Literature summary for 1.5.1.33 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 .

Application

Application	Comment	Organism
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)

Crystallization (Comment)	Organism
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

Crystallization (Comment)

Organism

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

Inhibitors	Comment	Organism	Structure
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
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]

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

Natural Substrates/ Products (Substrates)

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

Organism

Organism	UniProt	Comment	Textmining
Trypanosoma brucei brucei	O76290	-	-

Substrates and Products (Substrate)

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

Synonyms

Synonyms	Comment	Organism
pteridine reductase 1	-	Trypanosoma brucei brucei
PTR1	-	Trypanosoma brucei brucei
TbPTR1	-	Trypanosoma brucei brucei

Temperature Optimum [°C]

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

Turnover Number [1/s]

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

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
5	-	recombinant enzyme	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
0.083	-	2,4-diaminopyrimido[4,5-b]indol-6-ol	pH 5.0, 25°C, recombinant enzyme	Trypanosoma brucei brucei

General Information

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