Protein Variants | Comment | Organism |
---|---|---|
R132H | site-directed mutagenesis | Homo sapiens |
Inhibitors | Comment | Organism | Structure |
---|---|---|---|
(+)-ML309 | reversible binding analysis and mechanism, detailed overview. The reversible inhibitor binds to IDH1 R132H competitively with respect to 2-oxoglutarate and uncompetitively with respect to NADPH. ML309 competes with 2-oxoglutarate but is uncompetitive with NADPH and rapidly and reversibly affects cellular 2-hydroxyglutarate levels. The rapidly equilibrating inhibitor is active in both biochemical and cellular assays. The (+) isomer is active, whereas the (-) isomer is over 400fold less active for IDH1 R132H inhibition. IDH1 R132C is similarly inhibited by (-)-ML309. ML309 is also able to inhibit 2-hydroxyglutarate production in a glioblastoma cell line and had minimal cytotoxicity. In the presence of racemic ML309, 2-hydroxyglutarate levels drop rapidly | Homo sapiens | |
(-)-ML309 | reversible binding analysis and mechanism, detailed overview. The reversible inhibitor binds to IDH1 R132H competitively with respect to 2-oxoglutarate and uncompetitively with respect to NADPH. ML309 competes with 2-oxoglutarate but is uncompetitive with NADPH and rapidly and reversibly affects cellular 2-hydroxyglutarate levels. The rapidly equilibrating inhibitor is active in both biochemical and cellular assays. The (+) isomer is active, whereas the (-) isomer is over 400fold less active for IDH1 R132H inhibition. IDH1 R132C is similarly inhibited by (-)-ML309. Wild-type IDH1 is largely unaffected by (+)-ML309. ML309 is also able to inhibit 2-hydroxyglutarate production in a glioblastoma cell line and had minimal cytotoxicity. In the presence of racemic ML309, 2-hydroxyglutarate levels drop rapidly | Homo sapiens |
KM Value [mM] | KM Value Maximum [mM] | Substrate | Comment | Organism | Structure |
---|---|---|---|---|---|
additional information | - |
additional information | stopped-flow kinetics and steady-state kientics | Homo sapiens |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
isocitrate + NADP+ | Homo sapiens | - |
2-oxoglutarate + CO2 + NADPH + H+ | - |
r |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | P48735 | - |
- |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
isocitrate + NADP+ | - |
Homo sapiens | 2-oxoglutarate + CO2 + NADPH + H+ | - |
r |
Synonyms | Comment | Organism |
---|---|---|
IDH1 | - |
Homo sapiens |
isocitrate dehydrogenase | - |
Homo sapiens |
Temperature Optimum [°C] | Temperature Optimum Maximum [°C] | Comment | Organism |
---|---|---|---|
22 | - |
assay at room temperature | Homo sapiens |
pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
---|---|---|---|
7.5 | - |
assay at | Homo sapiens |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
NADP+ | - |
Homo sapiens | |
NADPH | - |
Homo sapiens |
IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
---|---|---|---|---|---|
0.000068 | - |
inhibition of enzyme mutant IDH1 R132H, pH 7.5, 22°C | Homo sapiens | (+)-ML309 | |
0.029 | - |
inhibition of enzyme mutant IDH1 R132H, pH 7.5, 22°C | Homo sapiens | (-)-ML309 | |
0.036 | - |
inhibition of wild-type enzyme, pH 7.5, 22°C | Homo sapiens | (+)-ML309 |
General Information | Comment | Organism |
---|---|---|
malfunction | two mutant forms (R132H and R132C) of isocitrate dehydrogenase 1 (IDH1) have been associated with a number of cancers including glioblastoma and acute myeloid leukemia. These mutations confer a neomorphic activity of 2-hydroxyglutarate (2-HG) production, and 2-HG has previously been implicated as an oncometabolite. Inhibitors of mutant IDH1 can potentially be used to treat these diseases | Homo sapiens |