PMID- 19935646
OWN - NLM
STAT- MEDLINE
DCOM- 20100126
LR  - 20240312
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 462
IP  - 7274
DP  - 2009 Dec 10
TI  - Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.
PG  - 739-44
LID - 10.1038/nature08617 [doi]
AB  - 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.
FAU - Dang, Lenny
AU  - Dang L
AD  - Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
FAU - White, David W
AU  - White DW
FAU - Gross, Stefan
AU  - Gross S
FAU - Bennett, Bryson D
AU  - Bennett BD
FAU - Bittinger, Mark A
AU  - Bittinger MA
FAU - Driggers, Edward M
AU  - Driggers EM
FAU - Fantin, Valeria R
AU  - Fantin VR
FAU - Jang, Hyun Gyung
AU  - Jang HG
FAU - Jin, Shengfang
AU  - Jin S
FAU - Keenan, Marie C
AU  - Keenan MC
FAU - Marks, Kevin M
AU  - Marks KM
FAU - Prins, Robert M
AU  - Prins RM
FAU - Ward, Patrick S
AU  - Ward PS
FAU - Yen, Katharine E
AU  - Yen KE
FAU - Liau, Linda M
AU  - Liau LM
FAU - Rabinowitz, Joshua D
AU  - Rabinowitz JD
FAU - Cantley, Lewis C
AU  - Cantley LC
FAU - Thompson, Craig B
AU  - Thompson CB
FAU - Vander Heiden, Matthew G
AU  - Vander Heiden MG
FAU - Su, Shinsan M
AU  - Su SM
LA  - eng
SI  - PDB/3INM
GR  - P01 CA104838-05/CA/NCI NIH HHS/United States
GR  - R21 CA128620/CA/NCI NIH HHS/United States
GR  - R01 CA105463-06/CA/NCI NIH HHS/United States
GR  - P30 EB009998/EB/NIBIB NIH HHS/United States
GR  - P01 CA104838/CA/NCI NIH HHS/United States
GR  - R01 CA105463/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Glutarates)
RN  - 0 (Ketoglutaric Acids)
RN  - 0 (Mutant Proteins)
RN  - 2889-31-8 (alpha-hydroxyglutarate)
RN  - 4QD397987E (Histidine)
RN  - 94ZLA3W45F (Arginine)
RN  - EC 1.1.1.41 (Isocitrate Dehydrogenase)
RN  - EC 1.1.1.42. (IDH1 protein, human)
SB  - IM
MH  - Arginine/genetics
MH  - Brain Neoplasms/*genetics/*metabolism/pathology
MH  - Catalytic Domain
MH  - Cell Line
MH  - Crystallography, X-Ray
MH  - Disease Progression
MH  - Enzyme Assays
MH  - Glioma/genetics/metabolism/pathology
MH  - Glutarates/*metabolism
MH  - Histidine/genetics/metabolism
MH  - Humans
MH  - Isocitrate Dehydrogenase/*genetics/*metabolism
MH  - Ketoglutaric Acids/metabolism
MH  - Models, Molecular
MH  - Mutant Proteins/*genetics/*metabolism
MH  - Mutation/genetics
MH  - Protein Conformation
PMC - PMC2818760
MID - NIHMS165905
EDAT- 2009/11/26 06:00
MHDA- 2010/01/27 06:00
PMCR- 2010/02/09
CRDT- 2009/11/26 06:00
PHST- 2009/07/15 00:00 [received]
PHST- 2009/10/29 00:00 [accepted]
PHST- 2009/11/26 06:00 [entrez]
PHST- 2009/11/26 06:00 [pubmed]
PHST- 2010/01/27 06:00 [medline]
PHST- 2010/02/09 00:00 [pmc-release]
AID - nature08617 [pii]
AID - 10.1038/nature08617 [doi]
PST - ppublish
SO  - Nature. 2009 Dec 10;462(7274):739-44. doi: 10.1038/nature08617.