Crystallization (Comment) | Organism |
---|---|
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 |
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 | Comment | Organism | Structure |
---|---|---|---|
2-(3,4-dihydroxyphenyl)-3,6-dihydroxy-4H-1-benzopyran-4-one | - |
Leishmania major | |
2-(3,4-dihydroxyphenyl)-3,6-dihydroxy-4H-1-benzopyran-4-one | - |
Trypanosoma brucei | |
2-(3,4-dihydroxyphenyl)-6-hydroxy-2,3-dihydro-4H-1-benzopyran-4-one | - |
Leishmania major | |
2-(3,4-dihydroxyphenyl)-6-hydroxy-2,3-dihydro-4H-1-benzopyran-4-one | - |
Trypanosoma brucei | |
3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-1-benzopyran-4-one | - |
Leishmania major | |
3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-1-benzopyran-4-one | - |
Trypanosoma brucei | |
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 | |
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 | |
6-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one | - |
Leishmania major | |
6-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one | - |
Trypanosoma brucei | |
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 | |
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 | |
pyrimethamine | complete inhibition at 0.05 mM | Leishmania major | |
pyrimethamine | complete inhibition at 0.05 mM | Trypanosoma brucei |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
biopterin + 2 NADPH + 2 H+ | Trypanosoma brucei | - |
5,6,7,8-tetrahydrobiopterin + 2 NADP+ | - |
? | |
biopterin + 2 NADPH + 2 H+ | Leishmania major | - |
5,6,7,8-tetrahydrobiopterin + 2 NADP+ | - |
? |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Leishmania major | Q01782 | - |
- |
no activity in Homo sapiens | - |
- |
- |
Trypanosoma brucei | O76290 | - |
- |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
biopterin + 2 NADPH + 2 H+ | - |
Trypanosoma brucei | 5,6,7,8-tetrahydrobiopterin + 2 NADP+ | - |
? | |
biopterin + 2 NADPH + 2 H+ | - |
Leishmania major | 5,6,7,8-tetrahydrobiopterin + 2 NADP+ | - |
? |
Subunits | Comment | Organism |
---|---|---|
tetramer | - |
Trypanosoma brucei |
tetramer | - |
Leishmania major |
Synonyms | Comment | Organism |
---|---|---|
LmPTR1 | - |
Leishmania major |
pteridine reductase 1 | - |
Trypanosoma brucei |
pteridine reductase 1 | - |
Leishmania major |
PTR1 | - |
Trypanosoma brucei |
PTR1 | - |
Leishmania major |
TbPTR1 | - |
Trypanosoma brucei |
Temperature Optimum [°C] | Temperature Optimum Maximum [°C] | Comment | Organism |
---|---|---|---|
30 | - |
assay at | Trypanosoma brucei |
30 | - |
assay at | Leishmania major |
pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
---|---|---|---|
6 | - |
assay at | Trypanosoma brucei |
6 | - |
assay at | Leishmania major |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
NADPH | - |
Trypanosoma brucei | |
NADPH | - |
Leishmania major |
IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
---|---|---|---|---|---|
0.0043 | - |
pH 6.0, 30°C | Trypanosoma brucei | 3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-1-benzopyran-4-one | |
0.0125 | - |
pH 6.0, 30°C | Leishmania major | 3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-1-benzopyran-4-one | |
0.031 | - |
pH 6.0, 30°C | Trypanosoma brucei | 6-hydroxy-2-(3-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one | |
0.035 | - |
pH 6.0, 30°C | Leishmania major | 6-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one | |
0.035 | - |
pH 6.0, 30°C | Leishmania major | 2-(3,4-dihydroxyphenyl)-3,6-dihydroxy-4H-1-benzopyran-4-one | |
0.036 | - |
pH 6.0, 30°C | Leishmania major | 2-(3,4-dihydroxyphenyl)-6-hydroxy-2,3-dihydro-4H-1-benzopyran-4-one | |
0.038 | - |
pH 6.0, 30°C | Trypanosoma brucei | 2-(3,4-dihydroxyphenyl)-3,6-dihydroxy-4H-1-benzopyran-4-one | |
0.057 | - |
pH 6.0, 30°C | Leishmania major | 6-hydroxy-2-(3-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one | |
0.082 | - |
pH 6.0, 30°C | Trypanosoma brucei | 2-(3,4-dihydroxyphenyl)-6-hydroxy-2,3-dihydro-4H-1-benzopyran-4-one | |
0.133 | - |
pH 6.0, 30°C | Trypanosoma brucei | 6-hydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one |
General Information | Comment | Organism |
---|---|---|
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 |
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 |