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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"Gut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis,"
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