The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases

DOI: 10.1038/embor.2011.43
PMID: 21460794

Authors: Rasheduzzaman Chowdhury (University of Oxford) , Kar Kheng Yeoh (University of Oxford) , Ya-Min Tian (University of Oxford) , Lars Hillringhaus (University of Oxford) , Eleanor Bagg (University of Oxford) , Nathan R. Rose (University of Oxford) , Ivanhoe K. H. Leung (University of Oxford) , Xuan S. Li (University of Oxford) , Esther C. Y. Woon (University of Oxford) , Ming Yang (University of Oxford) , Michael A. Mcdonough (University of Oxford) , Oliver N. King (University of Oxford) , Ian J. Clifton (University of Oxford) , Robert J. Klose (University of Oxford) , Timothy D. W. Claridge (University of Oxford) , Peter J. Ratcliffe (University of Oxford) , Christopher J. Schofield (University of Oxford) , Akane Kawamura (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Embo Reports , VOL 12 (5) , PAGES 463-469

State: Published (Approved)
Published: April 2011

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 (IC50) values for the R-form of 2HG varied from approximately 25 μM for the histone Nε-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.

Journal Keywords: isocitrate dehydrogenase; 2-hydroxyglutarate; 2-oxoglutarate; oxygenases; hypoxia-inducible factor

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I04-Macromolecular Crystallography

Added On: 05/04/2011 18:40

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)