Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

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, Robert M. Prins, Patrick S. Ward, Katharine E. Yen, Linda M. Liau, Joshua D. Rabinowitz, Lewis C. Cantley, Craig B. Thompson, Matthew G. Vander Heiden and Shinsan M. Su ()
Additional contact information
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
Shinsan M. Su: Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA

Nature, 2009, vol. 462, issue 7274, 739-744

Abstract: 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.

Date: 2009
References: Add references at CitEc
Citations: View citations in EconPapers (8)

Downloads: (external link)
https://www.nature.com/articles/nature08617 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:462:y:2009:i:7274:d:10.1038_nature08617

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/nature08617

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().