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EMBO Rep. 2011 May;12(5):463-9. doi: 10.1038/embor.2011.43. Epub 2011 Apr 1.

The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases.

Author information

1
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.

Abstract

Mutations in isocitrate dehydrogenases (IDHs) have a gain-of-function effect leading to R(-)-2-hydroxyglutarate (R-2HG) accumulation. By using biochemical, structural and cellular assays, we show that either or both R- and S-2HG inhibit 2-oxoglutarate (2OG)-dependent oxygenases with varying potencies. Half-maximal inhibitory concentration (IC(50)) values for the R-form of 2HG varied from approximately 25 μM for the histone N(ɛ)-lysine demethylase JMJD2A to more than 5 mM for the hypoxia-inducible factor (HIF) prolyl hydroxylase. The results indicate that candidate oncogenic pathways in IDH-associated malignancy should include those that are regulated by other 2OG oxygenases than HIF hydroxylases, in particular those involving the regulation of histone methylation.

PMID:
21460794
PMCID:
PMC3090014
DOI:
10.1038/embor.2011.43
[Indexed for MEDLINE]
Free PMC Article

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