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

Journal article

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.

Authors: Langley, G; Brinkø, A; Münzel, M; Walport, L; Schofield, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: ACS Chemical Biology
• Volume: 11
• Issue: 3
• Pages: 755-762
• Publication date: 2015-11-25
• Acceptance date: 2015-11-11
• DOI: 10.1021/acschembio.5b00738
• EISSN: 1554-8937
• ISSN: 1554-8929
• Pmid: 26555343
• Language: English
• Keywords: Jumonji Domain-Containing Histone Demethylases; Catalysis; Substrate Specificity; SBTMR; Research Support, Non-U.S. Gov't; Lysine; Methylation; Binding Sites; Journal Article