Analysis of JmjC Demethylase-Catalyzed Demethylation Using Geometrically-Constrained Lysine Analogues

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• 作者：Gareth W. Langley ; Anne Brinkø ; Martin Münzel ; Louise J. Walport ; Christopher J. Schofield ; Richard J. Hopkinson
• 刊名：ACS Chemical Biology
• 出版年：2016
• 出版时间：March 18, 2016
• 年：2016
• 卷：11
• 期：3
• 页码：755-762
• 全文大小：430K
• ISSN：1554-8937

文摘

The dynamic post-translational modifications of histones play important roles in the regulation of transcription in animals. The demethylation of N^ε-methyl lysine residues in the N-terminal tail of histone H3 is catalyzed by demethylases, of which the largest family is the ferrous iron and 2-oxoglutarate dependent demethylases (JmjC KDMs), which catalyze demethylation via initial hydroxylation of the N-methyl groups. We report studies on the conformational requirements of the JmjC KDM substrates using N-methylated lysine analogues prepared by metathesis reactions of suitably protected N-allylglycine. The results support the proposed requirement for a positively charged N^ε-amino group in JmjC KDM catalysis. Demethylation of a trans-C-4/C-5 dehydrolysine substrate analogue was observed with representative KDM4 subfamily members KDM4A, KDM4B and KDM4E, and KDM7B, which are predicted, based on crystallographic analyses, to bind the N^ε-methylated lysine residue in different conformations during catalysis. This information may be useful in the design of JmjC KDM selective inhibitors.