Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Open accessAbstract
Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.
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2-hydroxyglutarate interferes with iron-dependent hydroxylases, including the TET family of 5-methylcytosine hydroxylases.
“Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylases, including the TET family of 5′-methylcytosine hydroxylases3–7.”
From Insulator dysfunction and oncogene activation in IDH mutant gliomas (2016) · cites this paper as [3]
The section “Mutant IDH1 directly converts αKG to 2HG” confirms that mutant IDH1 produces 2HG. The Discussion suggests that 2HG may inhibit αKG-dependent prolyl hydroxylases, but presents this as a possibility, not an established effect. Our copy does not identify TET 5-methylcytosine hydroxylases as targets. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMutant IDH protein generates the oncometabolite 2-hydroxyglutarate.
“Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylases, including the TET family of 5′-methylcytosine hydroxylases3–7.”
From Insulator dysfunction and oncogene activation in IDH mutant gliomas (2016) · cites this paper as [3]
Wild-type IDH1 and IDH2 catalyze the reversible oxidative decarboxylation of isocitrate to alpha-ketoglutarate and CO2; cancer-associated mutations eliminate this function and confer a neomorphic activity generating D-2-hydroxyglutarate via reduction of alpha-ketoglutarate.
“Wild-type IDH1 and IDH2 catalyze the reversible oxidative decarboxylation of isocitrate to alpha-ketoglutarate (αKG) and CO2 (Figure 4a). Cancer associated mutations in IDH1 and IDH2 eliminate this function and confer a neomorphic activity to the enzyme, generating D-2-hydroxyglutarate (D-2HG) via the reduction of αKG (Figure 4b)(Dang et al., 2009; Ward et al., 2010).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Dang et al., 2009
Cancer-associated IDH1 R132 mutants display a loss-of-function for isocitrate as substrate and a concomitant gain-of-function for the reduction of α-ketoglutarate to 2HG.
“cancer-associated IDH1 R132 mutants display a loss-of-function for the use of isocitrate as substrate, with a concomitant gain-of-function for the reduction of α-ketoglutarate to 2HG”
From The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate (2010) · cites this paper as Dang et al., 2009
There is a marked difference between the rate of isocitrate-dependent NADPH production by wild-type IDH1/IDH2 and the rate of α-ketoglutarate-dependent NADPH consumption by the mutant proteins.
“There is a marked difference in the enzymatic rate of isocitrate-dependent NADPH production by the wild-type proteins and α-ketoglutarate-dependent NADPH consumption by both IDH1 and IDH2 mutants (Figure 2 and Dang et al., 2009).”
From The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate (2010) · cites this paper as Dang et al., 2009
2HG is elevated in IDH1-mutated gliomas.
“2HG was found to be elevated in IDH1-mutated gliomas”
From The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate (2010) · cites this paper as Dang et al., 2009
The R132H IDH1 mutation observed in gliomas displays a gain of function for the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate.
“The R132H IDH1 mutation observed in gliomas was found to display a gain of function for the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG)”
From The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate (2010) · cites this paper as Dang et al., 2009
A local supply of NADPH and α-ketoglutarate is required to drive 2HG production by IDH1 mutant proteins.
“In the case of IDH1 mutant proteins, it has been reported that a local supply of NADPH and α-ketoglutarate is required to drive 2HG production (Dang et al., 2009).”
From The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate (2010) · cites this paper as Dang et al., 2009
Various tumors, including glioma, secondary glioblastoma, and acute myeloid leukemia, harboring heterozygous point mutations in the active sites of IDH1/2 show dramatic increases in R-2-HG levels.
“Thus, various tumors, including glioma, secondary glioblastoma, and acute myeloid leukemia (AML), harboring heterozygous point mutations in the active sites of IDH1/2 show dramatic increases in the R-2-HG levels111,113–115.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [111]
R-2-HG, succinate, and fumarate are recognized as oncometabolites based on ample experimental data.
“Although additional studies are needed, ample experimental data support the recognition of R-2-HG, succinate, and fumarate as oncometabolites.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [111]
2HG, and in particular the R-enantiomer produced by IDH1 mutants, is probably an ineffective inhibitor of HIF Pro-hydroxylation and would be relatively ineffective at inducing HIF1α.
“These results suggest that 2HG-and in particular the R-enantiomer produced by IDH1 mutants (Dang et al, 2009)-is probably an ineffective inhibitor of HIF Pro-hydroxylation, and predict that it would be relatively ineffective in inducing HIF1a.”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Dang et al, 2009
The high R-2HG concentrations observed in malignant brain tumours and leukaemias, more than 10 mM, might be sufficient to inhibit even the less-susceptible 2OG oxygenases.
“The high concentrations of R-2HG (more than 10 mM) that have been observed in malignant brain tumours and leukaemias (Dang et al, 2009;Gross et al, 2010;Ward et al, 2010), might be sufficient to inhibit even the less-susceptible 2OG oxygenases.”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Dang et al, 2009
Production of 2HG by IDH mutations is stereospecific.
“As production of 2HG by IDH mutations is stereospecific (Dang et al, 2009;Ward et al, 2010), the specificity of inhibition by the 2HG enantiomers is relevant to their potential as mediators of oncogenic pathways.”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Dang et al, 2009
IDH mutations also cause a gain of function that converts 2OG to R-2HG.
“However, they also cause a gain of function comprising catalysis of 2OG to the R-enantiomer of 2-hydroxyglutarate (R-2HG; Dang et al, 2009;Gross et al, 2010;Ward et al, 2010).”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Dang et al, 2009
Tumor-associated IDH mutations enable production of R-2-hydroxyglutarate, which accumulates to low millimolar levels in IDH mutant tumors.
“Tumor-associated IDH mutations unmask a latent ability of these enzymes to produce the R enantiomer of 2-hydroxyglutarate, which accumulates to low millimolar levels in IDH mutant tumors (Dang et al., 2009; Gross et al., 2010; Ward et al., 2010).”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Dang et al., 2009
The mutant IDH enzyme competitively blocks hydroxylases, among them TET enzymes that hydroxylate 5mC.
“Mutant IDH protein is a competitive inhibitor of hydroxylases, including the TET family of 5mC hydroxylases120–122.”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [121]
Oncogenic mutations in genes encoding IDH1/2 result in neomorphic enzyme activity that favors reduction of αKG to d-2-hydroxyglutarate (D-2HG).
“Oncogenic mutations in genes encoding IDH1/2 result in neomorphic enzyme activity that favors reduction of αKG to d-2-hydroxyglutarate (D-2HG) (167, 168).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [167]
The IDH1 mutation alters the enzymatic ability of IDH1, allowing it to convert α-KG to 2-hydroxyglutarate (2-HG) rather than promote normal isocitrate-to-α-KG inter-conversion.
“This mutation alters the enzymatic ability of IDH1, allowing it to convert α-KG to 2-hydroxyglutarate (2-HG) rather than promote normal isocitrate–to–α-KG inter-conversion (78).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [78]
The weight of evidence suggests that regulation of HIF-1 stability through decreased PHD2 activity is not the primary effect of IDH mutations.
“The weight of the evidence now suggests that regulation of HIF-1 stability through decreased PHD2 activity is not the primary effect of IDH mutations (Chowdhury et al., 2011; Dang et al., 2009; Jin et al., 2011; Mardis et al., 2009; Metellus et al., 2011; Williams et al., 2011).”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Dang et al., 2009
IDH1 mutations at R132 are not simply loss-of-function for isocitrate and α-ketoglutarate interconversion; they also acquire a novel reductive activity converting α-ketoglutarate to 2-hydroxyglutarate (2HG).
“IDH1 mutations at R132 are not simply loss-of-function for isocitrate and α-ketoglutarate interconversion, but also acquire a novel reductive activity to convert α-ketoglutarate to 2-hydroxyglutarate (2HG)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Dang et al., 2009
2HG is a rare metabolite found at only trace amounts in mammalian cells under normal conditions.
“a rare metabolite found at only trace amounts in mammalian cells under normal conditions (Dang et al., 2009)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Dang et al., 2009
R(-)-2HG (D-2HG) is the exclusive 2HG stereoisomer produced by IDH1 and IDH2 mutants.
“R(-)-2HG (also known as D-2HG) is the exclusive 2HG stereoisomer produced by IDH1 and IDH2 mutants (Dang et al., 2009; Ward et al., 2010)”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Dang et al., 2009
Tumor tissue and cell lines expressing mutant IDH1 or IDH2 produced large quantities of (D)-2-hydroxyglutarate (2-HG), which is vanishingly scarce when only wild-type enzymes were expressed.
“This suspicion was confirmed by metabolomics: tumor tissue and cell lines expressing mutant IDH1 or IDH2 produced large quantities of a metabolite, (D)-2-hydroxyglutarate (2-HG), that is vanishingly scarce when only the wild-type enzymes were expressed (Dang et al., 2009).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Dang et al., 2009
Even large accumulations of 2-HG do not cause wholesale perturbations of metabolite levels in IDH1-mutant tumors.
“Surprisingly, even large accumulations of 2-HG do not cause wholesale perturbations of metabolite levels in IDH1-mutant tumors (Dang et al., 2009).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Dang et al., 2009
Suppression of RIP3-mediated necroptosis and MLK3-mediated apoptosis by D-2-HG may contribute to IDH-mutant carcinogenesis.
“These findings therefore suggest that both suppression of RIP3-mediated necroptosis and MLK3-mediated apoptosis by D-2-HG may contribute to IDH-mutant carcinogenesis140,141.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [141]
D-2-HG impairs necroptosis and the small GTPase Cdc42, leading to suppression of MLK3-mediated apoptosis.
“Finally, D-2HG also impairs necroptosis and the small GTPase Cdc42, leading to suppression of mixed lineage kinase 3 (MLK3)-mediated apoptosis140,141.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [141]
D-2-HG binds DNA methyltransferase DNMT1, which represses RIP3.
“D-2-HG has also been found to bind the DNA methyltransferase DNMT1, which subsequently represses receptor-interacting protein kinase 3 (RIP3).”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [141]
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- Authors
- 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.
- Affiliations
- Agios Pharmaceuticals (United States) (US)
- Princeton University (US)
- University of California, Los Angeles (US)
- Abramson Cancer Center (US)
- Beth Israel Deaconess Medical Center (US)
- ORCID
- Venue
- Nature
- Published
- 2009-11-22
- Volume
- 462
- Issue
- 7274
- Pages
- 739-744
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2818760
- OpenAlex
- W2080452140
- Cited by
- 4,154
- References
- 26
- Citations by year
- 2026: 184 · 2025: 230 · 2024: 250 · 2023: 257 · 2022: 285 · 2021: 315 · 2020: 297 · 2019: 267 · 2018: 280 · 2017: 270 · 2016: 273 · 2015: 245 · 2014: 218 · 2013: 225 · 2012: 218
- FWCI
- 88.03
- Type
- journal article
- Language
- en
- Update notices
- erratum (2010-06-17)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (P01CA104838, R21CA128620, R01CA105463)
- National Institute of Biomedical Imaging and Bioengineering (P30EB009998)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- IDH1 mutation, 2-hydroxyglutarate, gain-of-function mutations, isocitrate dehydrogenase, high-grade glioma, glioblastoma, oncometabolites, carcinogenesis, brain cancer, enzyme structure, tumor progression
- MeSH terms
- Arginine, Brain Neoplasms, Cell Line, Glioma, Glutarates, Histidine, Humans, Isocitrate Dehydrogenase, Ketoglutaric Acids, Models, Molecular, Mutation, Protein Conformation, Crystallography, X-Ray, Disease Progression, Catalytic Domain, Mutant Proteins, Enzyme Assays
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