Abstract
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 α-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 α-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 α-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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Balss, J. et al. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 116, 597–602 (2008)
Watanabe, T., Nobusawa, S., Kleihues, P. & Ohgaki, H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am. J. Pathol. 174, 1149–1153 (2009)
Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009)
Hartmann, C. et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol. 118, 469–474 (2009)
Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008)
Bleeker, F. E. et al. IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum. Mutat. 30, 7–11 (2009)
Zhao, S. et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1α. Science 324, 261–265 (2009)
Lu, W., Kimball, E. & Rabinowitz, J. D. A high-performance liquid chromatography-tandem mass spectrometry method for quantitation of nitrogen-containing intracellular metabolites. J. Am. Soc. Mass Spectrom. 17, 37–50 (2006)
Struys, E. A., Jansen, E. E., Verhoeven, N. M. & Jakobs, C. Measurement of urinary d- and l-2-hydroxyglutarate enantiomers by stable-isotope-dilution liquid chromatography-tandem mass spectrometry after derivatization with diacetyl-l-tartaric anhydride. Clin. Chem. 50, 1391–1395 (2004)
Xu, X. et al. Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J. Biol. Chem. 279, 33946–33957 (2004)
Aktas, D. F. & Cook, P. F. A lysine-tyrosine pair carries out acid-base chemistry in the metal ion-dependent pyridine dinucleotide-linked β-hydroxyacid oxidative decarboxylases. Biochemistry 48, 3565–3577 (2009)
Struys, E. A. et al. Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria. Am. J. Hum. Genet. 76, 358–360 (2005)
Kölker, S., Mayatepek, E. & Hoffmann, G. F. White matter disease in cerebral organic acid disorders: clinical implications and suggested pathomechanisms. Neuropediatrics 33, 225–231 (2002)
Wajner, M., Latini, A., Wyse, A. T. & Dutra-Filho, C. S. The role of oxidative damage in the neuropathology of organic acidurias: insights from animal studies. J. Inherit. Metab. Dis. 27, 427–448 (2004)
Aghili, M., Zahedi, F. & Rafiee, E. Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review. J. Neurooncol. 91, 233–236 (2009)
Kolker, S. et al. NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in d-2-hydroxyglutaric aciduria. Eur. J. Neurosci. 16, 21–28 (2002)
Latini, A. et al. d-2-hydroxyglutaric acid induces oxidative stress in cerebral cortex of young rats. Eur. J. Neurosci. 17, 2017–2022 (2003)
Tsacopoulos, M. Metabolic signaling between neurons and glial cells: a short review. J. Physiol. (Paris) 96, 283–288 (2002)
Mardis, E. R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009)
Luo, B., Groenke, K., Takors, R., Wandrey, C. & Oldiges, M. Simultaneous determination of multiple intracellular metabolites in glycolysis, pentose phosphate pathway and tricarboxylic acid cycle by liquid chromatography-mass spectrometry. J. Chromatogr. A 1147, 153–164 (2007)
Munger, J. et al. Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy. Nature Biotechnol. 26, 1179–1186 (2008)
Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode (HKL2000). Methods Enzymol. 276, 307–326 (1997)
McCoy, A. J. et al. Phaser Crystallographic Software. J. Appl. Cryst. 40, 658–674 (2007)
Emsley, P. & Cowtan, K. COOT: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126–2132 (2004)
Collaborative Computational Project, Number 4. The CCP4 Suite: Programs for Protein Crystallography. Acta Crystallogr. D 50, 760–763 (1994)
DeLano, W. L. The PyMOL Molecular Graphics System (DeLano Scientific, 2002)
Acknowledgements
We thank R. K. Suto, R. S. Brown and E. Fontano at Xtal BioStructures for performing crystallographic studies, and S. Wang at ChemPartner for assistance with biochemical experiments. We thank G. Petsko for his review of the structure data. We also thank T. Mak, N. Wu, L. Tartaglia, J. Saunders, F. Salituro and D. Schenkein for discussions and/or comments on the manuscript. Asterand, PLC provided some of the glioma specimens and SeqWright Inc. assisted with genomic DNA SNP analysis. J.D.R. is supported by NIH R21 CA128620.
Author Contributions L.D., D.W.W., S.G., B.D.B., M.A.B., E.M.D., V.R.F., H.G.J., S.J., M.C.K., K.M.M., R.M.P., P.S.W., K.E.Y., J.D.R., L.M.L. and S.M.S. contributed extensively to the work presented in this paper. L.C.C., C.B.T., M.G.V.H. and S.M.S. provided support and conceptual advice. L.D., M.G.V.H. and S.M.S. wrote the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
L.D., D.W.W., S.G., M.A.B., E.M.D., V.R.F., H.G.J., S.J., M.C.K., K.M.M., K.E.Y., J.D.R., L.C.C, C.B.T., M.G.V.H. and S.M.S. are employees or consultants of Agios Pharmaceuticals and have financial interest in Agios.
Supplementary information
Supplementary Information
This file contains Supplementary Figures 1-5 with Legends and Supplementary Tables 1-2. (PDF 663 kb)
Rights and permissions
About this article
Cite this article
Dang, L., White, D., Gross, S. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009). https://doi.org/10.1038/nature08617
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature08617
This article is cited by
-
Distinguishing IDH mutation status in gliomas using FTIR-ATR spectra of peripheral blood plasma indicating clear traces of protein amyloid aggregation
BMC Cancer (2024)
-
Beyond invasive biopsies: using VASARI MRI features to predict grade and molecular parameters in gliomas
Cancer Imaging (2024)
-
IDH1/MDH1 deacetylation promotes acute liver failure by regulating NETosis
Cellular & Molecular Biology Letters (2024)
-
A universal metabolite repair enzyme removes a strong inhibitor of the TCA cycle
Nature Communications (2024)
-
Metabolic alterations in hereditary and sporadic renal cell carcinoma
Nature Reviews Nephrology (2024)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.