The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases

DOI: 10.1038/embor.2011.43
PMID: 21460794

Authors: Rasheduzzaman Chowdhury (Department of Chemistry, University of Oxford) , Kar Kheng Yeoh (Department of Chemistry, University of Oxford) , Ya-min Tian (Henry Wellcome Building for Molecular Physiology, University of Oxford) , Lars Hillringhaus (epartment of Chemistry, University of Oxford) , Eleanor Bagg (Department of Chemistry, University of Oxford) , Nathan Rose (Department of Chemistry, University of Oxford) , Ivanhoe Leung (Department of Chemistry, University of Oxford) , Xuan Li (Epigenetic Regulation of Chromatin Function Group, University of Oxford) , C. Y. Woon (Department of Chemistry, University of Oxford) , Ming Yang (Department of Chemistry, University of Oxford) , Michael Mcdonough (Department of Chemistry, University of Oxford) , Oliver King (Department of Chemistry, University of Oxford) , Ian Clifton (Department of Chemistry, University of Oxford) , Robert Klose (Epigenetic Regulation of Chromatin Function Group, University of Oxford) , Timothy Claridge (Department of Chemistry, University of Oxford) , Peter Ratcliffe (Henry Wellcome Building for Molecular Physiology, University of Oxford) , Christopher Schofield (Department of Chemistry, University of Oxford) , Akane Kawamura (Department of Chemistry, 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 ?M for the histone N??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: Tumor; Crystallography; Glutarates; Histone; Humans; Inhibitory; Isocitrate; Jumonji; Magnetic; Mass; Mixed; Models; Molecular; Mutation; Neoplasms; Procollagen-Proline; Repressor; Signal Transduction

Subject Areas: Chemistry


Instruments: I04-Macromolecular Crystallography