BRENDA - Enzyme Database

Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha

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.; Science 324, 261-265 (2009)

Data extracted from this reference:

Application
EC Number
Application
Commentary
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
Commentary
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
Engineering
EC Number
Amino acid exchange
Commentary
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
Commentary
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
Commentary
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
Commentary
Organism
GeneOntology No.
Textmining
1.1.1.42
cytosol
IDH1
Homo sapiens
5829
-
1.1.1.42
mitochondrion
IDH2 and IDH3
Homo sapiens
5739
-
1.1.1.42
mitochondrion
IDH2
Sus scrofa
5739
-
1.1.1.42
peroxisome
IDH1
Homo sapiens
5777
-
Metals/Ions
EC Number
Metals/Ions
Commentary
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
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
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
Primary Accession No. (UniProt)
Commentary
Textmining
1.1.1.42
Homo sapiens
-
-
-
1.1.1.42
Sus scrofa
-
-
-
Purification (Commentary)
EC Number
Commentary
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
Commentary
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
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
1.1.1.42
isocitrate + NADP+
-
713508
Homo sapiens
2-oxoglutarate + NADPH + H+ + CO2
-
-
-
?
1.1.1.42
isocitrate + NADP+
-
713508
Sus scrofa
2-oxoglutarate + NADPH + H+ + CO2
-
-
-
?
Subunits
EC Number
Subunits
Commentary
Organism
1.1.1.42
dimer
-
Homo sapiens
1.1.1.42
dimer
-
Sus scrofa
Cofactor
EC Number
Cofactor
Commentary
Organism
Structure
1.1.1.42
NADP+
-
Sus scrofa
1.1.1.42
NADP+
-
Homo sapiens
Application (protein specific)
EC Number
Application
Commentary
Organism
1.1.1.42
diagnostics
IDH1 mutational analysis can serve as a useful diagnostic marker of a glioma
Homo sapiens
Cloned(Commentary) (protein specific)
EC Number
Commentary
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
Cofactor (protein specific)
EC Number
Cofactor
Commentary
Organism
Structure
1.1.1.42
NADP+
-
Sus scrofa
1.1.1.42
NADP+
-
Homo sapiens
Engineering (protein specific)
EC Number
Amino acid exchange
Commentary
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 (protein specific)
EC Number
Inhibitors
Commentary
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] (protein specific)
EC Number
KM Value [mM]
KM Value Maximum [mM]
Substrate
Commentary
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 (protein specific)
EC Number
Localization
Commentary
Organism
GeneOntology No.
Textmining
1.1.1.42
cytosol
IDH1
Homo sapiens
5829
-
1.1.1.42
mitochondrion
IDH2 and IDH3
Homo sapiens
5739
-
1.1.1.42
mitochondrion
IDH2
Sus scrofa
5739
-
1.1.1.42
peroxisome
IDH1
Homo sapiens
5777
-
Metals/Ions (protein specific)
EC Number
Metals/Ions
Commentary
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) (protein specific)
EC Number
Natural Substrates
Organism
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
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
-
-
?
Purification (Commentary) (protein specific)
EC Number
Commentary
Organism
1.1.1.42
recombinant His-tagged wild-type and mutant IDH1s from Escherichia coli by nickel affinity chromatography
Homo sapiens
Source Tissue (protein specific)
EC Number
Source Tissue
Commentary
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) (protein specific)
EC Number
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
1.1.1.42
isocitrate + NADP+
-
713508
Homo sapiens
2-oxoglutarate + NADPH + H+ + CO2
-
-
-
?
1.1.1.42
isocitrate + NADP+
-
713508
Sus scrofa
2-oxoglutarate + NADPH + H+ + CO2
-
-
-
?
Subunits (protein specific)
EC Number
Subunits
Commentary
Organism
1.1.1.42
dimer
-
Homo sapiens
1.1.1.42
dimer
-
Sus scrofa
General Information
EC Number
General Information
Commentary
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
General Information (protein specific)
EC Number
General Information
Commentary
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