title: The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases.
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.
authors: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
authors: Rasheduzzaman
authors: R
authors: Chowdhury
authors: Kar Kheng
authors: KK
authors: Yeoh
authors: Ya-Min
authors: YM
authors: Tian
authors: Lars
authors: L
authors: Hillringhaus
authors: Eleanor A
authors: EA
authors: Bagg
authors: Nathan R
authors: NR
authors: Rose
authors: Ivanhoe K H
authors: IK
authors: Leung
authors: Xuan S
authors: XS
authors: Li
authors: Esther C Y
authors: EC
authors: Woon
authors: Ming
authors: M
authors: Yang
authors: Michael A
authors: MA
authors: McDonough
authors: Oliver N
authors: ON
authors: King
authors: Ian J
authors: IJ
authors: Clifton
authors: Robert J
authors: RJ
authors: Klose
authors: Timothy D W
authors: TD
authors: Claridge
authors: Peter J
authors: PJ
authors: Ratcliffe
authors: Christopher J
authors: CJ
authors: Schofield
authors: Akane
authors: A
authors: Kawamura
mesh_terms: D045744:Cell Line, Tumor; D003461:Crystallography; D005977:Glutarates / Q000378:metabolism*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D006899:Mixed Function Oxygenases; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D005977:Glutarates; D012097:Repressor Proteins; C019417:alpha-hydroxyglutarate; D006899:Mixed Function Oxygenases; D007521:Isocitrate Dehydrogenase; C439790:HIF1AN protein, human; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; D011393:Procollagen-Proline Dioxygenase; C494424:KDM4A protein, human