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Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

Author

Listed:
  • Lenny Dang

    (Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA)

  • David W. White

    (Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA)

  • Stefan Gross

    (Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA)

  • Bryson D. Bennett

    (Princeton University, Princeton, New Jersey 08544, USA)

  • Mark A. Bittinger

    (Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA)

  • Edward M. Driggers

    (Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA)

  • Valeria R. Fantin

    (Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA)

  • Hyun Gyung Jang

    (Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA)

  • Shengfang Jin

    (Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA)

  • Marie C. Keenan

    (Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA)

  • Kevin M. Marks

    (Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA)

  • Robert M. Prins

    (UCLA Medical School, Los Angeles, California 90095, USA)

  • Patrick S. Ward

    (Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA)

  • Katharine E. Yen

    (Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA)

  • Linda M. Liau

    (UCLA Medical School, Los Angeles, California 90095, USA)

  • Joshua D. Rabinowitz

    (Princeton University, Princeton, New Jersey 08544, USA)

  • Lewis C. Cantley

    (Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA)

  • Craig B. Thompson

    (Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA)

  • Matthew G. Vander Heiden

    (Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA
    Present address: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.)

  • Shinsan M. Su

    (Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA)

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.

Suggested Citation

  • Lenny Dang & David W. White & Stefan Gross & Bryson D. Bennett & Mark A. Bittinger & Edward M. Driggers & Valeria R. Fantin & Hyun Gyung Jang & Shengfang Jin & Marie C. Keenan & Kevin M. Marks & Rober, 2009. "Cancer-associated IDH1 mutations produce 2-hydroxyglutarate," Nature, Nature, vol. 462(7274), pages 739-744, December.
  • Handle: RePEc:nat:nature:v:462:y:2009:i:7274:d:10.1038_nature08617
    DOI: 10.1038/nature08617
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    Citations

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    Cited by:

    1. Giovanni Codacci-Pisanelli, 2017. "Epigenetic Targets in the Treatment of cancer," Novel Approaches in Drug Designing & Development, Juniper Publishers Inc., vol. 1(4), pages 56-57, June.
    2. Syeda Maheen Batool & Ana K. Escobedo & Tiffaney Hsia & Emil Ekanayake & Sirena K. Khanna & Austin S. Gamblin & Hui Zheng & Johan Skog & Julie J. Miller & Anat O. Stemmer-Rachamimov & Daniel P. Cahill, 2024. "Clinical utility of a blood based assay for the detection of IDH1.R132H-mutant gliomas," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Zidan Wang & Donghui Zhang & Junhan Wu & Wenpeng Zhang & Yu Xia, 2024. "Illuminating the dark space of neutral glycosphingolipidome by selective enrichment and profiling at multi-structural levels," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Ling Tao & Mahmoud A. Mohammad & Giorgio Milazzo & Myrthala Moreno-Smith & Tajhal D. Patel & Barry Zorman & Andrew Badachhape & Blanca E. Hernandez & Amber B. Wolf & Zihua Zeng & Jennifer H. Foster & , 2022. "MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Muhammad Shemyal Nisar & Xiangwei Zhao, 2019. "High Resolution Mass Spectroscopy for Single Cell Analysis," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 18(4), pages 13820-13824, June.
    6. Mark A. McCoy & Jun Lu & F. Richard Miller & Stephen M. Soisson & Michael H. Lam & Christian Fischer, 2024. "Biostructural, biochemical and biophysical studies of mutant IDH1," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    7. Kotaro Soeda & Takayoshi Sasako & Kenichiro Enooku & Naoto Kubota & Naoki Kobayashi & Yoshiko Matsumoto Ikushima & Motoharu Awazawa & Ryotaro Bouchi & Gotaro Toda & Tomoharu Yamada & Takuma Nakatsuka , 2023. "Gut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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