The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases.


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.

DOI: 10.1038/embor.2011.43

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@article{Chowdhury2011TheO2, title={The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases.}, author={Rasheduzzaman Chowdhury and Kar Kheng Yeoh and Ya-Min Tian and Lars Hillringhaus and Eleanor A Bagg and Nathan R Rose and Ivanhoe K H Leung and Xuan S Li and Esther C Y Woon and Ming Yang and Michael A McDonough and Oliver N King and Ian J Clifton and Robert J Klose and Timothy D W Claridge and Peter J Ratcliffe and Christopher J Schofield and Akane Kawamura}, journal={EMBO reports}, year={2011}, volume={12 5}, pages={463-9} }