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Literature summary for 1.5.1.3 extracted from

  • 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 (2021), Pharmaceuticals, 14, 636 .
    View publication on PubMedView publication on EuropePMC
Search for more literature for 1.5.1.3

Cloned(Commentary)

Cloned (Comment) Organism
gene DHFR, recombinant expression of His-tagged enzyme in Escherichia coli Trypanosoma brucei brucei

Crystallization (Commentary)

Crystallization (Comment) Organism
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 Trypanosoma brucei brucei

Inhibitors

Inhibitors Comment Organism Structure
1-(3,4-dichlorophenyl)-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine competitive inhibition Trypanosoma brucei brucei
1-(3,4-dichlorophenyl)-6-(4-nitrophenyl)-1,6-dihydro-1,3,5-triazine-2,4-diamine competitive inhibition Trypanosoma brucei brucei
1-(4-chlorophenyl)-6-methyl-1,6-dihydro-1,3,5-triazine-2,4-diamine competitive inhibition Trypanosoma brucei brucei
1-(4-chlorophenyl)-6-propyl-1,6-dihydro-1,3,5-triazine-2,4-diamine competitive inhibition Trypanosoma brucei brucei
1-(4-methoxyphenyl)-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine competitive inhibition Trypanosoma brucei brucei
4-(4,6-diamino-2,2-dimethyl-1,3,5-triazin-1(2H)-yl)phenol competitive inhibition Trypanosoma brucei brucei
5-(4-chlorophenyl)-1,3,5-triazaspiro[5.5]undeca-1,3-diene-2,4-diamine competitive inhibition Trypanosoma brucei brucei
cycloguanil CYC, the known inhibitor of Plasmodial and Trypanosomal DHFR-TS enzymes is also as an inhibitor of TbPTR1 Trypanosoma brucei brucei
methotrexate MTX Trypanosoma brucei brucei
additional information selectivity of the ihibitors versus enzymes PTR1 and DHFR, overview Trypanosoma brucei brucei
N-[6-amino-5-(4-methoxyphenyl)-4,4-dimethyl-4,5-dihydrotriazin-2-yl]acetamide competitive inhibition Trypanosoma brucei brucei
pyrimethamine PYR Trypanosoma brucei brucei

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
additional information
-
 additional information kinetics by non-tight binding Michaelis-Menten model Trypanosoma brucei brucei

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
7,8-dihydrobiopterin + NADPH + H+ Trypanosoma brucei brucei
-
 5,6,7,8-tetrahydrobiopterin + NADP+
-
 ?
7,8-dihydrofolate + NADPH + H+ Trypanosoma brucei brucei
-
 5,6,7,8-tetrahydrofolate + NADP+
-
 ?
biopterin + NADPH + H+ Trypanosoma brucei brucei reaction of EC 1.5.1.33 7,8-dihydrobiopterin + NADP+
-
 ?
folate + NADPH + H+ Trypanosoma brucei brucei
-
 7,8-dihydrofolate + NADP+
-
 ?

Organism

Organism UniProt Comment Textmining
Trypanosoma brucei brucei Q27783
-
-

Purification (Commentary)

Purification (Comment) Organism
recombinant His-tagged enzyme from Escherichia coli Trypanosoma brucei brucei

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
7,8-dihydrobiopterin + NADPH + H+
-
 Trypanosoma brucei brucei 5,6,7,8-tetrahydrobiopterin + NADP+
-
 ?
7,8-dihydrofolate + NADPH + H+
-
 Trypanosoma brucei brucei 5,6,7,8-tetrahydrofolate + NADP+
-
 ?
biopterin + NADPH + H+ reaction of EC 1.5.1.33 Trypanosoma brucei brucei 7,8-dihydrobiopterin + NADP+
-
 ?
folate + NADPH + H+
-
 Trypanosoma brucei brucei 7,8-dihydrofolate + NADP+
-
 ?

Synonyms

Synonyms Comment Organism
bifunctional dihydrofolate reductase-thymidylate synthase
-
 Trypanosoma brucei brucei
DHFR
-
 Trypanosoma brucei brucei
DHFR-TS
-
 Trypanosoma brucei brucei
dihydrofolate reductase
-
 Trypanosoma brucei brucei
More cf. EC 1.5.1.33 Trypanosoma brucei brucei

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
22
-
 assay at room temperature Trypanosoma brucei brucei

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
10.5
-
 assay at Trypanosoma brucei brucei

Cofactor

Cofactor Comment Organism Structure
NADPH
-
 Trypanosoma brucei brucei

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
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 Trypanosoma brucei brucei

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.000024
-
 pH 10.5, 22°C Trypanosoma brucei brucei pyrimethamine
0.00004
-
 pH 10.5, 22°C Trypanosoma brucei brucei methotrexate
0.000103
-
 pH 3.7, 22°C, recombinant enzyme Trypanosoma brucei brucei 1-(4-chlorophenyl)-6-methyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
0.000256
-
 pH 10.5, 22°C Trypanosoma brucei brucei cycloguanil
0.00726
-
 pH 3.7, 22°C, recombinant enzyme Trypanosoma brucei brucei 1-(4-chlorophenyl)-6-propyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
0.0176
-
 pH 3.7, 22°C, recombinant enzyme Trypanosoma brucei brucei 5-(4-chlorophenyl)-1,3,5-triazaspiro[5.5]undeca-1,3-diene-2,4-diamine
0.0189
-
 pH 3.7, 22°C, recombinant enzyme Trypanosoma brucei brucei N-[6-amino-5-(4-methoxyphenyl)-4,4-dimethyl-4,5-dihydrotriazin-2-yl]acetamide
0.0332
-
 pH 3.7, 22°C, recombinant enzyme Trypanosoma brucei brucei 1-(4-methoxyphenyl)-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
0.089
-
 pH 3.7, 22°C, recombinant enzyme Trypanosoma brucei brucei 4-(4,6-diamino-2,2-dimethyl-1,3,5-triazin-1(2H)-yl)phenol

General Information

General Information Comment Organism
evolution PTR1 is a NADPH-dependent enzyme belonging to the short-chain dehydrogenase/reductase (SDR) family Trypanosoma brucei brucei
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) Trypanosoma brucei brucei
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 Trypanosoma brucei brucei
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 Trypanosoma brucei brucei