Cancer-associated IDH1 mutations produce 2-hydroxyglutarate (original) (raw)

Nature volume 462, pages 739–744 (2009)Cite this article

An Addendum to this article was published on 17 June 2010

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.

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Protein Data Bank

Data deposits

R132H mutant IDH1 structure files are deposited in the Protein Data Bank under accession code 3INM.

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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.

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  1. Matthew G. Vander Heiden
    Present address: Present address: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.,

Authors and Affiliations

  1. Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA ,
    Lenny Dang, David W. White, Stefan Gross, Mark A. Bittinger, Edward M. Driggers, Valeria R. Fantin, Hyun Gyung Jang, Shengfang Jin, Marie C. Keenan, Kevin M. Marks, Katharine E. Yen, Matthew G. Vander Heiden & Shinsan M. Su
  2. Department of Chemistry and Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA,
    Bryson D. Bennett & Joshua D. Rabinowitz
  3. Department of Neurosurgery, UCLA Medical School, Los Angeles, California 90095, USA,
    Robert M. Prins & Linda M. Liau
  4. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA ,
    Patrick S. Ward & Craig B. Thompson
  5. Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA ,
    Lewis C. Cantley

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  1. Lenny Dang
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Correspondence toShinsan M. Su.

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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.

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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

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Editorial Summary

Role of 2-hydroxyglutarate in cancer

A high percentage of human glioblastomas has been found to harbour mutations in the metabolic enzyme cytosolic isocitrate dehydrogenase 1 (IDH1). The predominant R132H mutation is now shown to act as a gain-of-function mutation, enabling IDH1 to convert α-ketoglutarate to 2-hydroxyglutarate (2-HG). Human glioblastoma samples with IDH1 mutations indeed contain elevated levels of 2-HG. Future work will be directed at understanding the mechanisms by which 2-HG can contribute to tumorigenesis.