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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
Added On:
05/04/2011 18:40
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