Unknown

Dataset Information

0

Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of ?-ketoglutarate-dependent dioxygenases.

ABSTRACT: IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of ?-ketoglutarate (?-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple ?-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as ?-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations reduce ?-KG and accumulate an ?-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations.

SUBMITTER: Xu W 

PROVIDER: S-EPMC3229304 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple α-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as α-KG does in the active site of histone demethylases. Ectop  ...[more]

Similar Datasets

Unknown Registered report: Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of ?-ketoglutarate-dependent dioxygenases.
| S-EPMC4521140 | biostudies-literature
Unknown Oncometabolite d-2-hydroxyglutarate impairs ?-ketoglutarate dehydrogenase and contractile function in rodent heart.
| S-EPMC5027422 | biostudies-literature
Unknown Cofactor Generation Cascade for ?-Ketoglutarate and Fe(II)-Dependent Dioxygenases.
| S-EPMC7493210 | biostudies-literature
Unknown The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases.
| S-EPMC3090014 | biostudies-literature
Unknown Human phosphoglycerate dehydrogenase produces the oncometabolite D-2-hydroxyglutarate.
| S-EPMC4340346 | biostudies-literature
Unknown The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway.
| S-EPMC5027283 | biostudies-literature
Transcriptomics Suppression of antitumor immunity by the oncometabolite 2-hydroxyglutarate
2016-07-27 | E-GEOD-84849 | biostudies-arrayexpress
Unknown Fe(II)-dependent, uridine-5'-monophosphate ?-ketoglutarate dioxygenases in the synthesis of 5'-modified nucleosides.
| S-EPMC3831618 | biostudies-literature
Unknown The oncometabolite R-2-hydroxyglutarate activates NF-?B-dependent tumor-promoting stromal niche for acute myeloid leukemia cells.
| S-EPMC5006242 | biostudies-literature
Unknown Electronic structure analysis of the oxygen-activation mechanism by Fe(II)- and ?-ketoglutarate (?KG)-dependent dioxygenases.
| S-EPMC3955955 | biostudies-literature