
catalytic mechanism; cofactor binding mechanism, pH-dependence investigation
-
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+
kinetic mechanism; 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+
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
-
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+
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+
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+
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
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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+
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
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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
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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
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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
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5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
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-
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redox reaction
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-
-
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reduction
reduction
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-
-
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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.
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CAS REGISTRY NUMBER
COMMENTARY
9002-03-3
-
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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+
-
-
-
-
?
7,8-dihydrofolate + acetylpyridine adenine nucleotide, reduced
5,6,7,8-tetrahydrofolate + acetylpyridine adenine nucleotide, oxidized
-
-
-
?
7,8-dihydrofolate + NADH + H+
5,6,7,8-tetrahydrofolate + NAD+
-
-
-
-
?
dihydrobiopterin + NADPH
? + NADP+
-
10% of the activity with 7,8-dihydrofolate
-
-
?
7,8-dihydrofolate + NADP + H+
5,6,7,8-tetrahydrofolate + NADP+
-
assay at 37°C
-
-
?
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+
-
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+
-
enzyme plays important role in nucleotide biosynthesis
-
-
?
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+
-
-
-
?
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
-
r
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
clear evidence against dihydrofolate substrate channeling in the bifunctional thymidylate synthase-dihydrofolate reductase
-
-
?
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+
-
-
-
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+
-
-
-
-
?
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+
-
-
-
?
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
?
-
-
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 SUBSTRATE
NATURAL 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
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+
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+
-
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
G4VJD6
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
Q2YY41
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
P13955
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
Q27783
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
Q27783
-
-
-
r
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
?
-
-
in Cryptosporidium, DHFR and thymidylate synthase are present as a bifunctional enzyme, DHFR-TS
-
-
-
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
?
-
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
-
-
-
additional information
?
-
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
-
-
-
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
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
-
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
-
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
-
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
-
effects of 1,3,5-triazine-2,4-diamine derivatives on the cofactor NADPH binding, overview
NADPH
-
-
NADPH
-
-
392208, 392210, 392212, 392214, 392218, 392220, 392224, 392226, 392239, 392240, 392241, 392277, 654202, 654970, 655867, 674351, 674549, 685126, 685386, 693567, 701696, 703803, 705044, 711480, 724168, 724293, 724390, 724416, 725204, 742491, 743678
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Cs+
-
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
Rb+
-
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
-
animal enzyme: activated, bacterial enzyme: unaffected or inhibited
organic mercurials
-
animal enzyme: activated, bacterial enzyme: unaffected or inhibited
organic mercurials
-
animal enzyme: activated, bacterial enzyme: unaffected or inhibited
organic mercurials
-
animal enzyme: activated, bacterial enzyme: unaffected or inhibited
organic mercurials
-
animal enzyme: activated, bacterial enzyme: unaffected or inhibited
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(-)-epicatechin gallate
-
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
-
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
-
-
(2,5-dimethyl-1,4-phenylene)bis(methylene) bis(N-[amino(imino)methyl](imidothiocarbamate))
-
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
-
(2E)-3-[5-[(2,4-diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl]-1-(1-phenoxyphthalazin-2(1H)-yl)prop-2-en-1-one
-
(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
-
(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
-
(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
-
(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
-
(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
-
(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
-
(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
-
(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
-
(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
-
(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
-
(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
-
(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
-
(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
-
(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
-
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
-
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
-
i.e, methotrexate, A DHFR inhibitor, binds at the DHFR active site
(2S)-2-[(5-{methyl[(2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl]amino}thiophen-2-yl)formamido]pentanedioic acid
-
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)
-
minimal inhibitory concentration: 0.003536 mM
1,1'-{6-[(4-nitrophenyl)amino]-1,3,5-triazine-2,4-diyl}bis(4-methylpyrazinediium)
-
minimal inhibitory concentration: 0.002418 mM
1,1'-{6-[(4-nitrophenyl)amino]-1,3,5-triazine-2,4-diyl}bis(4-phenylpyrazinediium)
-
minimal inhibitory concentration: 0.018 mM
1,3-phenylenebis(methylene) bis(N-[amino(imino)methyl](imidothiocarbamate))
-
50% inhibition at 0.000075 mM
1,4-bis-([N-(1-imino-1-guanidino-methyl)]sulfanylmethyl)-3,6-dimethyl-benzene
-
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))
-
-
1,6-bis-(4-fluoro-phenyl)-[1,3,5]triazine-2,4-diamine
-
IC50: 0.011 nM, 0.03 mM 7,8-dihydrofolate
1-(4-nitrophenyl)-3-[4-[4-[(4-nitrophenyl)carbamoylamino]phenoxy]phenyl]urea
-
NSC80735, complete inhibition at 1 mM
1-([N-(1-imino-guanidino-methyl)]sulfanylmethyl)-3-trifluoromethyl-benzene
-
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
-
NSC55152, complete inhibition at 1 mM
1-[3-(aminomethyl)phenyl]-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
-
-
1-[3-chloro-4-(5-phenylpentyl)phenyl]-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
-
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
-
-
1-[4-(dimethylamino)phenyl]-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
-
-
1-[4-[4-(2,4-dichlorophenyl)butyl]phenyl]-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
-
-
2,2'-({6-[(4-nitrophenyl)amino]-1,3,5-triazine-2,4-diyl}diimino)diethanol
-
minimal inhibitory concentration: 0.149 mM
2,4-diamino-5-(3-(2,5-dimethoxyphenyl)prop-1-ynyl)-6-ethylpyrimidine
-
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
-
-
2,4-diamino-5-[(R)-3-(3-methoxy-5-phenylphenyl)but-1-ynyl]-6-methylpyrimidine
-
-
2,4-diamino-5-[(S)-3-(3-methoxy-5-phenylphenyl)but-1-ynyl]-6-methylpyrimidine
-
-
2,4-diamino-5-[3-(2-methoxy-5-phenylphenyl)prop-1-ynyl]-6-ethylpyrimidine
-
-
2,4-diamino-5-[3-(2-phenyl-5-methoxyphenyl)prop-1-ynyl]-6-ethylpyrimidine
-
-
2,4-diamino-5-[3-(3-methoxy-4-(2,6-diisopropylphenyl)phenyl)-but-1-ynyl]-6-methylpyrimidine
-
-
2,4-diamino-5-[3-(3-methoxy-4-(2,6-dimethylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
-
-
2,4-diamino-5-[3-(3-methoxy-4-(2-methylphenyl)phenyl)but-1-ynyl]-6-methylpyrimidine
-
-
2,4-diamino-5-[3-(3-methoxy-4-phenylphenyl)but-1-ynyl]-6-methylpyrimidine
-
-
2,4-diamino-5-[3-(3-methoxy-5-(2,6-diisopropylphenyl)phenyl)-but-1-ynyl]-6-methylpyrimidine
-
-
2,4-diamino-5-[3-(3-methoxy-5-phenylphenyl)but-1-ynyl]-6-methylpyrimidine
-
-
2,4-diamino-6-(2-hydroxydibenz[b,f]azepin-5-yl)methylpteridine
-
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
-
-
2-(3-(2-(hydroxyimino)-2-(pyridine-4-yl)-6,7-dimethylquinoxalin-2-yl)-1-(pyridine-4-yl)ethanone) oxime
-
i.e. 373265, a dual-site inhibitor, that targets both the substrate and cofactor binding site, docking modelling, overview
2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidine-methyl-phenyl-L-glutamic acid
potent enzyme inhibitor with anti-cryptosporidial activity in cell culture, chemical synthesis, overview. The inhibitor forms several hydrogen bonds and van der Waals interactions with the DHFR active site residues, binding close to the nicotinamide ring of NADPH. The carbonyl oxygens of the catalytic D32 hydrogen bond with N3 of the inhibitor forming a fork that holds the inhibitor in optimal position bound to the enzyme
2-amino-5-(4-bromobenzyl)-6-methyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
-
-
2-amino-5-(4-chlorobenzyl)-6-methyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
-
-
2-amino-5-(4-methoxybenzyl)-6-methyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
-
-
2-amino-6-methyl-5-(4-nitrobenzyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
-
-
2-amino-6-methyl-5-[4-(trifluoromethoxy)benzyl]-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
-
-
2-amino-8-(1,3-benzodioxol-5-yl)-9-phenyl-1,9-dihydro-6H-purin-6-one
-
synthesis, overview
2-hydroxy-5-nitrobenzyl N-[amino(imino)methyl]imidothiocarbamate
-
50% inhibition at 0.0151 mM
2-methoxybenzyl N-[amino(imino)methyl]imidothiocarbamate
-
50% inhibition at 0.0033 mM
2-[(3-[3-[(2,4-diaminopyrimidin-5-yl)methyl]-4-methoxyphenyl]prop-2-yn-1-yl)oxy]benzoic acid
2-[(5,7-diaminopyrimido[4,5-d]pyrimidin-2-yl)(1-[tricyclo[4.4.0.02,5]deca-1(10),2(5),6,8-tetraen-8-yl]ethyl)amino]ethanol
2-[(5,7-diaminopyrimido[4,5-d]pyrimidin-2-yl)(methyl)amino]-2-[tricyclo[4.4.0.02,5]deca-1(10),2(5),6,8-tetraen-7-yl]ethanol
2-[(E)-([2-amino-4-methoxy-6-(phenylamino)pyrimidin-5-yl]imino)methyl]phenol
-
synthesis, overview
2-[[(4-[[(2-amino-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)methyl]amino]phenyl)carbonyl]amino]hexanedioic acid
-
-
2-[[1-(3-chlorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]carbonyl]-N-prop-2-en-1-ylhydrazinecarbothioamide
-
-
3,4-dichlorobenzyl N-[amino(imino)methyl]imidothiocarbamate
-
50% inhibition at 0.0037 mM
3,5-bis(trifluoromethyl)benzyl N-[amino(imino)methyl]imidothiocarbamate
-
50% inhibition at 0.0056 mM
3-((5,7-diaminopyrimido[4,5-d]pyrimidin-2-yl)(1-(naphthalen-1-yl)ethyl)amino)propanoic acid
-
-
3-((5,7-diaminopyrimido[4,5-d]pyrimidin-2-yl)[1-(naphthalen-1-yl)ethyl]amino)propanoic acid
-
-
3-(trifluoromethyl)benzyl N-[amino(imino)methyl]imidothiocarbamate
-
50% inhibition at 0.0043 mM
3-([(2,4-diamino-5-methylpyrido[2,3-d]pyrimidin-6-yl)methyl]amino)-4-(2,5-dimethoxyethoxy)phenol
-
ratio of IC50 of human to Mycobacterium tuberculosis enzyme 7.6
3-benzyl-6-[(3,4-dimethoxybenzyl)(methyl)amino]-2-(methylsulfanyl)quinazolin-4(3H)-one
-
50% inhibition at 0.001 mM
3-benzyl-6-[(4-methoxybenzyl)(methyl)amino]-2-(methylsulfanyl)quinazolin-4(3H)-one
-
50% inhibition at 0.0005 mM
3-heptyl-4-hydroxy-1H-naphthalen-2-one
-
IC50: 0.48 mM, 0.03 mM 7,8-dihydrofolate
3-methoxybenzyl N-[amino(imino)methyl]imidothiocarbamate
-
50% inhibition at 0.0038 mM
3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin
-
i.e. TMECG, synthesis of a trimethoxy derivative of epicatechin-3-gallate, which shows high antiproliferative and proapoptotic activity against melanoma. It is a prodrug that is selectively activated by the specific melanocyte enzyme tyrosinase. Upon activation, the compound generates a stable quinone methide product that strongly inhibits dihydrofolate reductase in an irreversible manner. The treatment of melanoma cells affects cellular folate transport and the gene expression of DHFR
3-[(3-(3-[(2,4-diaminopyrimidin-5-yl)methyl]-4-methoxyphenyl)prop-2-yn-1-yl)oxy]benzoic acid
-
ratio of IC50 values human/Trypanosoma enzyme is 77
3-[(3-[3-[(2,4-diaminopyrimidin-5-yl)methyl]-4-methoxyphenyl]prop-2-yn-1-yl)oxy]benzoic acid
-
ratio of IC50 values human/Trypanosoma enzyme is 77
3-[[(4-chlorophenyl)sulfonyl]methyl]-N'-hydroxybenzenecarboximidamide
-
-
4,5-dideoxy-5-(2,6-diamino-5-phenylpyrimidin-4-yl)-D-erythro-pentitol
-
selective inhibition, little effect on human or yeast enzyme
4,6-di(5,8-dihydro-1,7-naphthyridin-7(6H)-yl)-N-(4-nitrophenyl)-1,3,5-triazin-2-amine
-
minimal inhibitory concentration: 0.020 mM
4,6-di(morpholin-4-yl)-N-(4-nitrophenyl)-1,3,5-triazin-2-amine
-
minimal inhibitory concentration: 0.0258 mM
4,6-Diamino-1,2-dihydro-2,2-dimethyl-1-(phenylalkylphenyl)-s-triazines
-
bearing a terminal sulfonyl fluoride
4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)-N-(4-sulfamoylphenethyl)-benzamide
-
4-((2,4-diaminopteridin-6-yl)methylamino)-N-(4-sulfamoylphenethyl)benzamide
-
4-((5,7-diaminopyrimido[4,5-d]pyrimidin-2-yl)(1-(naphthalen-1-yl)ethyl)amino)butanoic acid
4-((5,7-diaminopyrimido[4,5-d]pyrimidin-2-yl)[1-(naphthalen-1-yl)ethyl]amino)butanoic acid
-
-
4-(2-(4-((2,4-diaminopteridin-6-yl)methylamino)benzamido)ethyl) benzenesulfonic acid
-
4-(trifluoromethyl)benzyl N-[amino(imino)methyl]imidothiocarbamate
-
50% inhibition at 0.013 mM
4-([5-[(2,4-diaminopteridin-6-yl)methyl]-5H-dibenzo[b,f]azepin-2-yl]oxy)butane-1,1-diol
-
O-(3-carboxypropyl) inhibitor, crystallization data
4-benzyl-N-[3-benzyl-2-(methylsulfanyl)-4-oxo-3,4-dihydroquinazolin-6-yl]benzenesulfonamide
-
50% inhibition at 0.008 mM
4-bromo-N-[2-(methylthio)-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl]benzenesulfonamide
-
50% inhibition at 0.002 mM
4-methylbenzyl N-[amino(imino)methyl]imidothiocarbamate
-
50% inhibition at 0.0126 mM
4-[3-(4,6-diamino-2,2-dimethyl-1,3,5-triazin-1(2H)-yl)benzamido]benzene-1-sulfonyl fluoride
-
contains a fluorosulfonylphenylaminocarbonyl substitution at R2 on 1-phenyl-6,6-dimethyl-1,3,5-triazine-2,4-diamine ring, and shows the unique behavior of tight-binding and average inhibition, uncompetitive versus NADPH, competitive versus 7,8-dihydrofolate
4-[3-[(2,4-diamino-5-methylpyrido[2,3-d]pyrimidin-6-yl)methyl]-4-methoxyphenoxy]butanoic acid
50% inhibition of growth in culture at 0.00060 mM
4-[4,6-diamino-2-(4-chlorophenyl)-1,3,5-triazin-1(2H)-yl]benzene-1-sulfonamide
-
-
4-[4-[3-(4,6-diamino-2,2-dimethyl-1,3,5-triazin-1-yl)phenyl]butyl]benzenesulfonyl fluoride
-
uncompetitive versus NADPH, competitive versus 7,8-dihydrofolate
4-[6-[4-(4,6-diamino-2,2-dimethyl-1,3,5-triazin-1-yl)phenyl]hexyl]benzenesulfonyl fluoride
-
uncompetitive versus NADPH, competitive versus 7,8-dihydrofolate
4-[[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxy]benzaldehyde thiosemicarbazone
-
-
5-(3,4,5-trimethoxy-benzyl)-pyrimidine-2,4-diamine
-
IC50: 18 nM, 0.03 mM 7,8-dihydrofolate
5-(methoxymethyl)-6-[[(3,4,5-trimethoxyphenyl)amino]methyl]pyrido[2,3-d]pyrimidine-2,4-diamine
-
-
5-ethyl-6-([[2-methoxy-5-(trifluoromethyl)phenyl]amino]methyl)pyrido[2,3-d]pyrimidine-2,4-diamine
5-ethyl-6-[(4-methoxyphenyl)sulfanyl]-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
-
-
5-ethyl-6-[(naphthalen-1-yl)sulfanyl]-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
-
-
5-ethyl-6-[(naphthalen-2-yl)sulfanyl]-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
-
-
5-methoxy-6-[[(3,4,5-trimethoxyphenyl)amino]methyl]pyrido[2,3-d]pyrimidine-2,4-diamine
-
-
5-methyl-6-[(1,2,3,4-tetrahydronaphthalen-1-ylamino)methyl]pyrido[2,3-d]pyrimidine-2,4-diamine
-
-
5-methyl-6-[(5,6,7,8-tetrahydronaphthalen-1-ylamino)methyl]pyrido[2,3-d]pyrimidine-2,4-diamine
-
-
5-methyl-6-[(naphthalen-1-ylamino)methyl]pyrido[2,3-d]pyrimidine-2,4-diamine
-
-
5-methyl-6-[(naphthalen-1-ylsulfanyl)methyl]pyrido[2,3-d]pyrimidine-2,4-diamine
-
-
5-methyl-6-[(naphthalen-2-ylamino)methyl]pyrido[2,3-d]pyrimidine-2,4-diamine
-
-
5-methyl-6-[(naphthalen-2-ylsulfanyl)methyl]pyrido[2,3-d]pyrimidine-2,4-diamine
-
-
5-nitro-6-methylamino-isocytosine
-
inhibitor of dihydropteroate synthase, also acts on dihydrofolate reductase
5-phenyl-6-((3R,4S)-3,4,5-trihydroxypentyl)pyrimidine-2,4-diamine
-
selective inhibition of Mycobacterium tuberculosis enzyme, little effect on human or yeast enzyme
5-[3-(2,5-dimethoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
-
-
5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-propylpyrimidine-2,4-diamine
Q2YY41
-
5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
Q2YY41
-
5-[3-(2-methoxy-2',6'-dimethylbiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
Q2YY41
-
5-[3-(2-methoxy-2'-methylbiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
Q2YY41
-
5-[3-(3-methoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
-
-
5-[3-(5-methoxy-2',6'-dimethylbiphenyl-3-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
Q2YY41
-
5-[3-(5-methoxy-2'-methylbiphenyl-3-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
Q2YY41
-
5-[3-(5-methoxy-3',5'-dimethyl[1,1'-biphenyl]-3-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
5-[3-[(2,4-diamino-5-methylpyrido[2,3-d]pyrimidin-6-yl)methyl]-4-methoxyphenoxy]pentanoic acid
50% inhibition of growth in culture at 0.00167 mM
5-[3-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-methoxyphenyl]but-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine
5-[3-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-methoxyphenyl]prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine
6,6-dimethyl-1-[3-(4-phenylbutyl)phenyl]-1,6-dihydro-1,3,5-triazine-2,4-diamine
-
uncompetitive versus NADPH, competitive versus 7,8-dihydrofolate
6,7-dimethyl-5,6,7,8-tetrahydro-quinazoline-2,4-diamine
-
IC50: 790 nM, 0.03 mM 7,8-dihydrofolate
6-((5-methoxy-2-methylphenylamino)methyl)-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
-
-
6-(([4-chlorotricyclo[4.4.0.02,5]deca-1(10),2(5),6,8-tetraen-7-yl]amino)methyl)pteridine-2,4-diamine
6-(4-trifluoromethyl-phenoxy)-quinazoline-2,4-diamine
-
IC50: 660 nM, 0.03 mM 7,8-dihydrofolate
6-([(1E)-(4-methoxyphenyl)methylene]amino)-2-(methylthio)-3-phenylquinazolin-4(3H)-one
-
50% inhibition at 0.002 mM
6-([(2,5-dipropoxyphenyl)amino]methyl)-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
-
ratio of IC50 of human to Mycobacterium tuberculosis enzyme 65
6-([(2-bromo-3,4,5-trimethoxyphenyl)amino]methyl)quinazoline-2,4-diamine
50% inhibition of growth in culture at 0.0011 mM
6-([(2-butoxy-5-ethoxyoxyphenyl)amino]methyl)-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
-
ratio of IC50 of human to Mycobacterium tuberculosis enzyme 2.8
6-([(2-butoxy-5-propoxyphenyl)amino]methyl)-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
-
ratio of IC50 of human to Mycobacterium tuberculosis enzyme 19
6-([(2-ethoxy-5-butoxyphenyl)amino]methyl)-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
-
ratio of IC50 of human to Mycobacterium tuberculosis enzyme 4.1
6-([5-quinolylamino]-methyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine
-
enzyme-bound crystal structure analysis for inhibitor screening and docking studies, PDB ID 1KMS
6-([tricyclo[4.4.0.02,5]deca-1(10),2(5),6,8-tetraen-7-ylamino]methyl)pteridine-2,4-diamine
6-([tricyclo[4.4.0.02,5]deca-1(10),2(5),6,8-tetraen-8-ylamino]methyl)pteridine-2,4-diamine
6-([[2-(difluoromethoxy)-5-methylphenyl]amino]methyl)-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
-
-
6-([[2-(difluoromethoxy)phenyl]amino]methyl)-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
-
-
6-([[2-bromo-5-(trifluoromethyl)phenyl]amino]methyl)-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
6-([[2-fluoro-5-(trifluoromethyl)phenyl]amino]methyl)-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
6-([[2-methoxy-5-(trifluoromethyl)phenyl](methyl)amino]methyl)-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
-
-
6-([[2-methoxy-5-(trifluoromethyl)phenyl]amino]methyl)-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
6-([[3-methoxy-5-(trifluoromethyl)phenyl]amino]methyl)-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
6-([[4-(difluoromethoxy)phenyl]amino]methyl)-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
-
-
6-([[4-(fluoromethoxy)phenyl]amino]methyl)-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
-
-
6-amino-3-pentadecylphenyl beta-D-glucoside
-
i.e. 1357, a dual-site inhibitor, that targets both the substrate and cofactor binding site
6-ethyl-5-phenylpyrimidine-2,4-diamine
analogue of pyrimethamine lacking the 4-Cl group, effectively inhibits both wild-type and pyrimethamine-resistant mutant S58R/S117N
6-ethyl-5-[3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
-
-
6-ethyl-5-[3-(4-methoxybiphenyl-3-yl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
-
-
6-methoxy-5-[(E)-[(4-methylphenyl)methylidene]amino]-N~4~-phenylpyrimidine-2,4-diamine
-
-
6-methoxy-N~4~-phenyl-5-[(E)-[(pyridin-4-yl)methylidene]amino]pyrimidine-2,4-diamine
-
-
6-methoxy-N~4~-phenyl-5-[(E)-[[4-(trifluoromethyl)phenyl]methylidene]amino]pyrimidine-2,4-diamine
-
-
6-p-tolyloxy-quinazoline-2,4-diamine
-
IC50: 190 nM, 0.03 mM 7,8-dihydrofolate
6-p-tolylsulfanyl-quinazoline-2,4-diamine
-
IC50: 310 nM, 0.03 mM 7,8-dihydrofolate
6-[(2,4-dichlorophenyl)sulfanyl]-5-ethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
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6-[(2,5-dimethoxyphenyl)sulfanyl]-5-ethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
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6-[(2,6-dimethylphenyl)sulfanyl]-5-ethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
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6-[(3,4-dichlorophenyl)sulfanyl]-5-ethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine
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6-[(4-methoxybenzyl)(methyl)amino]-2-(methylsulfanyl)-3-phenylquinazolin-4(3H)-one
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50% inhibition at 0.001 mM
6-[(9H-fluoren-2-ylamino)methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
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6-[(9H-fluoren-9-ylamino)methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
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6-[(fluoranthen-3-ylamino)methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
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6-[(isoquinolin-5-ylamino)methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
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6-[3-[(2,4-diamino-5-methylpyrido[2,3-d]pyrimidin-6-yl)methyl]-4-methoxyphenoxy]hexanoic acid
50% inhibition of growth in culture at 0.00051 mM
6-[3-[(2,4-diamino-5-methylpyrido[2,3-d]pyrimidin-6-yl)methyl]-4-methoxyphenyl]hex-5-ynoic acid
50% inhibition of growth in culture at 0.00190 mM
6-[[(2,5-dibutoxyphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
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6-[[(2,5-diethoxyphenyl)(methyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
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6-[[(2,5-dimethoxyphenyl)amino]methyl]-5-(methoxymethyl)pyrido[2,3-d]pyrimidine-2,4-diamine
6-[[(2,5-dipropoxyphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
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6-[[(2-chloro-4,6-dimethylphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
6-[[(2-chloro-4-fluoro-5-methylphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
6-[[(3,4-dimethoxyphenyl)amino]methyl]-5-(methoxymethyl)pyrido[2,3-d]pyrimidine-2,4-diamine
6-[[(3,5-dimethoxyphenyl)(methyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
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6-[[(3-chloro-4-methylphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
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6-[[(3-chlorophenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
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6-[[(3-ethoxy-5-methoxyphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
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6-[[(3-methoxy-5-propoxyphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
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6-[[(4-bromo-3-methylphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
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6-[[(4-butoxy-3-methoxyphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
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6-[[(4-chloro-2-methoxy-5-methylphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
6-[[(4-chloronaphthalen-1-yl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
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6-[[(4-chlorophenyl)amino]methyl]-5-(methoxymethyl)pyrido[2,3-d]pyrimidine-2,4-diamine
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6-[[(4-chlorophenyl)amino]methyl]-5-methoxypyrido[2,3-d]pyrimidine-2,4-diamine
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6-[[(5-methoxy-2-methylphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
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7,8-dihydrofolate
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substrate inhibition at concentration above 0.008 mM for native enzyme and at concentration above 0.001 mM for the recombinant enzyme
7-methyl-5,6,7,8-tetrahydro-quinazoline-2,4-diamine
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IC50: 0.011 nM, 0.03 mM 7,8-dihydrofolate
7-[(4-aminophenyl)methyl]-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine
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NSC309401, AMPQD, a substrate analogue with the quinazoline-1, 3-diamine group, tight-binding inhibitor, complete inhibition at 1 mM, competitive inhibition of dihydrofolate binding. Potently inhibits the enzyme by competitive displacement of the substrate dihydrofolic acid, uncompetitive inhibition versus NADPH, the inhibitor has a markedly increased affinity for the NADPH-bound form of the enzyme. The mode of binding of the inhibitor to the enzyme-NADPH binary complex conforms to the slow-onset, tight-binding model
7-[3-[(2,4-diamino-5-methylpyrido[2,3-d]pyrimidin-6-yl)methyl]-4-methoxyphenyl]hept-6-ynoic acid
50% inhibition of growth in culture at 0.000027 mM
7H-pyrrolo[3,2-f]quinazoline-1,3-diamine
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PQD, the lack of (4-aminophenyl)-methyl group at position 7 abolishes the slow-onset of inhibition
AR-101
i.e. 5-[(2R)-2-cyclopropyl-7,8-dimethoxy-2H-chromene-5-ylmethyl]pyrimidine-2,4-diamine, binding structure from crystal structure, the cyclopropyl-dimethoxychromene moiety interacts with the conserved residues Leu28, Val31, Ile50 and Leu54 forming a hydrophobic pocket in the enzyme
Ar-102
i.e. 5-[(2S)-2-cyclopropyl-7,8-dimethoxy-2H-chromene-5-ylmethyl]pyrimidine-2,4-diamine, binding structure from crystal structure, the cyclopropyl-dimethoxychromene moiety interacts with the conserved residues Leu28, Val31, Ile50 and Leu54 forming a hydrophobic pocket in the enzyme