A chemical catalyst enabling histone acylation with endogenous Acyl-CoA

Post-translational modifications (PTMs) of proteins, e.g., epigenetic acetylation of lysine residues in histones, are crucial to cellular functions and related to diseases. Chemical tools to directly introducing epigenetic lysine acetylation hold promise for elucidating the PTM’s functions and treating diseases. Although several chemical catalysts introducing protein acetylation in live cells were reported, there is no precedent promoting in-cell acetylation of epigenetically important but often low-reactive histone proteins using endogenous acetyl-CoA, as histone acetyltransferases (HATs) do. Herein, we developed a chemical catalyst mBnA enabling selective in-cell histone lysine acylation (H2BK120ac) using endogenous acyl-CoA as a sole acyl donor. A hydroxamic acid of proper electronic characteristics as a nucleophilic catalytic site combined with a thiol-thioester exchange process enabled mBnA to activate low concentration of acyl-CoAs in cells, promoting histone lysine acylations (acetylation and malonylation). This chemical catalyst will be a small-molecule surrogate to HAT and thus a unique tool to synthetic epigenetics.