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Information on EC 1.5.1.3 - dihydrofolate reductase and Organism(s) Bacillus anthracis and UniProt Accession Q81R22
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1.5.1.3 dihydrofolate reductaseIUBMB Comments
The enzyme from animals and some micro-organisms also slowly reduces folate to 5,6,7,8-tetrahydrofolate.
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Word Map
- 1.5.1.3
- methotrexate
- antifolate
- plasmodium
- falciparum
- hamster
- malaria
- pyrimethamine
- ovary
-
antimalarial
- leukemia
- dihydropteroate
- thymidine
- pyrimidine
- carinii
- polyglutamates
- pneumocystis
-
hydride
- chloroquine
-
casey
-
drug-resistant
- tmp
-
ccrf-cem
- vivax
- glycinamide
- toxoplasma
-
uncomplicated
-
folate-dependent
- mthfr
- folylpolyglutamate
- pemetrexed
-
sublines
- leucovorin
- tetrahydrobiopterin
-
polyglutamylation
- gondii
-
nontranscribed
- sulfamethoxazole
- trimethoprim-sulfamethoxazole
- quinazoline
- 5-methyltetrahydrofolate
- sepiapterin
- integrons
- dihydropteridine
- analysis
- medicine
- artesunate
- synthesis
-
triazine
-
folinic
- 5,10-methylenetetrahydrofolate
- bh4
- biotechnology
- biopterins
- drug development
- pterins
The taxonomic range for the selected organisms is: Bacillus anthracis
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
dhfr, dihydrofolate reductase, thy-1, dhfr-ts, hdhfr, dihydrofolate reductase-thymidylate synthase, ecdhfr, pcdhfr, r67 dhfr, ts-dhfr, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
7,8-dihydrofolate reductase
-
-
-
-
dehydrogenase, tetrahydrofolate
-
-
-
-
DHFR
-
-
-
-
DHFR type IIIC
-
-
-
-
dihydrofolate reductase-thymidylate synthase
-
-
-
-
dihydrofolate reductase:thymidylate synthase
-
-
-
-
dihydrofolic acid reductase
-
-
-
-
dihydrofolic reductase
-
-
-
-
folic acid reductase
-
-
-
-
folic reductase
-
-
-
-
NADPH-dihydrofolate reductase
-
-
-
-
pteridine reductase:dihydrofolate reductase
-
-
-
-
reductase, dihydrofolate
-
-
-
-
tetrahydrofolate dehydrogenase
-
-
-
-
thymidylate synthetase-dihydrofolate reductase
-
-
-
-
Trimethoprim resistance protein
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
-
-
-
-
oxidation
-
-
-
-
reduction
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
-
-, -, -, -
SYSTEMATIC NAME
IUBMB Comments
5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase
The enzyme from animals and some micro-organisms also slowly reduces folate to 5,6,7,8-tetrahydrofolate.
CAS REGISTRY NUMBER
COMMENTARY
9002-03-3
-
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
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
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 + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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-[3-(2,3-dimethoxyphenyl)prop-1-ynyl]-6-ethylpyrimidine
-
2,4-diamino-5-[3-(2,5-dimethoxyphenyl)prop-1-ynyl]-6-ethylpyrimidine
-
2,4-diamino-5-[3-(2,5-dimethoxyphenyl)prop-1-ynyl]-6-methylpyrimidine
-
2,4-diamino-5-[3-(2,5-dimethoxyphenyl)prop-1-ynyl]-6-npropylpyrimidine
-
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-(3,4,5-trimethoxyphenyl)prop-1-ynyl]-6-ethylpyrimidine
-
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
3-(2,4-diamino-6-methylpyrimidin-5-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol
-
5-nitro-6-methylamino-isocytosine
inhibitor of dihydropteroate synthase, also acts on dihydrofolate reductase
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-ethylpyrimidine-2,4-diamine
-
5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
-
5-[3-(2-methoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
-
5-[3-(3-methoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
-
5-[3-(5-methoxybiphenyl-3-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
-
5-[3-(biphenyl-3-yl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine
-
5-[3-methoxy-3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]-6-methylpyrimidine-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-[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-methyl-5-[3-(3,4,5-trimethoxyphenyl)but-1-yn-1-yl]pyrimidine-2,4-diamine
-
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)pent-1-yn-1-yl]pyrimidine-2,4-diamine
-
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
-
6-methyl-5-[3-methyl-3-(3,4,5-trimethoxyphenyl)but-1-yn-1-yl]pyrimidine-2,4-diamine
-
RAB1
i.e. (S,E)-3-(5-((2,4-diaminopyrimidin-5-yl)methyl)-2,3-dimethoxyphenyl)-1-(1-propylphthalazin-2(1H)-yl)prop-2-en-1-one or BAL17662, a dihydrophthalazine-based trimethoprim derivative, synthesis, overview. Binding of RAB1 causes a conformational change of the side chain of Arg58 and Met37 to accommodate the dihydrophthalazine moiety. The dihydrophthalazine group provides a large hydrophobic anchor that embeds within the DHFR active site and accounts for its selective inhibitory activity against Bacillus anthracis, binding structure, overview
additional information
inhibitor design based on a trimethoprim-like scaffold, overview
-
additional information
-
inhibitor design based on a trimethoprim-like scaffold, overview
-
additional information
the enzyme from Bacillus anthracis is naturally resistant to trimethoprim, at least in part due to the presence of a Phe96 substitution in the putative trimethoprim binding site of the enzyme. Inhibitor development by virtual screening for dual-site inhibitors, overview
-
additional information
-
the enzyme from Bacillus anthracis is naturally resistant to trimethoprim, at least in part due to the presence of a Phe96 substitution in the putative trimethoprim binding site of the enzyme. Inhibitor development by virtual screening for dual-site inhibitors, overview
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000097 - 0.00049
2,4-diamino-5-[3-(2-methoxy-5-phenylphenyl)prop-1-ynyl]-6-ethylpyrimidine
0.00043 - 0.00259
2,4-diamino-5-[3-(2-phenyl-5-methoxyphenyl)prop-1-ynyl]-6-ethylpyrimidine
0.00039 - 0.00489
3-(2,4-diamino-6-methylpyrimidin-5-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol
0.00183 - 0.00752
5-[3-(2,5-dimethoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
0.0016 - 0.0092
5-[3-(2-methoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
0.00164 - 0.0117
5-[3-(3-methoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
0.00103 - 0.00266
5-[3-(5-methoxybiphenyl-3-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
0.002 - 0.00981
5-[3-methoxy-3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
0.000064 - 0.00119
6-ethyl-5-[3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
0.00023 - 0.0017
6-ethyl-5-[3-(4-methoxybiphenyl-3-yl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
0.00017 - 0.0341
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)but-1-yn-1-yl]pyrimidine-2,4-diamine
0.00119 - 0.00391
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)pent-1-yn-1-yl]pyrimidine-2,4-diamine
0.000049 - 0.00125
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
0.00294 - 0.00481
6-methyl-5-[3-methyl-3-(3,4,5-trimethoxyphenyl)but-1-yn-1-yl]pyrimidine-2,4-diamine
0.000097
2,4-diamino-5-[3-(2-methoxy-5-phenylphenyl)prop-1-ynyl]-6-ethylpyrimidine
mutant enzyme Y102F, at pH 7.0 and 25°C
0.00033
2,4-diamino-5-[3-(2-methoxy-5-phenylphenyl)prop-1-ynyl]-6-ethylpyrimidine
wild type enzyme, at pH 7.0 and 25°C
0.00049
2,4-diamino-5-[3-(2-methoxy-5-phenylphenyl)prop-1-ynyl]-6-ethylpyrimidine
mutant enzyme F96I, at pH 7.0 and 25°C
0.00043
2,4-diamino-5-[3-(2-phenyl-5-methoxyphenyl)prop-1-ynyl]-6-ethylpyrimidine
mutant enzyme Y102F, at pH 7.0 and 25°C
0.00104
2,4-diamino-5-[3-(2-phenyl-5-methoxyphenyl)prop-1-ynyl]-6-ethylpyrimidine
mutant enzyme F96I, at pH 7.0 and 25°C
0.00259
2,4-diamino-5-[3-(2-phenyl-5-methoxyphenyl)prop-1-ynyl]-6-ethylpyrimidine
wild type enzyme, at pH 7.0 and 25°C
0.00039
3-(2,4-diamino-6-methylpyrimidin-5-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol
mutant enzyme Y102F, at pH 7.0 and 25°C
0.00439
3-(2,4-diamino-6-methylpyrimidin-5-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol
mutant enzyme F96I, at pH 7.0 and 25°C
0.00489
3-(2,4-diamino-6-methylpyrimidin-5-yl)-1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol
wild type enzyme, at pH 7.0 and 25°C
0.00183
5-[3-(2,5-dimethoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
mutant enzyme Y102F, at pH 7.0 and 25°C
0.00516
5-[3-(2,5-dimethoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
wild type enzyme, at pH 7.0 and 25°C
0.00752
5-[3-(2,5-dimethoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
mutant enzyme F96I, at pH 7.0 and 25°C
0.0003
5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine
wild type enzyme, at pH 7.0 and 25°C
0.00069
5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine
mutant enzyme Y102F, at pH 7.0 and 25°C
0.0205
5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine
mutant enzyme F96I, at pH 7.0 and 25°C
0.0002
5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
mutant enzyme Y102F, at pH 7.0 and 25°C
0.00036
5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
wild type enzyme, at pH 7.0 and 25°C
0.00451
5-[3-(2,5-dimethoxyphenyl)prop-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
mutant enzyme F96I, at pH 7.0 and 25°C
0.0016
5-[3-(2-methoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
mutant enzyme Y102F, at pH 7.0 and 25°C
0.00583
5-[3-(2-methoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
wild type enzyme, at pH 7.0 and 25°C
0.0092
5-[3-(2-methoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
mutant enzyme F96I, at pH 7.0 and 25°C
0.00164
5-[3-(3-methoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
mutant enzyme Y102F, at pH 7.0 and 25°C
0.0104
5-[3-(3-methoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
mutant enzyme F96I, at pH 7.0 and 25°C
0.0117
5-[3-(3-methoxybiphenyl-4-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
wild type enzyme, at pH 7.0 and 25°C
0.00103
5-[3-(5-methoxybiphenyl-3-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
mutant enzyme Y102F, at pH 7.0 and 25°C
0.0011
5-[3-(5-methoxybiphenyl-3-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
mutant enzyme F96I, at pH 7.0 and 25°C
0.00266
5-[3-(5-methoxybiphenyl-3-yl)but-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
wild type enzyme, at pH 7.0 and 25°C
0.000083
5-[3-(biphenyl-3-yl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine
mutant enzyme Y102F, at pH 7.0 and 25°C
0.00037
5-[3-(biphenyl-3-yl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine
wild type enzyme, at pH 7.0 and 25°C
0.00131
5-[3-(biphenyl-3-yl)prop-1-yn-1-yl]-6-ethylpyrimidine-2,4-diamine
mutant enzyme F96I, at pH 7.0 and 25°C
0.002
5-[3-methoxy-3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
mutant enzyme Y102F, at pH 7.0 and 25°C
0.00635
5-[3-methoxy-3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
mutant enzyme F96I, at pH 7.0 and 25°C
0.00981
5-[3-methoxy-3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]-6-methylpyrimidine-2,4-diamine
wild type enzyme, at pH 7.0 and 25°C
0.000064
6-ethyl-5-[3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
mutant enzyme Y102F, at pH 7.0 and 25°C
0.00032
6-ethyl-5-[3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
wild type enzyme, at pH 7.0 and 25°C
0.00119
6-ethyl-5-[3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
mutant enzyme F96I, at pH 7.0 and 25°C
0.00023
6-ethyl-5-[3-(4-methoxybiphenyl-3-yl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
mutant enzyme Y102F, at pH 7.0 and 25°C
0.00121
6-ethyl-5-[3-(4-methoxybiphenyl-3-yl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
wild type enzyme, at pH 7.0 and 25°C
0.0017
6-ethyl-5-[3-(4-methoxybiphenyl-3-yl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
mutant enzyme F96I, at pH 7.0 and 25°C
0.00017
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)but-1-yn-1-yl]pyrimidine-2,4-diamine
mutant enzyme Y102F, at pH 7.0 and 25°C
0.0102
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)but-1-yn-1-yl]pyrimidine-2,4-diamine
wild type enzyme, at pH 7.0 and 25°C
0.0341
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)but-1-yn-1-yl]pyrimidine-2,4-diamine
mutant enzyme F96I, at pH 7.0 and 25°C
0.00119
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)pent-1-yn-1-yl]pyrimidine-2,4-diamine
mutant enzyme Y102F, at pH 7.0 and 25°C
0.00337
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)pent-1-yn-1-yl]pyrimidine-2,4-diamine
wild type enzyme, at pH 7.0 and 25°C
0.00391
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)pent-1-yn-1-yl]pyrimidine-2,4-diamine
mutant enzyme F96I, at pH 7.0 and 25°C
0.000049
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
mutant enzyme Y102F, at pH 7.0 and 25°C
0.00115
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
mutant enzyme F96I, at pH 7.0 and 25°C
0.00125
6-methyl-5-[3-(3,4,5-trimethoxyphenyl)prop-1-yn-1-yl]pyrimidine-2,4-diamine
wild type enzyme, at pH 7.0 and 25°C
0.00294
6-methyl-5-[3-methyl-3-(3,4,5-trimethoxyphenyl)but-1-yn-1-yl]pyrimidine-2,4-diamine
mutant enzyme Y102F, at pH 7.0 and 25°C
0.00428
6-methyl-5-[3-methyl-3-(3,4,5-trimethoxyphenyl)but-1-yn-1-yl]pyrimidine-2,4-diamine
wild type enzyme, at pH 7.0 and 25°C
0.00481
6-methyl-5-[3-methyl-3-(3,4,5-trimethoxyphenyl)but-1-yn-1-yl]pyrimidine-2,4-diamine
mutant enzyme F96I, at pH 7.0 and 25°C
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00089
2,4-diamino-5-(3-(2,5-dimethoxyphenyl)prop-1-ynyl)-6-ethylpyrimidine
Bacillus anthracis
pH 7.0, 25°C
0.0032
2,4-diamino-5-(3-phenylprop-1-ynyl)-6-ethylpyrimidine
Bacillus anthracis
pH 7.0, 25°C
0.0092
2,4-diamino-5-[3-(2,3-dimethoxyphenyl)prop-1-ynyl]-6-ethylpyrimidine
Bacillus anthracis
pH 7.0, 25°C
0.00089
2,4-diamino-5-[3-(2,5-dimethoxyphenyl)prop-1-ynyl]-6-ethylpyrimidine
Bacillus anthracis
pH 7.0, 25°C
0.0013
2,4-diamino-5-[3-(2,5-dimethoxyphenyl)prop-1-ynyl]-6-methylpyrimidine
Bacillus anthracis
pH 7.0, 25°C
0.0055
2,4-diamino-5-[3-(2,5-dimethoxyphenyl)prop-1-ynyl]-6-npropylpyrimidine
Bacillus anthracis
pH 7.0, 25°C
0.0017
2,4-diamino-5-[3-(2,5-dimethoxyphenyl)prop-1-ynyl]pyrimidine
Bacillus anthracis
pH 7.0, 25°C
0.00094
2,4-diamino-5-[3-(3,4,5-trimethoxyphenyl)prop-1-ynyl]-6-ethylpyrimidine
Bacillus anthracis
pH 7.0, 25°C
0.074
2-(3-(2-(hydroxyimino)-2-(pyridine-4-yl)-6,7-dimethylquinoxalin-2-yl)-1-(pyridine-4-yl)ethanone) oxime
Bacillus anthracis
pH 7.1, 25°C
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
25
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
DHFR is essential for the survival and pathogenesis of anthrax. DHFR is required for de novo DNA synthesis and amino acid synthesis
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). PDB
SCOP
CATH
UNIPROT
ORGANISM
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
enzyme in ternary complex with NADPH and inhibitor methotrexate, soaking of crystals in 0.1 M Bis-Tris, pH 5.5, 0.2 M CaCl2 and 22.5% w/v PEG 3350 supplemented with 5 mM beta-NADPH at 4°C for 8 h, cryoprotection with 20% v/v glycerol and 5 mM beta-NADPH, X-ray diffraction structure determination and analysis at 2.3 A resolution
in complex with methotrexate, at 2.4 A resolution. Modeling of inhibitor 5-nitro-6-methylamino-isocytosine into the active site reveals four potential hydrogen bonds
purified recombinant His-tagged enzyme in complex with inhibitors RAB1 and trimethoprim, DHFR-RAB1 cocrystals grow within 1 to 2 days at 22°C in a sitting-drop format from a 30 mg/ml protein solution mixed 1:1 with a well solution containing 12% PEG 3350, 0.2 M CaCl2, 0.1 M MES, pH 5.8, and 3% glycerol. DHFR-TMP cocrystals grow within 10 days at 22°C in a sitting-drop format from a 42.5 mg/ml protein solution mixed 1:1 with a well solution containing 13% PEG 3350, 0.2 M CaCl2, 0.1 M MES, pH 5.45, and 1% ethanol, X-ray diffraction structure determination and analysis at 2.3 A resolution
purified recombinant mutant V77A/I130M/I138V enzyme in complex with inhibitor 2,4-diamino-5-[3-(2,5-dimethoxyphenyl)prop-1-ynyl]-6-ethylpyrimidine, hanging-drop vapor diffusion in 25% w/v PEG 10,000, 0.1 M MES, pH 6.5, at an equal ratio of protein to crystallization solution. Microseeding is used to obtain isolated crystals in 10% w/v PEG 10000 and 0.1 M MES, pH 6.5, at a protein concentration of 10 mg/ml, improved by 15% ethylene glycol. X-ray diffraction structure determination and analysis at 2.5 A resolution
wild type and mutant enzymes bound to trimethoprim and propargyl-linked inhibitors, hanging drop vapor diffusion method, using 22.5% (w/v) PEG 10000, 0.1 M MES, pH 6.75. Microseeding is used to obtain isolated crystals in 12% (w/v) PEG 10000 and 0.1 MES, pH 6.7
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
F96I
the mutant shows strongly reduced catalytic efficiency compared to the wild type enzyme
Y102F
the mutant shows reduced catalytic efficiency compared to the wild type enzyme. The affinities of the antifolates increase up to 60fold with this mutant
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography and gel filtration to homogeneity
recombinant His-tagged mutant V77A/I130M/I138V from Escherichia colii strain M15 by nickel affinity chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression as His-tagged enzyme in Escherichia coli strain BL21(DE3)
expression of His-tagged mutant V77A/I130M/I138V in Escherichia colii strain M15
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
drug development
enzyme is identical to enzyme from Bacillus cereus. Use of enzyme from Bacillus cereus as antimicrobial target for Bacillus anthracis, homology modelling of inhibitors and growth inhibition assays
drug development
the essential enzyme is a target for development of specific inhibitors for treatment of the biodefense organism Bacillus anthracis
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Joska, T.M.; Anderson, A.C.
Structure-activity relationships of Bacillus cereus and Bacillus anthracis dihydrofolate reductase: toward the identification of new potent drug leads
Antimicrob. Agents Chemother.
50
3435-3443
2006
Bacillus cereus (Q81E04), Bacillus cereus, Bacillus anthracis (Q81R22), Bacillus anthracis
Bennett, B.C.; Xu, H.; Simmerman, R.F.; Lee, R.E.; Dealwis, C.G.
Crystal structure of the anthrax drug target, Bacillus anthracis dihydrofolate reductase
J. Med. Chem.
50
4374-4381
2007
Bacillus anthracis (Q81R22), Bacillus anthracis
Bourne, C.R.; Bunce, R.A.; Bourne, P.C.; Berlin, K.D.; Barrow, E.W.; Barrow, W.W.
Crystal structure of Bacillus anthracis dihydrofolate reductase with the dihydrophthalazine-based trimethoprim derivative RAB1 provides a structural explanation of potency and selectivity
Antimicrob. Agents Chemother.
53
3065-3073
2009
Bacillus anthracis (Q81R22), Bacillus anthracis
Beierlein, J.M.; Deshmukh, L.; Frey, K.M.; Vinogradova, O.; Anderson, A.C.
The solution structure of Bacillus anthracis dihydrofolate reductase yields insight into the analysis of structure-activity relationships for novel inhibitors
Biochemistry
48
4100-4108
2009
Bacillus anthracis (Q81R22), Bacillus anthracis
Beierlein, J.M.; Frey, K.M.; Bolstad, D.B.; Pelphrey, P.M.; Joska, T.M.; Smith, A.E.; Priestley, N.D.; Wright, D.L.; Anderson, A.C.
Synthetic and crystallographic studies of a new inhibitor series targeting Bacillus anthracis dihydrofolate reductase
J. Med. Chem.
51
7532-7540
2008
Homo sapiens, Bacillus anthracis (Q81R22), Bacillus anthracis
Bennett, B.C.; Wan, Q.; Ahmad, M.F.; Langan, P.; Dealwis, C.G.
X-ray structure of the ternary MTX-NADPH complex of the anthrax dihydrofolate reductase: a pharmacophore for dual-site inhibitor design
J. Struct. Biol.
166
162-171
2009
Bacillus anthracis (Q81R22), Bacillus anthracis
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