Lysine Ethylation by Histone Lysine Methyltransferases

Abbas H K Al Temimi, Michael Martin, Qingxi Meng, Danny C Lenstra, Ping Qian, Hong Guo*, Elmar Weinhold, Jasmin Mecinovic

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Biomedicinally important histone lysine methyltransferases (KMTs) catalyze the transfer of a methyl group from S-adenosylmethionine (AdoMet) cosubstrate to lysine residues in histones and other proteins. Herein, experimental and computational investigations on human KMT-catalyzed ethylation of histone peptides by using S-adenosylethionine (AdoEth) and Se-adenosylselenoethionine (AdoSeEth) cosubstrates are reported. MALDI-TOF MS experiments reveal that, unlike monomethyltransferases SETD7 and SETD8, methyltransferases G9a and G9a-like protein (GLP) do have the capacity to ethylate lysine residues in histone peptides, and that cosubstrates follow the efficiency trend AdoMet>AdoSeEth>AdoEth. G9a and GLP can also catalyze AdoSeEth-mediated ethylation of ornithine and produce histone peptides bearing lysine residues with different alkyl groups, such as H3K9meet and H3K9me2et. Molecular dynamics and free energy simulations based on quantum mechanics/molecular mechanics potential supported the experimental findings by providing an insight into the geometry and energetics of the enzymatic methyl/ethyl transfer process.

Original languageEnglish
Issue number3
Pages (from-to)392-400
Number of pages9
Publication statusPublished - 3. Feb 2020


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