| Literature DB >> 21460794 |
Rasheduzzaman Chowdhury1, Kar Kheng Yeoh, Ya-Min Tian, Lars Hillringhaus, Eleanor A Bagg, Nathan R Rose, Ivanhoe K H Leung, Xuan S Li, Esther C Y Woon, Ming Yang, Michael A McDonough, Oliver N King, Ian J Clifton, Robert J Klose, Timothy D W Claridge, Peter J Ratcliffe, Christopher J Schofield, Akane Kawamura.
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.Entities:
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Year: 2011 PMID： 21460794 PMCID： PMC3090014 DOI： 10.1038/embor.2011.43
Source DB: PubMed Journal: EMBO Rep ISSN： 1469-221X Impact factor: 8.807