Reversible histone deacetylase activity catalyzes lysine acylation

The dynamic modification of proteins by many metabolites suggests an intimate link between energy metabolism and post-translational modifications (PTMs). For instance, starvation and low-carbohydrate diets lead to the accumulation of β-hydroxybutyrate (BHB), whose blood concentrations can reach millimolar levels, concomitant with the accumulation of lysine β-hydroxybutyrylation (Kbhb) of proteins. Here we report that class I histone deacetylases (HDACs) unexpectedly catalyze the formation of Kbhb. Through mutational analysis, we show a shared reliance on key active site amino acids for classical deacetylation and noncanonical HDAC-catalyzed β-hydroxybutyrylation. On the basis of these data, we propose that HDACs catalyze a condensation reaction between the free amine group on lysine and the BHB carboxylic acid, thereby generating an amide bond. This reversible HDAC activity is not limited to BHB and extends to multiple short-chain fatty acids, representing a novel mechanism of PTM deposition relevant to metabolically sensitive proteome modifications.