Cancer-Associated IDH1 Mutations Produce 2-hydroxyglutarate

Journal Article · Thu Jan 01 04:00:00 EST 2009 · Nature

DOI:https://doi.org/10.1038/nature08617· OSTI ID:1019616

Dang, L; White, D; Gross, S; Bennett, B; Bittinger, M; Driggers, E; Fantin, V; Jang, H; Jin, S

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 {alpha}-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 {alpha}-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 {alpha}-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.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: DOE - OFFICE OF SCIENCE
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 1019616
• Report Number(s): BNL--95461-2011-JA
• Journal Information: Nature, Journal Name: Nature Journal Issue: 7274 Vol. 462; ISSN 0028-0836
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS
AMINO ACIDS
ARGININE
BRAIN
DECARBOXYLATION
ENZYMES
GENES
GLIOMAS
HISTIDINE
IN VIVO
METABOLISM
MUTATIONS
OXIDOREDUCTASES
PATIENTS
PRODUCTION
RESIDUES
national synchrotron light source