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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.

Original publication

DOI

10.1038/embor.2011.43

Type

Journal article

Journal

EMBO Rep

Publication Date

05/2011

Volume

12

Pages

463 - 469

Keywords

Cell Line, Tumor, Crystallography, Glutarates, Histone Demethylases, Humans, Inhibitory Concentration 50, Isocitrate Dehydrogenase, Jumonji Domain-Containing Histone Demethylases, Magnetic Resonance Spectroscopy, Mass Spectrometry, Mixed Function Oxygenases, Models, Molecular, Mutation, Neoplasms, Procollagen-Proline Dioxygenase, Repressor Proteins, Signal Transduction