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Literature summary extracted from

  • Landi, G.; Linciano, P.; Tassone, G.; Costi, M.P.; Mangani, S.; Pozzi, C.
    High-resolution crystal structure of Trypanosoma brucei pteridine reductase 1 in complex with an innovative tricyclic-based inhibitor (2020), Acta Crystallogr. Sect. D, 76, 558-564 .
    View publication on PubMed

Application

EC Number Application Comment Organism
1.5.1.33 drug development the classical antifolates targeting dihydrofolate reductase (DHFR) are ineffective towards trypanosomatid parasites owing to a metabolic bypass by the expression of pteridine reductase 1 (PTR1). The combined inhibition of PTR1 and DHFR activities in Trypanosoma parasites represents a promising strategy for the development of new effective treatments for human African trypanosomiasis (HAT) Trypanosoma brucei brucei

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
1.5.1.33 purified enzyme in a ternary complex with NADP(H) and inhibitor 2,4-diaminopyrimido[4,5-b]indol-6-ol, hanging drop vapor diffusion technique, using a precipitant solution composed of 2.0-2.5 M sodium acetate, 0.1 M sodium citrate, pH 5.0, a DMSO solution of the inhibitor compound is added to the cryoprotectant composed of the precipitant (enriched to 30% v/v glycerol) to a final concentration of 4 mM (the DMSO concentration is kept lower than 10% v/v), a few days at room temperature, X-ray diffraction structure determination and analysis at 1.30 A resolution, modelling Trypanosoma brucei brucei

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.5.1.33 2,4-diaminopyrimido[4,5-b]indol-6-ol synthesis, inhibits TbPTR1 activity by competitive inhibition, binding mode, and structural characterization of its ternary complex with TbPTR1 and the cofactor NADP(H) from crystal structure, overview. The compound adopts a substrate-like orientation inside the cavity that maximizes the binding contributions of hydrophobic and hydrogen-bond interactions Trypanosoma brucei brucei
1.5.1.33 additional information monocyclic and bicyclic aromatic systems have been proposed as inhibitors of Trypanosoma brucei PTR1 (TbPTR1), but the size of the catalytic cavity allows the accommodation of expanded molecular cores. Inhibitor development and evaluation, overview Trypanosoma brucei brucei

KM Value [mM]

EC Number KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
1.5.1.33 additional information
-
 additional information steady-state kinetic analysis Trypanosoma brucei brucei
1.5.1.33 0.0171
-
 dihydrobiopterin pH 5.0, 25°C, recombinant enzyme Trypanosoma brucei brucei

Natural Substrates/ Products (Substrates)

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

Organism

EC Number Organism UniProt Comment Textmining
1.5.1.33 Trypanosoma brucei brucei O76290
-
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.5.1.33 dihydrobiopterin + NADPH + H+
-
 Trypanosoma brucei brucei 5,6,7,8-tetrahydrobiopterin + NADP+
-
 ?

Synonyms

EC Number Synonyms Comment Organism
1.5.1.33 pteridine reductase 1
-
 Trypanosoma brucei brucei
1.5.1.33 PTR1
-
 Trypanosoma brucei brucei
1.5.1.33 TbPTR1
-
 Trypanosoma brucei brucei

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
1.5.1.33 25
-
 assay at Trypanosoma brucei brucei

Turnover Number [1/s]

EC Number Turnover Number Minimum [1/s] Turnover Number Maximum [1/s] Substrate Comment Organism Structure
1.5.1.33 0.12
-
 dihydrobiopterin pH 5.0, 25°C, recombinant enzyme Trypanosoma brucei brucei

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
1.5.1.33 5
-
 recombinant enzyme Trypanosoma brucei brucei

Cofactor

EC Number Cofactor Comment Organism Structure
1.5.1.33 NADPH
-
 Trypanosoma brucei brucei

Ki Value [mM]

EC Number Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
1.5.1.33 0.083
-
 2,4-diaminopyrimido[4,5-b]indol-6-ol pH 5.0, 25°C, recombinant enzyme Trypanosoma brucei brucei

General Information

EC Number General Information Comment Organism
1.5.1.33 additional information active site structure of TbPTR1, overview Trypanosoma brucei brucei