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Inhibitors of both the N-methyl lysyl- and arginyl-demethylase activities of the JmjC oxygenases.

ABSTRACT: The Jumonji C (JmjC) family of 2-oxoglutarate (2OG)-dependent oxygenases have established roles in the regulation of transcription via the catalysis of demethylation of N?-methylated lysine residues in histone tails, especially the N-terminal tail of histone H3. Most human JmjC N? -methyl lysine demethylases (KDMs) are complex enzymes, with 'reader domains' in addition to their catalytic domains. Recent biochemical evidence has shown that some, but not all, JmjC KDMs also have N?-methyl arginyl demethylase (RDM) activity. JmjC KDM activity has been linked to multiple cancers and some JmjC proteins are therapeutic targets. It is, therefore, important to test not only whether compounds in development inhibit the KDM activity of targeted JmjC demethylases, but also whether they inhibit other activities of these proteins. Here we report biochemical studies on the potential dual inhibition of JmjC KDM and RDM activities using a model JmjC demethylase, KDM4E (JMJD2E). The results reveal that all of the tested compounds inhibit both the KDM and RDM activities, raising questions about the in vivo effects of the inhibitors.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.

SUBMITTER: Bonnici J

PROVIDER: S-EPMC5915715 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Inhibitors of both the N-methyl lysyl- and arginyl-demethylase activities of the JmjC oxygenases.

Bonnici Joanna J Tumber Anthony A Kawamura Akane A Schofield Christopher J CJ

Philosophical transactions of the Royal Society of London. Series B, Biological sciences 20180601 1748

The Jumonji C (JmjC) family of 2-oxoglutarate (2OG)-dependent oxygenases have established roles in the regulation of transcription via the catalysis of demethylation of Nε-methylated lysine residues in histone tails, especially the N-terminal tail of histone H3. Most human JmjC Nɛ -methyl lysine demethylases (KDMs) are complex enzymes, with 'reader domains' in addition to their catalytic domains. Recent biochemical evidence has shown that some, but n ...[more]

PMID: 29685975

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Project description:The N ε-methyl lysine status of histones is important in the regulation of eukaryotic transcription. The Fe(ii) and 2-oxoglutarate (2OG) -dependent JmjC domain enzymes are the largest family of histone N ε-methyl lysine demethylases (KDMs). The human KDM4 subfamily of JmjC KDMs is linked with multiple cancers and some of its members are medicinal chemistry targets. We describe the use of combined molecular dynamics (MD) and Quantum Mechanical/Molecular Mechanical (QM/MM) methods to study the mechanism of KDM4A, which catalyzes demethylation of both tri- and di-methylated forms of histone H3 at K9 and K36. The results show that the oxygen activation at the active site of KDM4A is optimized towards the generation of the reactive Fe(iv)-oxo intermediate. Factors including the substrate binding mode, correlated motions of the protein and histone substrates, and molecular orbital control synergistically contribute to the reactivity of the Fe(iv)-oxo intermediate. In silico substitutions were performed to investigate the roles of residues (Lys241, Tyr177, and Asn290) in substrate orientation. The Lys241Ala substitution abolishes activity due to altered substrate orientation consistent with reported experimental studies. Calculations with a macrocyclic peptide substrate analogue reveal that induced conformational changes/correlated motions in KDM4A are sequence-specific in a manner that influences substrate binding affinity. Second sphere residues, such as Ser288 and Thr289, may contribute to KDM4A catalysis by correlated motions with active site residues. Residues that stabilize key intermediates, and which are predicted to be involved in correlated motions with other residues in the second sphere and beyond, are shown to be different in KDM4A compared to those in another JmjC KDM (PHF8), which acts on H3K9 di- and mono-methylated forms, suggesting that allosteric type inhibition is of interest from the perspective of developing selective JmjC KDM inhibitors.

Project description:BackgroundHistone methylation occurs primarily on lysine residues and requires a set of enzymes capable of reading, writing, and erasing to control its establishment and deletion, which is essential for maintaining chromatin structure and gene expression. Histone methylation and demethylation are contributed to plant growth and development, and are involved in adapting to environmental stresses. The JmjC domain-containing proteins are extensively studied for their function in histone lysine demethylation in plants, and play a critical role in sustaining histone methylation homeostasis.ResultsIn this study, a total of 21 JmjC domain-containing histone demethylase proteins (JHDMs) in birch were identified and classified into five subfamilies based on structural characteristics and phylogenetic relationships among Arabidopsis, rice, maize, and birch. Although the BpJMJ genes displayed significant schematic variation, their distribution on the chromosomes is relatively uniform. Additionally, the BpJMJ genes in birch have never experienced a tandem-duplication event proved by WGD analysis and were remaining underwent purifying selection (Ka/Ks < < 1). A typical JmjC domain was found in all BpJMJ genes, some of which have other essential domains for their functions. In the promoter regions of BpJMJ genes, cis-acting elements associated with hormone and abiotic stress responses were overrepresented. Under abiotic stresses, the transcriptome profile reveals two contrasting expression patterns within 21 BpJMJ genes. Furthermore, it was established that most BpJMJ genes had higher expression in young tissues under normal conditions, with BpJMJ06/16 having the highest expression in germinating seeds and participating in the regulation of BpGA3ox1/2 gene expression. Eventually, BpJMJ genes were found to directly interact with genes involved in the "intracellular membrane" in respond to cold stress.ConclusionsThe present study will provide a foundation for future experiments on histone demethylases in birch and a theoretical basis for epigenetic research on growth and development in response to abiotic stresses.

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Inhibitors of both the N-methyl lysyl- and arginyl-demethylase activities of the JmjC oxygenases.

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Inhibitors of both the <i>N</i>-methyl lysyl- and arginyl-demethylase activities of the JmjC oxygenases.

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