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Information on EC 1.5.1.3 - dihydrofolate reductase and Organism(s) Pneumocystis carinii and UniProt Accession P16184
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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: Pneumocystis carinii
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
-
-
-
-
DHFR
-
-
-
-
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+
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
r
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+
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
r
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2,4-diamino-6-[(2',5'-dichloroanilino)methyl]pyrido[2,3-d]pyrimidine
OAAG324, a potent inhibitor of dihydrofolate reductase
2,4-diamino-6-[(3',4',5'-trichloroanilino)methyl]pyrido[2,3-d]pyrimidine
-
3-(2,4-diaminophenyl)-1-(3-(4-methylbenzyloxy)phenyl)prop-2-en-1-one
-
3-(2,4-diaminopyrimidin-5-yl)-1-(4-methoxyphenyl)-prop-2-en-1-one
-
5-((10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)methyl)-pyrimidine-2,4-diamine
-
6-((10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)methyl)-1,3,5-triazine-2,4-diamine
-
6-((2-chloro-10H-phenothiazin-10-yl)methyl)-1,3,5-triazine-2,4-diamine
-
N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine
binding complex structure analysis
N6-methyl-N6-(4-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine
binding complex structure analysis
N6-methyl-N6-1-naphthylpyrido[2,3-d]pyrimidine-2,4,6-triamine
binding complex structure analysis
2,4-diamino-5-methyl-6-(2',3',5',6'-tetrafluoro-4'-trifluoromethylphenylsulfanyl)-furo[2,3-d]pyrimidine
-
-
2,4-diamino-5-methyl-6-(2',5'-dimethoxyphenylsulfanyl)-furo[2,3-d]pyrimidine
-
-
2,4-diamino-5-methyl-6-(2',6'-dichlorophenylsulfanyl)-furo[2,3-d]pyrimidine
-
-
2,4-diamino-5-methyl-6-(2',6'-dimethylphenylsulfanyl)-furo[2,3-d]pyrimidine
-
-
2,4-diamino-5-methyl-6-(2'-isopropyl-6'-methylphenylsulfanyl)-furo[2,3-d]pyrimidine
-
-
2,4-diamino-5-methyl-6-(2'-methoxyphenylsulfanyl)-furo[2,3-d]pyrimidine
-
-
2,4-diamino-5-methyl-6-(3',4'-dimethoxyphenylsulfanyl)-furo[2,3-d]pyrimidine
-
-
2,4-diamino-5-methyl-6-(3'-methoxyphenylsulfanyl)-furo[2,3-d]pyrimidine
-
-
2,4-diamino-5-methyl-6-(4'-methoxyphenylsulfanyl)-furo[2,3-d]pyrimidine
-
-
2,4-diamino-6-[N-(2,5-dimethoxybenzyl)-N-cyclopropyl methylamino]quinazoline
-
-
2,4-diamino-6-[N-(beta-naphthyl)-N-cyclopropyl methylamino]-quinazoline
-
-
N-[4-[(2,4-diamino-5-methyl-furo[2,3-d]pyrimidin-6-yl)-thio]-benzoyl]-L-glutamic acid
-
-
N6-(2,5-dimethoxybenzyl)-N6-methylpyrido[2,3-d]pyrimidine-2,4,6-triamine
-
-
additional information
design and synthesis of a series of bicyclic pyrido[2,3-d]pyrimidines that contain an N6-(substituted phenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine scaffold in which the substituted aniline is directly attached to the 6-position of the pyrido[2,3-d] pyrimidine ring as selective and potent inhibitors. Analysis of the interactions that enhance the selectivity of binding and to directly compare the binding of the most potent analogue in the series, N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine with enzyme from Homosapiens, Pneumocystis carinii, and Pneumocystis jirovecii, overview
-
additional information
-
design and synthesis of a series of bicyclic pyrido[2,3-d]pyrimidines that contain an N6-(substituted phenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine scaffold in which the substituted aniline is directly attached to the 6-position of the pyrido[2,3-d] pyrimidine ring as selective and potent inhibitors. Analysis of the interactions that enhance the selectivity of binding and to directly compare the binding of the most potent analogue in the series, N6-methyl-N6-(3,4,5-trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine with enzyme from Homosapiens, Pneumocystis carinii, and Pneumocystis jirovecii, overview
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0035
7,8-dihydrofolate
recombinant wild-type enzyme, pH 7.4, 37°C
0.0097
7,8-dihydrofolate
recombinant mutant K37S/F69N, pH 7.4, 37°C
0.0107
7,8-dihydrofolate
recombinant mutant K37Q/F69N, pH 7.4, 37°C
0.0116
7,8-dihydrofolate
recombinant mutant K37S/F69S, pH 7.4, 37°C
0.0185
7,8-dihydrofolate
recombinant mutant K37Q/F69S, pH 7.4, 37°C
additional information
additional information
Michaelis-Menten steady-state kinetics
-
additional information
additional information
-
Michaelis-Menten steady-state kinetics
-
additional information
additional information
-
buffer and salt conditions significantly alter the Km-values for the substrates
-
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
0.00000026 - 0.0000063
2,4-diamino-6-[(2',5'-dichloroanilino)methyl]pyrido[2,3-d]pyrimidine
0.00000026
2,4-diamino-6-[(2',5'-dichloroanilino)methyl]pyrido[2,3-d]pyrimidine
mutant K37Q enzyme, pH 7.4, 37°C
0.00000071
2,4-diamino-6-[(2',5'-dichloroanilino)methyl]pyrido[2,3-d]pyrimidine
mutant K37Q/F69N enzyme, pH 7.4, 37°C
0.0000063
2,4-diamino-6-[(2',5'-dichloroanilino)methyl]pyrido[2,3-d]pyrimidine
wild-type enzyme, pH 7.4, 37°C
additional information
additional information
inhibition kinetics of wild-type and mutant enzymes, comparison with the inhibition kinetics of enzymes and enzyme mutants from Homo sapiens and Pneumocystis jirovecii, overview
-
additional information
additional information
-
inhibition kinetics of wild-type and mutant enzymes, comparison with the inhibition kinetics of enzymes and enzyme mutants from Homo sapiens and Pneumocystis jirovecii, overview
-
additional information
additional information
-
comparison of inhibition kinetics of wild-type enzyme with those of wild-type and mutant enzyme from Homo sapiens
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0078
(2,4-diaminopyrimidin-5-yl)methyl naphthalene-2-sulfonate
Pneumocystis carinii
37°C, pH not specified in the publication
0.011
3-(2,4-diaminophenyl)-1-(3-(4-methylbenzyloxy)phenyl)prop-2-en-1-one
Pneumocystis carinii
37°C, pH not specified in the publication
0.151
3-(2,4-diaminopyrimidin-5-yl)-1-(4-methoxyphenyl)-prop-2-en-1-one
Pneumocystis carinii
37°C, pH not specified in the publication
0.00084
5-((10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)methyl)-pyrimidine-2,4-diamine
Pneumocystis carinii
37°C, pH not specified in the publication
0.363
5-((4-methoxyphenylamino)methyl)pyrimidine-2,4-diamine
Pneumocystis carinii
37°C, pH not specified in the publication
0.026
5-((5H-dibenzo[b,f]azepin-5-yl)methyl)pyrimidine-2,4-diamine
Pneumocystis carinii
37°C, pH not specified in the publication
0.035
5-((benzo[d]oxazol-2-ylthio)methyl)pyrimidine-2,4-diamine
Pneumocystis carinii
37°C, pH not specified in the publication
0.038
5-((methyl(naphthalen-1-yl)amino)methyl)pyrimidine-2,4-diamine
Pneumocystis carinii
37°C, pH not specified in the publication
0.15
5-((naphthalen-1-ylamino)methyl)pyrimidine-2,4-diamine
Pneumocystis carinii
37°C, pH not specified in the publication
1.265
6-((10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)methyl)-1,3,5-triazine-2,4-diamine
Pneumocystis carinii
37°C, pH not specified in the publication
0.235
6-((10H-phenothiazin-10-yl)methyl)-1,3,5-triazine-2,4-diamine
Pneumocystis carinii
37°C, pH not specified in the publication
0.603
6-((2-chloro-10H-phenothiazin-10-yl)methyl)-1,3,5-triazine-2,4-diamine
Pneumocystis carinii
37°C, pH not specified in the publication
0.112
6-(2-(5H-dibenzo[b,f]azepin-5-yl)ethoxy)pyrimidine-2,4-diamine
Pneumocystis carinii
37°C, pH not specified in the publication
0.148
6-(3,4,5-trimethoxybenzyloxy)pyrimidine-2,4-diamine
Pneumocystis carinii
37°C, pH not specified in the publication
0.0000048
2,4-diamino-5-isopropyl-6-arylthio-7H-pyrrolo[2,3-d]pyrimidine
Pneumocystis carinii
-
37°C
0.0086
2,4-diamino-5-methyl-6-(1-naphthylthio)furo[2,3-d]pyrimidine
Pneumocystis carinii
-
37°C, pH not specified in the publication
0.031
2,4-diamino-5-methyl-6-(2',3',5',6'-tetrafluoro-4'-trifluoromethylphenylsulfanyl)-furo[2,3-d]pyrimidine
Pneumocystis carinii
-
37°C, pH not specified in the publication
0.024
2,4-diamino-5-methyl-6-(2',5'-dimethoxyphenylsulfanyl)-furo[2,3-d]pyrimidine
Pneumocystis carinii
-
37°C, pH not specified in the publication
0.06
2,4-diamino-5-methyl-6-(2',6'-dichlorophenylsulfanyl)-furo[2,3-d]pyrimidine
Pneumocystis carinii
-
37°C, pH not specified in the publication
0.02
2,4-diamino-5-methyl-6-(2',6'-dimethylphenylsulfanyl)-furo[2,3-d]pyrimidine
Pneumocystis carinii
-
37°C, pH not specified in the publication
0.036
2,4-diamino-5-methyl-6-(2'-isopropyl-6'-methylphenylsulfanyl)-furo[2,3-d]pyrimidine
Pneumocystis carinii
-
37°C, pH not specified in the publication
0.02
2,4-diamino-5-methyl-6-(2'-methoxyphenylsulfanyl)-furo[2,3-d]pyrimidine
Pneumocystis carinii
-
37°C, pH not specified in the publication
0.012
2,4-diamino-5-methyl-6-(2-naphthylthio)furo[2,3-d]pyrimidine
Pneumocystis carinii
-
37°C, pH not specified in the publication
0.036
2,4-diamino-5-methyl-6-(3',4'-dimethoxyphenylsulfanyl)-furo[2,3-d]pyrimidine
Pneumocystis carinii
-
37°C, pH not specified in the publication
0.025
2,4-diamino-5-methyl-6-(3'-methoxyphenylsulfanyl)-furo[2,3-d]pyrimidine
Pneumocystis carinii
-
37°C, pH not specified in the publication
0.0347
2,4-diamino-5-methyl-6-(4'-methoxyphenylsulfanyl)-furo[2,3-d]pyrimidine
Pneumocystis carinii
-
37°C, pH not specified in the publication
0.00000311
2,4-diamino-5-propyl-6-arylthio-7H-pyrrolo[2,3-d]pyrimidine
Pneumocystis carinii
-
37°C
0.0000069
2,4-diamino-6-[N-(2,3,5-trichlorobenzyl)-N-ethylamino]quinazoline
Pneumocystis carinii
-
-
0.000025
2,4-diamino-6-[N-(2,5-dimethoxybenzyl)-N-cyclopropyl methylamino]quinazoline
Pneumocystis carinii
-
-
0.0000099
2,4-diamino-6-[N-(2,5-dimethoxybenzyl)-N-ethylamino]quinazoline
Pneumocystis carinii
-
-
0.000038
2,4-diamino-6-[N-(2,5-dimethoxybenzyl)-N-propylamino]quinazoline
Pneumocystis carinii
-
-
0.0000025
2,4-diamino-6-[N-(alpha-naphthyl)-N-ethylamino]quinazoline
Pneumocystis carinii
-
-
0.000042
2,4-diamino-6-[N-(beta-naphthyl)-N-cyclopropyl methylamino]-quinazoline
Pneumocystis carinii
-
-
0.000078
N-[4-[(2,4-diamino-5-methyl-furo[2,3-d]pyrimidin-6-yl)-thio]-benzoyl]-L-glutamic acid
Pneumocystis carinii
-
37°C, pH not specified in the publication
0.000084
N6-(2,5-dimethoxybenzyl)-N6-methylpyrido[2,3-d]pyrimidine-2,4,6-triamine
Pneumocystis carinii
-
-
0.000087
N6-(2,5-dimethoxybenzyl)-N6-methylquinazoline-2,4,6-triamine
Pneumocystis carinii
-
-
0.0038
N6-(2,5-dimethoxybenzyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine
Pneumocystis carinii
-
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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). DYR_PNECA
206
0
23884
Swiss-Prot
Secretory Pathway (Reliability: 5)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified enzyme complexed with inhibitor N6-methyl-N6-1-naphthylpyrido[2,3-d]pyrimidine-2,4,6-triamine, and NADPH, hanging drop vapor diffusion method, mixing of 11.4-14.1 mg/ml protein in 50 mM MES, pH 6.0, 100 ml KCl, and a tenfold excess of NADPH and inhibitor, with reservoir solution containiing 35% PEG 2000, 49 mM MES, pH 6.0, and 100 mM KCl, equilibration against a reservoir solution consisting of 0.1 M HEPES pH 7.5, 25% PEG 2000 MM, X-ray diffraction structure determination and analyis at 1.61 A resolution, modeling
purified recombinant detagged wild-type enzyme and mutant K37Q in complex with inhibitor 2,4-diamino-6-[(2',5'-dichloro anilino)methyl]pyrido[2,3-d]pyrimidine, hanging drop vapour diffusion method, mixing of 20.4 mg/ml protein in 20 mM MES, pH 6.0, 100 mM KCl with a 0:1 molar excess of NADPH and inhibitor, and with reservoir solution containing 100 mM K2HPO4, pH 6.9, 60-64% saturated (NH4)2SO4, and 3% (v/v) ethyl alcohol, 0.01 ml drops, 4°C, for mutant K37Q/F69N, 10.9 mg/ml protein in 10 mM MES, pH 6.0, and 100 mM KCl, is mixed with with a 0:1 molar excess of NADPH and inhibitor, and with a reservoir solution containing 33-36% PEG 2000, 50 mM MES, pH 6.0, and 100 mM KCl, 14°C, X-ray diffraction structure determination and analysis at 2.2 A resolution, modeling
crystallization of refolded recombinant enzyme as ternary complex with NADPH and various inhibitors
-
modeling data of inhibitor PT682 in the active site indicate that binding would require ligand-induced conformational changes to the enzyme for the inhibitor to fit or that the inhibitor side-chain would have to adopt an alternative binding mode to that observed for similar inhibitors. The complexes have an increased active-site volume compared with complexes of the enzyme from Mus musculus
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
K37Q
site-directed mutagenesis, the mutant exhibits increased sensitivity for inhibition by 2,4-diamino-6-[(2',5'-dichloro anilino)methyl]pyrido[2,3-d]pyrimidine compared to the wild-type enzyme
K37Q/F69N
site-directed mutagenesis, the mutant exhibits increased sensitivity for inhibition by 2,4-diamino-6-[(2',5'-dichloro anilino)methyl]pyrido[2,3-d]pyrimidine compared to the wild-type enzyme. Structure analysis of the mutant in complex with TMP, overview
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged wild-type and mutant enzymes from Escherichia coli Rosetta Gami B (DE3) by nickel affinity chromatography, and tag cleavage through the SUMO protease Ulp1, followed by another step of nickel affinity chromatography to remove the tag
recombinant His-tagged enzyme from Escherichia coli by two steps of nickel affinity chromatography with Ulp1 protease cleavage after the first step
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant expression of His-tagged wild-type and mutant enzymes in Escherichia coli Rosetta Gami B (DE3)
RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
refolding after solubilisation from inclusion bodies with 4 M guanidium hydrochloride in 0.5% polyethylene glycol 1450, pH 7.0
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
-
use of multiple protein structure technique for structure-based drug discovery. Construction of receptor-based pharmacophores using multiple X-ray crystallographic structures. Models incorporate a fair degree of protein flexibility and are highly selective for known inhibitors over drug-like non-inhibitors
drug development
drug development
-
use of multiple protein structure technique for structure-based drug discovery. Construction of receptor-based pharmacophores using multiple X-ray crystallographic structures. Models incorporate a fair degree of protein flexibility and are highly selective for known inhibitors over drug-like non-inhibitors
drug development
-
the enzyme is a target for drug development since the organism causes the opportunistic infection Pneumocystis pneumonia, a major cause of mortality in acquired immunodeficiency syndrome, AIDS, patients
drug development
-
the essential enzyme is a target for development of specific inhibitors for treatment of the causative agent in AIDS pneumonia
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Ma, L.; Kovacs, J.A.
Expression and characterization of recombinant human-derived Pneumocystis carinii dihydrofolate reductase
Antimicrob. Agents Chemother.
44
3092-3096
2000
Pneumocystis carinii
Delves, C.J.; Ballantine, S.P.; Tansik, R.L.; Baccanari, D.P.; Stammers, D.K.
Refolding of recombinant Pneumocystis carinii dihydrofolate reductase and characterization of the enzyme
Protein Expr. Purif.
4
16-23
1993
Pneumocystis carinii, Rattus norvegicus
Cody, V.; Pace, J.; Rosowsky, A.
Structural analysis of a holoenzyme complex of mouse dihydrofolate reductase with NADPH and a ternary complex with the potent and selective inhibitor 2,4-diamino-6-(2-hydroxydibenz[b,f]azepin-5-yl)methylpteridine
Acta Crystallogr. Sect. D
64
977-984
2008
Pneumocystis carinii, Mus musculus (P00375), Mus musculus
Bowman, A.L.; Lerner, M.G.; Carlson, H.A.
Protein flexibility and species specificity in structure-based drug discovery: dihydrofolate reductase as a test system
J. Am. Chem. Soc.
129
3634-3640
2007
Homo sapiens, Pneumocystis carinii
Gangjee, A.; Jain, H.D.; Queener, S.F.; Kisliuk, R.L.
The effect of 5-alkyl modification on the biological activity of pyrrolo[2,3-d]pyrimidine containing classical and nonclassical antifolates as inhibitors of dihydrofolate reductase and as antitumor and/or antiopportunistic infection agents
J. Med. Chem.
51
4589-4600
2008
Pneumocystis carinii, Rattus norvegicus, Toxoplasma gondii, Homo sapiens (P00374), Homo sapiens
Cody, V.; Pace, J.; Makin, J.; Piraino, J.; Queener, S.F.; Rosowsky, A.
Correlations of inhibitor kinetics for Pneumocystis jirovecii and human dihydrofolate reductase with structural data for human active site mutant enzyme complexes (dagger) (double dagger)
Biochemistry
48
1702-1711
2009
Pneumocystis carinii, Pneumocystis jirovecii, Homo sapiens (P00374), Homo sapiens
Gangjee, A.; Adair, O.O.; Pagley, M.; Queener, S.F.
N9-substituted 2,4-diaminoquinazolines: synthesis and biological evaluation of lipophilic inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase
J. Med. Chem.
51
6195-6200
2008
Pneumocystis carinii, Toxoplasma gondii
Bag, S.; Tawari, N.R.; Degani, M.S.; Queener, S.F.
Design, synthesis, biological evaluation and computational investigation of novel inhibitors of dihydrofolate reductase of opportunistic pathogens
Bioorg. Med. Chem.
18
3187-3197
2010
Mycobacterium avium, Rattus norvegicus, Toxoplasma gondii, Pneumocystis carinii (P16184), Pneumocystis carinii
Gangjee, A.; Jain, H.D.; Phan, J.; Guo, X.; Queener, S.F.; Kisliuk, R.L.
2,4-Diamino-5-methyl-6-substituted arylthio-furo[2,3-d]pyrimidines as novel classical and nonclassical antifolates as potential dual thymidylate synthase and dihydrofolate reductase inhibitors
Bioorg. Med. Chem.
18
953-961
2010
Mycobacterium avium, Pneumocystis carinii, Rattus norvegicus, Toxoplasma gondii
Cody, V.; Pace, J.; Namjoshi, O.; Gangjee, A.
Structure-activity correlations for three pyrido[2,3-d]pyrimidine antifolates binding to human and Pneumocystis carinii dihydrofolate reductase
Acta Crystallogr. Sect. F
71
799-803
2015
Homo sapiens (P00374), Homo sapiens, Pneumocystis carinii (P16184), Pneumocystis carinii, Pneumocystis jirovecii (Q9UUP5), Pneumocystis jirovecii
Cody, V.; Pace, J.; Queener, S.; Adair, O.; Gangjee, A.
Kinetic and structural analysis for potent antifolate inhibition of Pneumocystis jirovecii, Pneumocystis carinii, and human dihydrofolate reductases and their active-site variants
Antimicrob. Agents Chemother.
57
2669-2677
2013
Homo sapiens (P00374), Homo sapiens, Pneumocystis carinii (P16184), Pneumocystis carinii, Pneumocystis jirovecii (Q9UUP5), Pneumocystis jirovecii
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