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Information on EC 1.5.1.3 - dihydrofolate reductase and Organism(s) Toxoplasma gondii and UniProt Accession Q07422
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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: Toxoplasma gondii
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+
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
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
?
-
-
molecular mechanism of the distinct differences in substrate channeling behavior between Toxoplasma gondii TS-DHFR and Cryptosporidium hominis TS-DHFR, overview
-
-
?
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+
-
-
-
r
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(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
2,4-diamino-5-((R)-3-(3,4,5-trimethoxyphenyl)but-1-ynyl)-6-methylpyrimidine
pH 7.0
2,4-diamino-5-((S)-3-(3,4,5-trimethoxyphenyl)but-1-ynyl)-6-methylpyrimidine
pH 7.0
2,4-diamino-5-(3-(3,4,5-trimethoxyphenyl)but-1-ynyl)-6-methylpyrimidine
pH 7.0
2,4-diamino-5-(3-(3,4,5-trimethoxyphenyl)but-1-ynyl)pyrimidine
pH 7.0
2,4-diamino-5-(3-(3,4,5-trimethoxyphenyl)prop-1-ynyl)-6-methylpyrimidine
pH 7.0
2,4-diamino-5-(3-methoxy-3-(3,4,5-trimethoxyphenyl)prop-1-ynyl)-6-methylpyrimidine
pH 7.0
N10-propargyl-5,8-dideazafolate
PDDF, a TS folate inhibitor, binds at the TS active site
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-5-propyl-6-(1'-naphthylsulfanyl)-7H-pyrrolo[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
-
-
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-5-[(2,5-dimethoxyphenyl)sulfanyl]-6-ethylthieno[2,3-d ]pyrimidin-4(3H)-one
-
-
2-amino-5-[(2,5-dimethoxyphenyl)sulfanyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one
-
-
2-amino-5-[(2-chlorophenyl)sulfanyl]-6-ethylthieno[2,3-d ]pyrimidin-4(3H)-one
-
-
2-amino-5-[(3,4-dichlorophenyl)sulfanyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one
-
-
2-amino-5-[(3,4-dichlorophenyl)thio]-6-ethylthieno[2,3-d ]pyrimidin-4(3H)-one
-
-
2-amino-5-[(3,5-dichlorophenyl)sulfanyl]-6-ethylthieno[2,3-d ]-pyrimidin-4(3H)-one
-
-
2-amino-5-[(3,5-dichlorophenyl)sulfanyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one
-
-
2-amino-5-[(3,5-dimethoxyphenyl)sulfanyl]-6-ethylthieno[2,3-d ]pyrimidin-4(3H)-one
-
-
2-amino-5-[(3-chlorophenyl)sulfanyl]-6-ethylthieno[2,3-d ]pyrimidin-4(3H)-one
-
-
2-amino-5-[(4-bromophenyl)sulfanyl]-6-ethylthieno[2,3-d ]pyrimidin-4(3H)-one
-
-
2-amino-5-[(4-chlorophenyl)sulfanyl]-6-ethylthieno[2,3-d]pyrimidin-4(3H)-one
-
-
2-amino-5-[(4-chlorophenyl)sulfanyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one
-
-
2-amino-5-[(4-fluorophenyl)sulfanyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one
-
-
2-amino-6-ethyl-5-(pyridin-4-ylsulfanyl)thieno[2,3-d ]pyrimidin-4(3H)-one
-
-
2-amino-6-ethyl-5-[(4-fluorophenyl)sulfanyl]thieno[2,3-d ]pyrimidin-4(3H)-one
-
-
2-amino-6-ethyl-5-[(4-nitrophenyl)sulfanyl]thieno[2,3-d]pyrimidin-4(3H)-one
-
-
2-amino-6-methyl-5-(2-naphthylsulfanyl)thieno[2,3-d]pyrimidin-4(3H)-one
-
-
2-amino-6-methyl-5-(4-nitrobenzyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
-
-
2-amino-6-methyl-5-(pyridin-4-ylsulfanyl)thieno[2,3-d]pyrimidin-4(3H)-one
-
-
2-amino-6-methyl-5-[(4-nitrophenyl)sulfanyl]thieno[2,3-d]pyrimidin-4(3H)-one
-
-
2-amino-6-methyl-5-[4-(trifluoromethoxy)benzyl]-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-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
-
-
N-(4-[(2-amino-6-ethyl-4-oxo-3,4-dihydrothieno[2,3-d ]pyrimidin-5-yl)thio]benzoyl)-L-glutamic acid
-
-
N-(4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoyl)-L-glutamic acid
-
inhibitory to human dihydrofolate reductase, little inhibition of Escherichia coli enzyme
N-(4-[(2-amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3-d ]pyrimidin-5-yl)thio]benzoyl)-L-glutamic acid
-
-
N-(4-[(2-amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)sulfanyl]benzoyl)-L-glutamic acid
-
binding mode, overview
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
-
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
single turnover, stopped-flow, and steady-state kinetics
-
additional information
additional information
-
single turnover, stopped-flow, and steady-state kinetics
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.124
(2,4-diaminopyrimidin-5-yl)methyl naphthalene-2-sulfonate
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.000064
2,4-diamino-5-isopropyl-6-(phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine
Toxoplasma gondii
-
37°C
0.083
2,4-diamino-5-methyl-6-(1-naphthylthio)furo[2,3-d]pyrimidine
Toxoplasma gondii
-
37°C, pH not specified in the publication, value above
0.081
2,4-diamino-5-methyl-6-(2',3',5',6'-tetrafluoro-4'-trifluoromethylphenylsulfanyl)-furo[2,3-d]pyrimidine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.038
2,4-diamino-5-methyl-6-(2',5'-dimethoxyphenylsulfanyl)-furo[2,3-d]pyrimidine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.025
2,4-diamino-5-methyl-6-(2',6'-dichlorophenylsulfanyl)-furo[2,3-d]pyrimidine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.019
2,4-diamino-5-methyl-6-(2',6'-dimethylphenylsulfanyl)-furo[2,3-d]pyrimidine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.016
2,4-diamino-5-methyl-6-(2'-isopropyl-6'-methylphenylsulfanyl)-furo[2,3-d]pyrimidine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.044
2,4-diamino-5-methyl-6-(2'-methoxyphenylsulfanyl)-furo[2,3-d]pyrimidine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.012
2,4-diamino-5-methyl-6-(2-naphthylthio)furo[2,3-d]pyrimidine
Toxoplasma gondii
-
37°C, pH not specified in the publication, value above
0.051
2,4-diamino-5-methyl-6-(3',4'-dimethoxyphenylsulfanyl)-furo[2,3-d]pyrimidine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.045
2,4-diamino-5-methyl-6-(3'-methoxyphenylsulfanyl)-furo[2,3-d]pyrimidine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.069
2,4-diamino-5-methyl-6-(4'-methoxyphenylsulfanyl)-furo[2,3-d]pyrimidine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.000058
2,4-diamino-5-propyl-6-(1'-naphthylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine
Toxoplasma gondii
-
37°C
0.000019
2,4-diamino-6-[N-(2,3,5-trichlorobenzyl)-N-ethylamino]quinazoline
Toxoplasma gondii
-
-
0.0000073
2,4-diamino-6-[N-(2,5-dimethoxybenzyl)-N-cyclopropyl methylamino]quinazoline
Toxoplasma gondii
-
-
0.0000037
2,4-diamino-6-[N-(2,5-dimethoxybenzyl)-N-ethylamino]quinazoline
Toxoplasma gondii
-
-
0.0000095
2,4-diamino-6-[N-(2,5-dimethoxybenzyl)-N-propylamino]quinazoline
Toxoplasma gondii
-
-
0.000025
2,4-diamino-6-[N-(beta-naphthyl)-N-cyclopropyl methylamino]-quinazoline
Toxoplasma gondii
-
-
0.00027
2-amino-5-(4-bromobenzyl)-6-methyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
Toxoplasma gondii
-
-
0.00035
2-amino-5-(4-chlorobenzyl)-6-methyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
Toxoplasma gondii
-
-
0.0035
2-amino-5-(4-methoxybenzyl)-6-methyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
Toxoplasma gondii
-
-
0.000014
2-amino-5-[(2,5-dimethoxyphenyl)sulfanyl]-6-ethylthieno[2,3-d ]pyrimidin-4(3H)-one
Toxoplasma gondii
-
pH 7.0, 37°C
0.000056
2-amino-5-[(2,5-dimethoxyphenyl)sulfanyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one
Toxoplasma gondii
-
-
0.000027
2-amino-5-[(2-chlorophenyl)sulfanyl]-6-ethylthieno[2,3-d ]pyrimidin-4(3H)-one
Toxoplasma gondii
-
pH 7.0, 37°C
0.000038
2-amino-5-[(3,4-dichlorophenyl)sulfanyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one
Toxoplasma gondii
-
-
0.0000081
2-amino-5-[(3,4-dichlorophenyl)thio]-6-ethylthieno[2,3-d ]pyrimidin-4(3H)-one
Toxoplasma gondii
-
pH 7.0, 37°C
0.000014
2-amino-5-[(3,5-dichlorophenyl)sulfanyl]-6-ethylthieno[2,3-d ]-pyrimidin-4(3H)-one
Toxoplasma gondii
-
pH 7.0, 37°C
0.000064
2-amino-5-[(3,5-dichlorophenyl)sulfanyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one
Toxoplasma gondii
-
-
0.000024
2-amino-5-[(3,5-dimethoxyphenyl)sulfanyl]-6-ethylthieno[2,3-d ]pyrimidin-4(3H)-one
Toxoplasma gondii
-
pH 7.0, 37°C
0.000012
2-amino-5-[(3-chlorophenyl)sulfanyl]-6-ethylthieno[2,3-d ]pyrimidin-4(3H)-one
Toxoplasma gondii
-
pH 7.0, 37°C
0.000013
2-amino-5-[(4-bromophenyl)sulfanyl]-6-ethylthieno[2,3-d ]pyrimidin-4(3H)-one
Toxoplasma gondii
-
pH 7.0, 37°C
0.000009
2-amino-5-[(4-chlorophenyl)sulfanyl]-6-ethylthieno[2,3-d]pyrimidin-4(3H)-one
Toxoplasma gondii
-
pH 7.0, 37°C
0.000031
2-amino-5-[(4-chlorophenyl)sulfanyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one
Toxoplasma gondii
-
-
0.000048
2-amino-5-[(4-fluorophenyl)sulfanyl]-6-methylthieno[2,3-d]pyrimidin-4(3H)-one
Toxoplasma gondii
-
-
0.0000084
2-amino-6-ethyl-5-(2-naphthylthio)thieno[2,3-d ]pyrimidin-4(3H)-one
Toxoplasma gondii
-
pH 7.0, 37°C
0.000033
2-amino-6-ethyl-5-(phenylsulfanyl)thieno[2,3-d]pyrimidin-4(3H)-one
Toxoplasma gondii
-
pH 7.0, 37°C
0.000017
2-amino-6-ethyl-5-(pyridin-4-ylsulfanyl)thieno[2,3-d ]pyrimidin-4(3H)-one
Toxoplasma gondii
-
pH 7.0, 37°C
0.000025
2-amino-6-ethyl-5-[(4-fluorophenyl)sulfanyl]thieno[2,3-d ]pyrimidin-4(3H)-one
Toxoplasma gondii
-
pH 7.0, 37°C
0.000087
2-amino-6-ethyl-5-[(4-nitrophenyl)sulfanyl]thieno[2,3-d]pyrimidin-4(3H)-one
Toxoplasma gondii
-
pH 7.0, 37°C
0.000044
2-amino-6-methyl-5-(2-naphthylsulfanyl)thieno[2,3-d]pyrimidin-4(3H)-one
Toxoplasma gondii
-
-
0.00033
2-amino-6-methyl-5-(4-nitrobenzyl)-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
Toxoplasma gondii
-
-
0.000034
2-amino-6-methyl-5-(pyridin-4-ylsulfanyl)thieno[2,3-d]pyrimidin-4(3H)-one
Toxoplasma gondii
-
-
0.000056
2-amino-6-methyl-5-[(4-nitrophenyl)sulfanyl]thieno[2,3-d]pyrimidin-4(3H)-one
Toxoplasma gondii
-
-
0.0003
2-amino-6-methyl-5-[4-(trifluoromethoxy)benzyl]-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
Toxoplasma gondii
-
-
0.116
3-(2,4-diaminophenyl)-1-(3-(4-methylbenzyloxy)phenyl)prop-2-en-1-one
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.151
3-(2,4-diaminopyrimidin-5-yl)-1-(4-methoxyphenyl)-prop-2-en-1-one
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.00014
5-((10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)methyl)-pyrimidine-2,4-diamine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.044
5-((4-methoxyphenylamino)methyl)pyrimidine-2,4-diamine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.008
5-((5H-dibenzo[b,f]azepin-5-yl)methyl)pyrimidine-2,4-diamine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.16
5-((benzo[d]oxazol-2-ylthio)methyl)pyrimidine-2,4-diamine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.0034
5-((methyl(naphthalen-1-yl)amino)methyl)pyrimidine-2,4-diamine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.022
5-((naphthalen-1-ylamino)methyl)pyrimidine-2,4-diamine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.139
6-((10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)methyl)-1,3,5-triazine-2,4-diamine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.142
6-((10H-phenothiazin-10-yl)methyl)-1,3,5-triazine-2,4-diamine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.397
6-((2-chloro-10H-phenothiazin-10-yl)methyl)-1,3,5-triazine-2,4-diamine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.00335
6-(2-(5H-dibenzo[b,f]azepin-5-yl)ethoxy)pyrimidine-2,4-diamine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.145
6-(3,4,5-trimethoxybenzyloxy)pyrimidine-2,4-diamine
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.0000021
N-(4-[(2-amino-6-ethyl-4-oxo-3,4-dihydrothieno[2,3-d ]pyrimidin-5-yl)thio]benzoyl)-L-glutamic acid
Toxoplasma gondii
-
pH 7.0, 37°C
0.000023
N-(4-[(2-amino-6-methyl-4-oxo-3,4-dihydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoyl)-L-glutamic acid
Toxoplasma gondii
-
37°C
0.000008
N-(4-[(2-amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3-d ]pyrimidin-5-yl)thio]benzoyl)-L-glutamic acid
Toxoplasma gondii
-
pH 7.0, 37°C
0.000008
N-(4-[(2-amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)sulfanyl]benzoyl)-L-glutamic acid
Toxoplasma gondii
-
-
0.012
N-[4-[(2,4-diamino-5-methyl-furo[2,3-d]pyrimidin-6-yl)-thio]-benzoyl]-L-glutamic acid
Toxoplasma gondii
-
37°C, pH not specified in the publication
0.0000063
N6-(2,5-dimethoxybenzyl)-N6-methylpyrido[2,3-d]pyrimidine-2,4,6-triamine
Toxoplasma gondii
-
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
several parasitic protozoa, including Toxoplasma gondii, contain a unique bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) having the catalytic activities contained on a single polypeptide chain in contrast to the human enzyme. Three-dimensional structures of Toxoplasma gondii enzyme TS-DHFR and of a loop truncated TS-DHFR enzyme, removing several flexible surface loops in the DHFR domain, shows that the TS-DHFR homodimer includes a junctional region containing a linked crossover helix between the DHFR domains of the two adjacent monomers, a long linker connecting the TS and DHFR domains, and a DHFR domain that is positively charged. The crystal structure suggests that the positively charged DHFR domain governs this electrostatically mediated movement of dihydrofolate, preventing release from the enzyme. Importance of this region not only in DHFR catalysis but also in modulating the distal TS activity suggests a role for TS-DHFR interdomain interactions
additional information
additional information
DHFR domain structure analysis, the domain consists of 252 residues from the N-terminus to the start of the junctional region, overview
additional information
-
DHFR domain structure analysis, the domain consists of 252 residues from the N-terminus to the start of the junctional region, overview
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). DRTS_TOXGO
610
0
68752
Swiss-Prot
other Location (Reliability: 4)
PDB
SCOP
CATH
UNIPROT
ORGANISM
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
three-dimensional structures of Toxoplasma gondii enzyme TS-DHFR at 3.7 A and of a loop truncated TS-DHFR enzyme, removing several flexible surface loops in the DHFR domain, improving resolution to 2.2 A. The TS-DHFR homodimer includes a junctional region containing a linked crossover helix between the DHFR domains of the two adjacent monomers, a long linker connecting the TS and DHFR domains, and a DHFR domain that is positively charged, importance of this region not only in DHFR catalysis but also in modulating the distal TS activity suggests a role for TS-DHFR interdomain interactions. The interactions between the TS and the DHFR domains within the same monomer are comprised of both electrostatic and hydrophobic interactions that are predominately hydrophobic, these include hydrophobic contacts between F231, F319, and M297 as well as P242, I573, and V596
additional information
-
three-dimensional structures of Toxoplasma gondii enzyme TS-DHFR at 3.7 A and of a loop truncated TS-DHFR enzyme, removing several flexible surface loops in the DHFR domain, improving resolution to 2.2 A. The TS-DHFR homodimer includes a junctional region containing a linked crossover helix between the DHFR domains of the two adjacent monomers, a long linker connecting the TS and DHFR domains, and a DHFR domain that is positively charged, importance of this region not only in DHFR catalysis but also in modulating the distal TS activity suggests a role for TS-DHFR interdomain interactions. The interactions between the TS and the DHFR domains within the same monomer are comprised of both electrostatic and hydrophobic interactions that are predominately hydrophobic, these include hydrophobic contacts between F231, F319, and M297 as well as P242, I573, and V596
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified recombinant wild-type TS-DHFR enzyme and truncated TS-DHFR mutant lacking the surface loops, complexed with dUMP and NADPH, as well as with inhibitors methotrexate and N10-propargyl-5,8-dideazafolate, 10 mg/ml protein with 10 mM of each ligand is mixed with mixed with 18% PEG 3350, 0.1 M potassium formate in a 1:1 ratio, 4-6 days, X-ray diffraction structure determination and analysis at 3.7 A and 2.2 A resolution, respectively
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
P292A
site-directed mutagenesis, the mutation, reduces the DHFR catalytic efficiency by 7fold
W296A
site-directed mutagenesis, reduces the DHFR catalytic efficiency by 100fold
additional information
additional information
a helix deletion reduces the DHFR catalytic efficiency by 30fold
additional information
-
a helix deletion reduces the DHFR catalytic efficiency by 30fold
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
-
the enzyme is a target for drug development since the organism causes the opportunistic infection toxoplasmosis, a major cause of mortality in acquired immunodeficiency syndrome, AIDS, patients
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Pelphrey, P.M.; Popov, V.M.; Joska, T.M.; Beierlein, J.M.; Bolstad, E.S.; Fillingham, Y.A.; Wright, D.L.; Anderson, A.C.
Highly efficient ligands for dihydrofolate reductase from Cryptosporidium hominis and Toxoplasma gondii inspired by structural analysis
J. Med. Chem.
50
940-950
2007
Cryptosporidium hominis (A0A0S4TER9), Cryptosporidium hominis, Toxoplasma gondii (Q07422), Toxoplasma gondii
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
Gangjee, A.; Li, W.; Yang, J.; Kisliuk, R.L.
Design, synthesis, and biological evaluation of classical and nonclassical 2-amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors
J. Med. Chem.
51
68-76
2008
Toxoplasma gondii, Homo sapiens (P00374), Homo sapiens
Gangjee, A.; Qiu, Y.; Li, W.; Kisliuk, R.L.
Potent dual thymidylate synthase and dihydrofolate reductase inhibitors: classical and nonclassical 2-amino-4-oxo-5-arylthio-substituted-6-methylthieno[2,3-d]pyrimidine antifolates
J. Med. Chem.
51
5789-5797
2008
Escherichia coli, Toxoplasma gondii, 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
Gangjee, A.; Li, W.; Kisliuk, R.L.; Cody, V.; Pace, J.; Piraino, J.; Makin, J.
Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents
J. Med. Chem.
52
4892-4902
2009
Escherichia coli, Toxoplasma gondii, Homo sapiens (P00374), Homo sapiens
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
Sharma, H.; Landau, M.; Vargo, M.; Spasov, K.; Anderson, K.
First three-dimensional structure of Toxoplasma gondii thymidylate synthase-dihydrofolate reductase Insights for catalysis, interdomain interactions, and substrate channeling
Biochemistry
52
7305-7317
2013
Toxoplasma gondii (Q07422), Toxoplasma gondii
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