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Literature summary extracted from

  • Di Pisa, F.; Landi, G.; Dello Iacono, L.; Pozzi, C.; Borsari, C.; Ferrari, S.; Santucci, M.; Santarem, N.; Cordeiro-Da-Silva, A.; Moraes, C.; Alcantara, L.; Fontana, V.; Freitas-Junior, L.; Gul, S.; Kuzikov, M.; Behrens, B.; Poehner, I.; Wade, R.; Costi,
    Chroman-4-one derivatives targeting pteridine reductase 1 and showing anti-parasitic activity (2017), Molecules, 22, E426 .
    View publication on PubMedView publication on EuropePMC

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
1.5.1.33 purified enzyme LmPtr1 in ternary complex with compounds 6-hydroxy-2-(3-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one and 2-(3,4-dihydroxyphenyl)-6-hydroxy-2,3-dihydro-4H-1-benzopyran-4-one, hanging drop vapour diffusion method, mixing of 0.002 ml of 12.5 mg/ml protein in 20 mM sodium acetate, pH 5.3, containing 1 mM NADPH, and 20 mM DTT, with 0.002 ml of reservoir solution containing 12% PEG 4600, 100 mM sodium acetate buffer pH 5.5 and 120-160 mM calcium acetate, equilibration against reservoir solution, at 20°C, for complex crystals the preformed crystals are soaked in a 2 mM inhibitor solution (dissolved in a 1:1 mixture of 1,4-dioxane and water) for 4.5 h, X-ray diffraction structure determination and analysis at 2.10-2.35 A resolution Leishmania major
1.5.1.33 purified enzyme TbPtr1 in ternary complex with compound 6-hydroxy-2-(3-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one, sitting drop vapor diffusion method, mixing of equal volumes of protein solution containing 6-10 mg/ml protein in 20 mM Tris-HCl, pH 7.5, and 10 mM DTT, with precipitant solution containing 1.5-2.5 M sodium acetate and 0.1 M sodium citrate, pH 5.0, equilibration against 0.6 ml of reservoir solution, at room temperature, several days, for complexed crystals are soaked in a 2 mM solution of the inhibitor (dissolved in a 1:1 mixture of 1,4-dioxane and water) for 4 h, X-ray diffraction structure determination and analysis at 1.70 A resolution Trypanosoma brucei

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.5.1.33 2-(3,4-dihydroxyphenyl)-3,6-dihydroxy-4H-1-benzopyran-4-one
-
 Leishmania major
1.5.1.33 2-(3,4-dihydroxyphenyl)-3,6-dihydroxy-4H-1-benzopyran-4-one
-
 Trypanosoma brucei
1.5.1.33 2-(3,4-dihydroxyphenyl)-6-hydroxy-2,3-dihydro-4H-1-benzopyran-4-one
-
 Leishmania major
1.5.1.33 2-(3,4-dihydroxyphenyl)-6-hydroxy-2,3-dihydro-4H-1-benzopyran-4-one
-
 Trypanosoma brucei
1.5.1.33 3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-1-benzopyran-4-one
-
 Leishmania major
1.5.1.33 3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-1-benzopyran-4-one
-
 Trypanosoma brucei
1.5.1.33 6-hydroxy-2-(3-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one the compound shows inhibitory activity both against the targeted enzyme and the parasite with a high selectivity and a low toxicity for humans. Only the (R)-isomer binds in the active site, 50% inhibition at 0.05 mM Leishmania major
1.5.1.33 6-hydroxy-2-(3-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one the compound shows inhibitory activity both against the targeted enzyme and the parasite with a high selectivity and a low toxicity for humans. Only the (R)-isomer binds in the active site, 81% inhibition at 0.05 mM Trypanosoma brucei
1.5.1.33 6-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one
-
 Leishmania major
1.5.1.33 6-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one
-
 Trypanosoma brucei
1.5.1.33 additional information chromen-4-one derivatives as pteridine reductase 1 (PTR1) inhibitors, observed and predicted binding modes of the compounds, docking and modeling, overview. There are differences between the binding modes of the chromen-4-one and the chroman-4-one moiety. No inhibition by 3,6-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one at 0.05 mM. Only the (R)-isomers bind in the active site Leishmania major
1.5.1.33 additional information chromen-4-one derivatives as pteridine reductase 1 (PTR1) inhibitors, observed and predicted binding modes of the compounds, docking and modeling, overview. There are differences between the binding modes of the chromen-4-one and the chroman-4-one moiety. No inhibition by 3,6-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one at 0.05 mM Trypanosoma brucei
1.5.1.33 pyrimethamine complete inhibition at 0.05 mM Leishmania major
1.5.1.33 pyrimethamine complete inhibition at 0.05 mM Trypanosoma brucei

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
1.5.1.33 biopterin + 2 NADPH + 2 H+ Trypanosoma brucei
-
 5,6,7,8-tetrahydrobiopterin + 2 NADP+
-
 ?
1.5.1.33 biopterin + 2 NADPH + 2 H+ Leishmania major
-
 5,6,7,8-tetrahydrobiopterin + 2 NADP+
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
1.5.1.33 Leishmania major Q01782
-
-
1.5.1.33 no activity in Homo sapiens
-
-
-
1.5.1.33 Trypanosoma brucei O76290
-
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.5.1.33 biopterin + 2 NADPH + 2 H+
-
 Trypanosoma brucei 5,6,7,8-tetrahydrobiopterin + 2 NADP+
-
 ?
1.5.1.33 biopterin + 2 NADPH + 2 H+
-
 Leishmania major 5,6,7,8-tetrahydrobiopterin + 2 NADP+
-
 ?

Subunits

EC Number Subunits Comment Organism
1.5.1.33 tetramer
-
 Trypanosoma brucei
1.5.1.33 tetramer
-
 Leishmania major

Synonyms

EC Number Synonyms Comment Organism
1.5.1.33 LmPTR1
-
 Leishmania major
1.5.1.33 pteridine reductase 1
-
 Trypanosoma brucei
1.5.1.33 pteridine reductase 1
-
 Leishmania major
1.5.1.33 PTR1
-
 Trypanosoma brucei
1.5.1.33 PTR1
-
 Leishmania major
1.5.1.33 TbPTR1
-
 Trypanosoma brucei

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
1.5.1.33 30
-
 assay at Trypanosoma brucei
1.5.1.33 30
-
 assay at Leishmania major

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
1.5.1.33 6
-
 assay at Trypanosoma brucei
1.5.1.33 6
-
 assay at Leishmania major

Cofactor

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

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
1.5.1.33 0.0043
-
 pH 6.0, 30°C Trypanosoma brucei 3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-1-benzopyran-4-one
1.5.1.33 0.0125
-
 pH 6.0, 30°C Leishmania major 3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-1-benzopyran-4-one
1.5.1.33 0.031
-
 pH 6.0, 30°C Trypanosoma brucei 6-hydroxy-2-(3-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one
1.5.1.33 0.035
-
 pH 6.0, 30°C Leishmania major 6-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one
1.5.1.33 0.035
-
 pH 6.0, 30°C Leishmania major 2-(3,4-dihydroxyphenyl)-3,6-dihydroxy-4H-1-benzopyran-4-one
1.5.1.33 0.036
-
 pH 6.0, 30°C Leishmania major 2-(3,4-dihydroxyphenyl)-6-hydroxy-2,3-dihydro-4H-1-benzopyran-4-one
1.5.1.33 0.038
-
 pH 6.0, 30°C Trypanosoma brucei 2-(3,4-dihydroxyphenyl)-3,6-dihydroxy-4H-1-benzopyran-4-one
1.5.1.33 0.057
-
 pH 6.0, 30°C Leishmania major 6-hydroxy-2-(3-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one
1.5.1.33 0.082
-
 pH 6.0, 30°C Trypanosoma brucei 2-(3,4-dihydroxyphenyl)-6-hydroxy-2,3-dihydro-4H-1-benzopyran-4-one
1.5.1.33 0.133
-
 pH 6.0, 30°C Trypanosoma brucei 6-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one

General Information

EC Number General Information Comment Organism
1.5.1.33 physiological function the enzyme is able to reduce both unconjugated and conjugated pterins and provides a metabolic bypass to alleviate a dihydrofolate reductase inhibition Trypanosoma brucei
1.5.1.33 physiological function the enzyme is able to reduce both unconjugated and conjugated pterins and provides a metabolic bypass to alleviate a dihydrofolate reductase inhibition Leishmania major