BRENDA - Enzyme Database

Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

Dang, L.; White, D.W.; Gross, S.; Bennett, B.D.; Bittinger, M.A.; Driggers, E.M.; Fantin, V.R.; Jang, H.G.; Jin, S.; Keenan, M.C.; Marks, K.M.; Prins, R.M.; Ward, P.S.; Yen, K.E.; Liau, L.M.; Rabinowitz, J.D.; Cantley, L.C.; Thompson, C.B.; Vander Heiden, M.G.; Su, S.M.; Nature 462, 739-744 (2009)

Data extracted from this reference:

Cloned(Commentary)
EC Number
Commentary
Organism
1.1.1.42
expression of myc-tagged wild-type IDH1 and R132H mutant IDH1 in U-87MG glioblastoma cells
Homo sapiens
Engineering
EC Number
Amino acid exchange
Commentary
Organism
1.1.1.42
R132H
naturally occuring mutant of IDH1, the mutation causes loss in binding affinity for both isocitrate and MgCl2 along with a 1000fold decrease in catalytic turnover. The mutant IDH1 directly converts 2-oxoglutarate to 2-hydroxyglutarate, that rapidly accumulates in the medium of cells expressing R132H mutant IDH1, metabolite profiling in comparison to the wild-type IDH1, overview. Mutation to histidine results in a significant shift in position of the highly conserved residues Y139 from the A subunit and K212' from the B subunit both of which are thought to be critical for catalysis by this enzyme family. exchange of Arg132 to His affects the conformation equilibrium and the reorganization of the active-site. Also, not only the expected loss of key salt-bridge interactions between the guanidinium of R132 and the alpha/beta carboxylates of isocitrate, as well as changes in the network that coordinates the metal ion, but also an unexpected reorganization of the active-site, structure analyis, overview
Homo sapiens
Localization
EC Number
Localization
Commentary
Organism
GeneOntology No.
Textmining
1.1.1.42
cytosol
isozyme IDH1
Homo sapiens
5829
-
Metals/Ions
EC Number
Metals/Ions
Commentary
Organism
Structure
1.1.1.42
Mg2+
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
additional information
Homo sapiens
the R132H mutant IDH1 directly converts 2-oxoglutarate to 2-hydroxyglutarate, that rapidly accumulates in the medium of cells expressing R132H mutant IDH1
?
-
-
-
Organism
EC Number
Organism
Primary Accession No. (UniProt)
Commentary
Textmining
1.1.1.42
Homo sapiens
O75874
-
-
Source Tissue
EC Number
Source Tissue
Commentary
Organism
Textmining
1.1.1.42
glioblastoma cell
of secondary glioblastomas
Homo sapiens
-
1.1.1.42
glioma cell
of grade II-III gliomas
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+
-
713100
Homo sapiens
2-oxoglutarate + NADPH + H+ + CO2
-
-
-
?
1.1.1.42
additional information
the R132H mutant IDH1 directly converts 2-oxoglutarate to 2-hydroxyglutarate, that rapidly accumulates in the medium of cells expressing R132H mutant IDH1
713100
Homo sapiens
?
-
-
-
-
Subunits
EC Number
Subunits
Commentary
Organism
1.1.1.42
More
exchange of Arg132 to His affects the conformation equilibrium and the reorganization of the active-site. Also, not only the expected loss of key salt-bridge interactions between the guanidinium of R132 and the alpha/beta carboxylates of isocitrate, as well as changes in the network that coordinates the metal ion, but also an unexpected reorganization of the active-site, structure analyis, overview
Homo sapiens
Cofactor
EC Number
Cofactor
Commentary
Organism
Structure
1.1.1.42
NADP+
-
Homo sapiens
Cloned(Commentary) (protein specific)
EC Number
Commentary
Organism
1.1.1.42
expression of myc-tagged wild-type IDH1 and R132H mutant IDH1 in U-87MG glioblastoma cells
Homo sapiens
Cofactor (protein specific)
EC Number
Cofactor
Commentary
Organism
Structure
1.1.1.42
NADP+
-
Homo sapiens
Engineering (protein specific)
EC Number
Amino acid exchange
Commentary
Organism
1.1.1.42
R132H
naturally occuring mutant of IDH1, the mutation causes loss in binding affinity for both isocitrate and MgCl2 along with a 1000fold decrease in catalytic turnover. The mutant IDH1 directly converts 2-oxoglutarate to 2-hydroxyglutarate, that rapidly accumulates in the medium of cells expressing R132H mutant IDH1, metabolite profiling in comparison to the wild-type IDH1, overview. Mutation to histidine results in a significant shift in position of the highly conserved residues Y139 from the A subunit and K212' from the B subunit both of which are thought to be critical for catalysis by this enzyme family. exchange of Arg132 to His affects the conformation equilibrium and the reorganization of the active-site. Also, not only the expected loss of key salt-bridge interactions between the guanidinium of R132 and the alpha/beta carboxylates of isocitrate, as well as changes in the network that coordinates the metal ion, but also an unexpected reorganization of the active-site, structure analyis, overview
Homo sapiens
Localization (protein specific)
EC Number
Localization
Commentary
Organism
GeneOntology No.
Textmining
1.1.1.42
cytosol
isozyme IDH1
Homo sapiens
5829
-
Metals/Ions (protein specific)
EC Number
Metals/Ions
Commentary
Organism
Structure
1.1.1.42
Mg2+
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
additional information
Homo sapiens
the R132H mutant IDH1 directly converts 2-oxoglutarate to 2-hydroxyglutarate, that rapidly accumulates in the medium of cells expressing R132H mutant IDH1
?
-
-
-
Source Tissue (protein specific)
EC Number
Source Tissue
Commentary
Organism
Textmining
1.1.1.42
glioblastoma cell
of secondary glioblastomas
Homo sapiens
-
1.1.1.42
glioma cell
of grade II-III gliomas
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+
-
713100
Homo sapiens
2-oxoglutarate + NADPH + H+ + CO2
-
-
-
?
1.1.1.42
additional information
the R132H mutant IDH1 directly converts 2-oxoglutarate to 2-hydroxyglutarate, that rapidly accumulates in the medium of cells expressing R132H mutant IDH1
713100
Homo sapiens
?
-
-
-
-
Subunits (protein specific)
EC Number
Subunits
Commentary
Organism
1.1.1.42
More
exchange of Arg132 to His affects the conformation equilibrium and the reorganization of the active-site. Also, not only the expected loss of key salt-bridge interactions between the guanidinium of R132 and the alpha/beta carboxylates of isocitrate, as well as changes in the network that coordinates the metal ion, but also an unexpected reorganization of the active-site, structure analyis, overview
Homo sapiens
General Information
EC Number
General Information
Commentary
Organism
1.1.1.42
metabolism
metabolite profiling identifies elevated 2-hydroxyglutarate levels in IDH1 mutant R132H expressing cells compared to wild-type
Homo sapiens
1.1.1.42
additional information
mutations in the enzyme cytosolic IDH1 at R132 are a common feature of a major subset of primary human brain cancers, especially in grade II-III gliomas and secondary glioblastomas. The mutations result in loss of the enzyme's ability to catalyze conversion of isocitrate to 2-oxoglutarate. Expression of R132H mutant IDH1 results in no measurable production of NADPH from isocitrate, and isocitrate-dependent NADPH production increases with increasing amounts of wild-type enzyme
Homo sapiens
General Information (protein specific)
EC Number
General Information
Commentary
Organism
1.1.1.42
metabolism
metabolite profiling identifies elevated 2-hydroxyglutarate levels in IDH1 mutant R132H expressing cells compared to wild-type
Homo sapiens
1.1.1.42
additional information
mutations in the enzyme cytosolic IDH1 at R132 are a common feature of a major subset of primary human brain cancers, especially in grade II-III gliomas and secondary glioblastomas. The mutations result in loss of the enzyme's ability to catalyze conversion of isocitrate to 2-oxoglutarate. Expression of R132H mutant IDH1 results in no measurable production of NADPH from isocitrate, and isocitrate-dependent NADPH production increases with increasing amounts of wild-type enzyme
Homo sapiens