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Literature summary extracted from

  • Zhao, S.; Lin, Y.; Xu, W.; Jiang, W.; Zha, Z.; Wang, P.; Yu, W.; Li, Z.; Gong, L.; Peng, Y.; Ding, J.; Lei, Q.; Guan, K.L.; Xiong, Y.
    Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha (2009), Science, 324, 261-265.
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
1.1.1.42 diagnostics IDH1 mutational analysis can serve as a useful diagnostic marker of a glioma Homo sapiens

Cloned(Commentary)

EC Number Cloned (Comment) Organism
1.1.1.42 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

EC Number Protein Variants Comment Organism
1.1.1.42 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
1.1.1.42 R132C naturally occuring mutation of IDH1, results in 60fold increased Km for isocitrate compared to the wild-type IDH1 Homo sapiens
1.1.1.42 R132H naturally occuring mutation of IDH1, results in 94fold increased Km for isocitrate compared to the wild-type IDH1 Homo sapiens
1.1.1.42 R132S naturally occuring mutation of IDH1, results in 70fold increased Km for isocitrate compared to the wild-type IDH1 Homo sapiens
1.1.1.42 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
1.1.1.42 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

EC Number Inhibitors Comment Organism Structure
1.1.1.42 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]

EC Number KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
1.1.1.42 0.0062
-
 isocitrate recombinant wild-type IDH1, pH not specified in the publication, temperature not specified in the publication Homo sapiens
1.1.1.42 0.0068
-
 NADP+ recombinant mutant R132C IDH1, pH not specified in the publication, temperature not specified in the publication Homo sapiens
1.1.1.42 0.0073
-
 NADP+ recombinant wild-type IDH1, pH not specified in the publication, temperature not specified in the publication Homo sapiens
1.1.1.42 0.0122
-
 NADP+ recombinant mutant R132H IDH1, pH not specified in the publication, temperature not specified in the publication Homo sapiens
1.1.1.42 0.0144
-
 NADP+ recombinant mutant R132S IDH1, pH not specified in the publication, temperature not specified in the publication Homo sapiens
1.1.1.42 0.3686
-
 isocitrate recombinant mutant R132C IDH1, pH not specified in the publication, temperature not specified in the publication Homo sapiens
1.1.1.42 0.4341
-
 isocitrate recombinant mutant R132S IDH1, pH not specified in the publication, temperature not specified in the publication Homo sapiens
1.1.1.42 0.5824
-
 isocitrate recombinant mutant R132H IDH1, pH not specified in the publication, temperature not specified in the publication Homo sapiens

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
1.1.1.42 cytosol IDH1 Homo sapiens 5829
-
1.1.1.42 mitochondrion IDH2 Sus scrofa 5739
-
1.1.1.42 mitochondrion IDH2 and IDH3 Homo sapiens 5739
-
1.1.1.42 peroxisome IDH1 Homo sapiens 5777
-

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
1.1.1.42 Ca2+ structure of IDH1 with bound Ca2+, overview Homo sapiens
1.1.1.42 Mn2+ activates Homo sapiens

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
1.1.1.42 isocitrate + NADP+ Homo sapiens
-
 2-oxoglutarate + NADPH + H+ + CO2
-
 ?
1.1.1.42 isocitrate + NADP+ Sus scrofa
-
 2-oxoglutarate + NADPH + H+ + CO2
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
1.1.1.42 Homo sapiens
-
-
-
1.1.1.42 Sus scrofa
-
-
-

Purification (Commentary)

EC Number Purification (Comment) Organism
1.1.1.42 recombinant His-tagged wild-type and mutant IDH1s from Escherichia coli by nickel affinity chromatography Homo sapiens

Source Tissue

EC Number Source Tissue Comment Organism Textmining
1.1.1.42 brain tumor cell IDH1 Homo sapiens
-
1.1.1.42 glioblastoma cell
-
 Homo sapiens
-
1.1.1.42 glioma cell IDH1, diffuse gliomas graded II-IV Homo sapiens
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.1.1.42 isocitrate + NADP+
-
 Homo sapiens 2-oxoglutarate + NADPH + H+ + CO2
-
 ?
1.1.1.42 isocitrate + NADP+
-
 Sus scrofa 2-oxoglutarate + NADPH + H+ + CO2
-
 ?

Subunits

EC Number Subunits Comment Organism
1.1.1.42 dimer
-
 Homo sapiens
1.1.1.42 dimer
-
 Sus scrofa

Synonyms

EC Number Synonyms Comment Organism
1.1.1.42 IDH1
-
 Homo sapiens
1.1.1.42 IDH2
-
 Homo sapiens
1.1.1.42 IDH2
-
 Sus scrofa
1.1.1.42 IDH3
-
 Homo sapiens
1.1.1.42 isocitrate dehydrogenase
-
 Homo sapiens
1.1.1.42 isocitrate dehydrogenase
-
 Sus scrofa

Cofactor

EC Number Cofactor Comment Organism Structure
1.1.1.42 NADP+
-
 Homo sapiens
1.1.1.42 NADP+
-
 Sus scrofa

General Information

EC Number General Information Comment Organism
1.1.1.42 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
1.1.1.42 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