Application | Comment | Organism |
---|---|---|
diagnostics | IDH1 mutational analysis can serve as a useful diagnostic marker of a glioma | Homo sapiens |
Cloned (Comment) | Organism |
---|---|
expression of the IDH1R132H mutant at a level similar to the endogenous protein in the cytoplasm of glioblastoma U-87MG cells causes a dose-dependent reduction of 2-oxoglutarate levels. Overexpression of the IDH1R132H mutant in U-87MG cells stimulates expression of HIF-1alpha target genes. Overexpression of wild-type IDH1 reduces HIF-1alpha protein levels in HeLa and U-87MG cells. Expression of FLAG-tagged wild-type and R132 mutants IDH1 in HEK-293T cells and of His-tagged enzymes in Escherichia coli | Homo sapiens |
Protein Variants | Comment | Organism |
---|---|---|
additional information | two independent short hairpin RNAs decrease IDH1 mRNA by more than 75% and reduce cellular 2-oxoglutarate levels by up to 50% | Homo sapiens |
R132C | naturally occuring mutation of IDH1, results in 60fold increased Km for isocitrate compared to the wild-type IDH1 | Homo sapiens |
R132H | naturally occuring mutation of IDH1, results in 94fold increased Km for isocitrate compared to the wild-type IDH1 | Homo sapiens |
R132S | naturally occuring mutation of IDH1, results in 70fold increased Km for isocitrate compared to the wild-type IDH1 | Homo sapiens |
R132X | identification of frequent IDH1 mutations in grade II and IV diffuse gliomas reducing the produciton of NADPH. Forced expression of mutant IDH1 in cultured cells reduces formation of the enzyme product, 2-oxoglutarate, and increases the levels of hypoxia-inducible factor subunit HIF-1alpha, a transcription factor that facilitates tumor growth when oxygen is low and whose stability is regulated by 2-oxoglutarate. IDH1 normally functions as a homodimer, we hypothesized that the mutant IDH1 molecules in tumor cells form heterodimers with wild-type molecules and, in so doing, dominantly inhibit the activity of wild-type IDH1 | Homo sapiens |
R132X | mutation of an arginine residue in pig mitochondrial IDH2 equivalent to R132 in human IDH1 causes a dramatic increase in Km for isocitrate by a factor of 165, with minimal effect on Vmax | Sus scrofa |
Inhibitors | Comment | Organism | Structure |
---|---|---|---|
additional information | tumor-derived mutant IDH1 dominantly inhibits the wild-type IDH1 by forming a catalytically inactive heterodimer, resulting in a decrease of cellular 2-oxoglutarate | Homo sapiens |
KM Value [mM] | KM Value Maximum [mM] | Substrate | Comment | Organism | Structure |
---|---|---|---|---|---|
0.0062 | - |
isocitrate | recombinant wild-type IDH1, pH not specified in the publication, temperature not specified in the publication | Homo sapiens | |
0.0068 | - |
NADP+ | recombinant mutant R132C IDH1, pH not specified in the publication, temperature not specified in the publication | Homo sapiens | |
0.0073 | - |
NADP+ | recombinant wild-type IDH1, pH not specified in the publication, temperature not specified in the publication | Homo sapiens | |
0.0122 | - |
NADP+ | recombinant mutant R132H IDH1, pH not specified in the publication, temperature not specified in the publication | Homo sapiens | |
0.0144 | - |
NADP+ | recombinant mutant R132S IDH1, pH not specified in the publication, temperature not specified in the publication | Homo sapiens | |
0.3686 | - |
isocitrate | recombinant mutant R132C IDH1, pH not specified in the publication, temperature not specified in the publication | Homo sapiens | |
0.4341 | - |
isocitrate | recombinant mutant R132S IDH1, pH not specified in the publication, temperature not specified in the publication | Homo sapiens | |
0.5824 | - |
isocitrate | recombinant mutant R132H IDH1, pH not specified in the publication, temperature not specified in the publication | Homo sapiens |
Localization | Comment | Organism | GeneOntology No. | Textmining |
---|---|---|---|---|
cytosol | IDH1 | Homo sapiens | 5829 | - |
mitochondrion | IDH2 | Sus scrofa | 5739 | - |
mitochondrion | IDH2 and IDH3 | Homo sapiens | 5739 | - |
peroxisome | IDH1 | Homo sapiens | 5777 | - |
Metals/Ions | Comment | Organism | Structure |
---|---|---|---|
Ca2+ | structure of IDH1 with bound Ca2+, overview | Homo sapiens | |
Mn2+ | activates | Homo sapiens |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
isocitrate + NADP+ | Homo sapiens | - |
2-oxoglutarate + NADPH + H+ + CO2 | - |
? | |
isocitrate + NADP+ | Sus scrofa | - |
2-oxoglutarate + NADPH + H+ + CO2 | - |
? |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | - |
- |
- |
Sus scrofa | - |
- |
- |
Purification (Comment) | Organism |
---|---|
recombinant His-tagged wild-type and mutant IDH1s from Escherichia coli by nickel affinity chromatography | Homo sapiens |
Source Tissue | Comment | Organism | Textmining |
---|---|---|---|
brain tumor cell | IDH1 | Homo sapiens | - |
glioblastoma cell | - |
Homo sapiens | - |
glioma cell | IDH1, diffuse gliomas graded II-IV | Homo sapiens | - |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
isocitrate + NADP+ | - |
Homo sapiens | 2-oxoglutarate + NADPH + H+ + CO2 | - |
? | |
isocitrate + NADP+ | - |
Sus scrofa | 2-oxoglutarate + NADPH + H+ + CO2 | - |
? |
Subunits | Comment | Organism |
---|---|---|
dimer | - |
Homo sapiens |
dimer | - |
Sus scrofa |
Synonyms | Comment | Organism |
---|---|---|
IDH1 | - |
Homo sapiens |
IDH2 | - |
Homo sapiens |
IDH2 | - |
Sus scrofa |
IDH3 | - |
Homo sapiens |
isocitrate dehydrogenase | - |
Homo sapiens |
isocitrate dehydrogenase | - |
Sus scrofa |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
NADP+ | - |
Homo sapiens | |
NADP+ | - |
Sus scrofa |
General Information | Comment | Organism |
---|---|---|
additional information | heterozygous mutations in the gene encoding IDH1 occur in certain human brain tumors, IDH is a strong factor in the development of gliomas. Tumor-derived IDH1 mutations impair the enzyme's affinity for its substrate and dominantly inhibit wild-type IDH1 activity through the formation of catalytically inactive heterodimers. HIF-1alpha levels are higher in human gliomas harboring an IDH1 mutation than in tumors without a mutation. Rise in HIF-1alpha levels occur, reversible by an 2-oxoglutarate derivative | Homo sapiens |
physiological function | IDH1 regulates HIF-1alpha levels by controlling the level of 2-oxoglutarate. IDH1 appears to function as a tumor suppressor that, when mutationally inactivated, contributes to tumorigenesis in part through induction of the HIF-1 pathway. IDH1 is likely to function as a tumor suppressor gene rather than as an oncogene | Homo sapiens |