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Information on EC 1.5.1.3 - dihydrofolate reductase and Organism(s) Trypanosoma brucei brucei and UniProt Accession Q27783
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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: Trypanosoma brucei brucei
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
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-
-
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dehydrogenase, tetrahydrofolate
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-
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DHFR
DHFR type IIIC
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-
-
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dihydrofolate reductase-thymidylate synthase
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dihydrofolate reductase:thymidylate synthase
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-
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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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folic acid reductase
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-
-
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folic reductase
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-
-
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NADPH-dihydrofolate reductase
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-
-
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pteridine reductase:dihydrofolate reductase
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-
-
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reductase, dihydrofolate
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-
-
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tetrahydrofolate dehydrogenase
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-
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thymidylate synthetase-dihydrofolate reductase
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-
-
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Trimethoprim resistance protein
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-
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DHFR
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-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
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-
-
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oxidation
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-
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reduction
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PATHWAY SOURCE
PATHWAYS
BRENDA
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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.
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
7,8-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
biopterin + NADPH + H+
7,8-dihydrobiopterin + NADP+
reaction of EC 1.5.1.33
-
-
?
folate + NADPH + H+
7,8-dihydrofolate + NADP+
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-
-
?
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-dihydrobiopterin + NADPH + H+
5,6,7,8-tetrahydrobiopterin + NADP+
-
-
-
?
7,8-dihydrofolate + NADPH + H+
5,6,7,8-tetrahydrofolate + NADP+
-
-
-
?
biopterin + NADPH + H+
7,8-dihydrobiopterin + NADP+
reaction of EC 1.5.1.33
-
-
?
folate + NADPH + H+
7,8-dihydrofolate + NADP+
-
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1-(3,4-dichlorophenyl)-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
competitive inhibition
1-(3,4-dichlorophenyl)-6-(4-nitrophenyl)-1,6-dihydro-1,3,5-triazine-2,4-diamine
competitive inhibition
-
1-(4-chlorophenyl)-6-methyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
competitive inhibition
-
1-(4-chlorophenyl)-6-propyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
competitive inhibition
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1-(4-methoxyphenyl)-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
competitive inhibition
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4-(4,6-diamino-2,2-dimethyl-1,3,5-triazin-1(2H)-yl)phenol
competitive inhibition
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5-(4-chlorophenyl)-1,3,5-triazaspiro[5.5]undeca-1,3-diene-2,4-diamine
competitive inhibition
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cycloguanil
CYC, the known inhibitor of Plasmodial and Trypanosomal DHFR-TS enzymes is also as an inhibitor of TbPTR1
N-[6-amino-5-(4-methoxyphenyl)-4,4-dimethyl-4,5-dihydrotriazin-2-yl]acetamide
competitive inhibition
-
additional information
selectivity of the ihibitors versus enzymes PTR1 and DHFR, overview
-
additional information
successful dual inhibition of Trypanosoma brucei dihydrofolate reductase (TbDHFR) and Trypanosoma brucei pteridine reductase 1 (TbPTR1, EC 1.5.1.33) has implications in the exploitation of anti-folates. Molecular docking of a ligand library of 5742 compounds against TbPTR1 and identification of compounds showing promising binding modes. The protein-ligand complexes are subjected to molecular dynamics to characterize their molecular interactions and energetics, followed by in vitro testing. Five compounds show low micromolar Trypanosome growth inhibition in in vitro experiments that might be acting by inhibition of TbPTR1. Docking study with TbPTR1 and comparison with Trypanosoma cruzi PTR2, moleuclar dynamics, overview
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
kinetics by non-tight binding Michaelis-Menten model
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
all the investigated molecules are assumed to act as full competitive inhibitor and analysed according to the non-tight binding Michaelis-Menten model
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000103
1-(4-chlorophenyl)-6-methyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
Trypanosoma brucei brucei
pH 3.7, 22°C, recombinant enzyme
-
0.00726
1-(4-chlorophenyl)-6-propyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
Trypanosoma brucei brucei
pH 3.7, 22°C, recombinant enzyme
-
0.0332
1-(4-methoxyphenyl)-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
Trypanosoma brucei brucei
pH 3.7, 22°C, recombinant enzyme
-
0.089
4-(4,6-diamino-2,2-dimethyl-1,3,5-triazin-1(2H)-yl)phenol
Trypanosoma brucei brucei
pH 3.7, 22°C, recombinant enzyme
-
0.0176
5-(4-chlorophenyl)-1,3,5-triazaspiro[5.5]undeca-1,3-diene-2,4-diamine
Trypanosoma brucei brucei
pH 3.7, 22°C, recombinant enzyme
-
0.0189
N-[6-amino-5-(4-methoxyphenyl)-4,4-dimethyl-4,5-dihydrotriazin-2-yl]acetamide
Trypanosoma brucei brucei
pH 3.7, 22°C, recombinant enzyme
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
metabolism
physiological function
additional information
pterin and folate substrates, along with inhibitors, interact with PTR1 complexes quite similarly, often via binding in a Pi-sandwich between the NADPH nicotinamide ring and residue Phe97. The NADPH cofactor is known to be essential in creating both the substrate binding site as well as the catalytic center. Arg14, Ser95, Phe97, Asp161, and Tyr174 are important residues that interact with the folate and pterin substrates
evolution
PTR1 is a NADPH-dependent enzyme belonging to the short-chain dehydrogenase/reductase (SDR) family
evolution
PTR1 is a short-chain dehydrogenase reductase family member. The trypanosomatid PTR1s are structurally very similar, sequence comparisons
metabolism
key enzymes involved in trypanosome folate metabolism are dihydrofolate reductase (DHFR) and pteridine reductase (PTR1)
metabolism
traditional antifolates, such as methotrexate (MTX) inhibiting DHFR, are poorly effective towards trypanosome parasites because of the metabolic bypass provided by PTR1 also catalyzing folate reduction in addition to the conversion of biopterin to 7,8-dihydrobiopterin (DHB) and subsequently to 5,6,7,8-tetrahydrobiopterin (THB)
physiological function
in addition to folate reduction, PTR1 (EC 1.5.1.33) also catalyzes the conversion of biopterin to 7,8-dihydrobiopterin (DHB) and subsequently to 5,6,7,8-tetrahydrobiopterin (THB). Under dihydrofolate reductase (DHFR) inhibition, PTR1 is upregulated providing reduced folates necessary for parasite survival
physiological function
pteridine reductase 1 (PTR1) has the ability to catalyze the NADPH-dependent two-stage reduction of biopterins to their 7,8-dihydro and 5,6,7,8-tetrahydro forms as well as folates to their H2F and H4F forms. PTR1 is a trypanosomatid multifunctional enzyme that provides a mechanism for escape of dihydrofolate reductase (DHFR, EC 1.5.1.3) inhibition. This is because PTR1 can reduce pterins and folates. Trypanosomes require folates and pterins for survival and are unable to synthesize them de novo
physiological function
the bifunctional dihydrofolate reductase-thymidylate synthase, DHFR-TS, enzyme includes dthe ihydrofolate reductase, EC 1.5.1.3, and the thymidylate synthase, EC 2.1.1.45. Under dihydrofolate reductase (DHFR) inhibition, the PTR1 (EC 1.5.1.33) gene is upregulated, providing reduced folates necessary for parasite survival
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_TRYBB
527
0
58805
Swiss-Prot
Mitochondrion (Reliability: 3)
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified recombinant His-tagged TbDHFR-TS, sitting drop vapour diffusion method, a few days at at 8°C or at room temperature, drops consist of 0.001 ml of protein solution and 0.001 ml of precipitant equilibrated against a 0.2 ml of reservoir solution. No crystal growth is observed over one year of incubation, preventing to obtain structural information on the enzyme
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene DHFR, recombinant expression of His-tagged enzyme in Escherichia coli
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Kimuda, M.P.; Laming, D.; Hoppe, H.C.; Tastan Bishop, Oe.
Identification of novel potential inhibitors of pteridine reductase 1 in Trypanosoma brucei via computational structure-based approaches and in vitro inhibition assays
Molecules
24
142
2019
Trypanosoma cruzi (O44029), Trypanosoma brucei brucei (Q27783)
Tassone, G.; Landi, G.; Linciano, P.; Francesconi, V.; Tonelli, M.; Tagliazucchi, L.; Costi, M.P.; Mangani, S.; Pozzi, C.
Evidence of pyrimethamine and cycloguanil analogues as dual inhibitors of Trypanosoma brucei pteridine reductase and dihydrofolate reductase
Pharmaceuticals
14
636
2021
Trypanosoma brucei brucei (Q27783)
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