Examining sterically demanding lysine analogs for histone lysine methyltransferase catalysis

Abbas H K Al Temimi, Vu Tran, Ruben S Teeuwen, Arthur J Altunc, Helene I V Amatdjais-Groenen, Paul B White, Danny C Lenstra, Giordano Proietti, Yali Wang, Anita Wegert, Richard H Blaauw, Ping Qian, Wansheng Ren, Hong Guo, Jasmin Mecinović*

*Corresponding author for this work

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Methylation of lysine residues in histone proteins is catalyzed by S-adenosylmethionine (SAM)-dependent histone lysine methyltransferases (KMTs), a genuinely important class of epigenetic enzymes of biomedical interest. Here we report synthetic, mass spectrometric, NMR spectroscopic and quantum mechanical/molecular mechanical (QM/MM) molecular dynamics studies on KMT-catalyzed methylation of histone peptides that contain lysine and its sterically demanding analogs. Our synergistic experimental and computational work demonstrates that human KMTs have a capacity to catalyze methylation of slightly bulkier lysine analogs, but lack the activity for analogs that possess larger aromatic side chains. Overall, this study provides an important chemical insight into molecular requirements that contribute to efficient KMT catalysis and expands the substrate scope of KMT-catalyzed methylation reactions.

Original languageEnglish
Article number3671
JournalScientific Reports
Number of pages11
Publication statusPublished - 2020


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