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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)