Dataset Information

Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases.

ABSTRACT: The JmjC oxygenases catalyze the N-demethylation of N(?)-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.

SUBMITTER: Rose NR

PROVIDER: S-EPMC4673902 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases.

Rose Nathan R NR Woon Esther C Y EC Tumber Anthony A Walport Louise J LJ Chowdhury Rasheduzzaman R Li Xuan Shirley XS King Oliver N F ON Lejeune Clarisse C Ng Stanley S SS Krojer Tobias T Chan Mun Chiang MC Rydzik Anna M AM Hopkinson Richard J RJ Che Ka Hing KH Daniel Michelle M Strain-Damerell Claire C Gileadi Carina C Kochan Grazyna G Leung Ivanhoe K H IK Dunford James J Yeoh Kar Kheng KK Ratcliffe Peter J PJ Burgess-Brown Nicola N von Delft Frank F Muller Susanne S Marsden Brian B Brennan Paul E PE McDonough Michael A MA Oppermann Udo U Klose Robert J RJ Schofield Christopher J CJ Kawamura Akane A

Journal of medicinal chemistry 20120711 14

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 ...[more]

PMID: 22724510

Similar Datasets

Project description:BACKGROUND:Epigenetic modifications, particularly DNA methylation and posttranslational histone modifications regulate heritable changes in transcription without changes in the DNA sequence. Despite a number of studies showing clear links between environmental factors and DNA methylation, little is known about the effect of environmental factors on the recently identified histone lysine methylation. Since their identification numerous studies have establish critical role played by these enzymes in mammalian development. OBJECTIVES:Identification of the Jumonji (Jmj) domain containing histone lysine demethylase have added a new dimension to epigenetic control of gene expression by dynamic regulation of histone methylation marks. The objective of our study was to evaluate the effect of prohexadione and trinexapac, widely used plant growth regulators of the acylcyclohexanediones class, on the enzymatic activity of histone lysine demethylases and histone modifications during the neural stem/progenitor cell differentiation. METHODS:Here we show that prohexadione, but not trinexapac, directly inhibits non-heme iron (II), 2-oxoglutarate-dependent histone lysine demethylase such as Jmjd2a. We used molecular modeling to show binding of prohexadione to Jmjd2a. We also performed in vitro demethylation assays to show the inhibitory effect of prohexadione on Jmjd2a. Further we tested this molecule in cell culture model of mouse hippocampal neural stem/progenitor cells to demonstrate its effect toward neuronal proliferation and differentiation. RESULTS:Molecular modeling studies suggest that prohexadione binds to the 2-oxoglutarate binding site of Jmjd2a demethylase. Treatment of primary neural stem/progenitor cells with prohexadione showed a concentration dependent reduction in their proliferation. Further, the prohexadione treated neurospheres were induced toward neurogenic lineage upon differentiation. CONCLUSIONS:Our results describe an important chemico-biological interaction of prohexadione, in light of critical roles played by histone lysine demethylases in human health and diseases.

Dataset Information

Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases.

Publications

Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets