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Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases |
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| Authors: | Rose Nathan R Woon Esther C Y Tumber Anthony Walport Louise J Chowdhury Rasheduzzaman Li Xuan Shirley King Oliver N F Lejeune Clarisse Ng Stanley S Krojer Tobias Chan Mun Chiang Rydzik Anna M Hopkinson Richard J Che Ka Hing Daniel Michelle Strain-Damerell Claire Gileadi Carina Kochan Grazyna Leung Ivanhoe K H Dunford James Yeoh Kar Kheng Ratcliffe Peter J Burgess-Brown Nicola von Delft Frank Muller Susanne Marsden Brian Brennan Paul E McDonough Michael A Oppermann Udo Klose Robert J Schofield Christopher J Kawamura Akane |
| Affiliation: | Epigenetic Regulation of Chromatin Function Group, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K. |
| Abstract: | The JmjC oxygenases catalyze the N-demethylation of N(ε)-methyl lysine residues in histones and are current therapeutic targets. A set of human 2-oxoglutarate analogues were screened using a unified assay platform for JmjC demethylases and related oxygenases. Results led to the finding that daminozide (N-(dimethylamino)succinamic acid, 160 Da), a plant growth regulator, selectively inhibits the KDM2/7 JmjC subfamily. Kinetic and crystallographic studies reveal that daminozide chelates the active site metal via its hydrazide carbonyl and dimethylamino groups. |
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