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Title: Cancer-Associated IDH1 Mutations Produce 2-hydroxyglutarate

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 {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 excessmore » 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.« less

Authors:
; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
DOE - OFFICE OF SCIENCE
OSTI Identifier:
1019616
Report Number(s):
BNL-95461-2011-JA
Journal ID: ISSN 0028-0836; TRN: US201115%%257
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Journal Name:
Nature
Additional Journal Information:
Journal Volume: 462; Journal Issue: 7274; Journal ID: ISSN 0028-0836
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; AMINO ACIDS; ARGININE; BRAIN; DECARBOXYLATION; ENZYMES; GENES; GLIOMAS; HISTIDINE; IN VIVO; METABOLISM; MUTATIONS; OXIDOREDUCTASES; PATIENTS; PRODUCTION; RESIDUES; national synchrotron light source

Citation Formats

Dang, L, White, D, Gross, S, Bennett, B, Bittinger, M, Driggers, E, Fantin, V, Jang, H, Jin, S, and et al. Cancer-Associated IDH1 Mutations Produce 2-hydroxyglutarate. United States: N. p., 2009. Web. doi:10.1038/nature08617.
Dang, L, White, D, Gross, S, Bennett, B, Bittinger, M, Driggers, E, Fantin, V, Jang, H, Jin, S, & et al. Cancer-Associated IDH1 Mutations Produce 2-hydroxyglutarate. United States. doi:10.1038/nature08617.
Dang, L, White, D, Gross, S, Bennett, B, Bittinger, M, Driggers, E, Fantin, V, Jang, H, Jin, S, and et al. Thu . "Cancer-Associated IDH1 Mutations Produce 2-hydroxyglutarate". United States. doi:10.1038/nature08617.
@article{osti_1019616,
title = {Cancer-Associated IDH1 Mutations Produce 2-hydroxyglutarate},
author = {Dang, L and White, D and Gross, S and Bennett, B and Bittinger, M and Driggers, E and Fantin, V and Jang, H and Jin, S and et al.},
abstractNote = {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.},
doi = {10.1038/nature08617},
journal = {Nature},
issn = {0028-0836},
number = 7274,
volume = 462,
place = {United States},
year = {2009},
month = {1}
}