HDAC8 Catalyzes the Hydrolysis of Long Chain Fatty Acyl Lysine

The histone deacetylase (HDAC) family regulates many biological pathways through the deacetylation of lysine residues on histone and nonhistone proteins. Mammals have 18 HDACs that are classified into four classes. Class I, II, and IV are zinc-dependent, while class III is nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylase or sirtuins. HDAC8, a class I HDAC family member, has been shown to have low deacetylation activity compared to other HDACs in vitro. Recent studies showed that several sirtuins, with low deacetylase activities, can actually hydrolyze other acyl lysine modifications more efficiently. Inspired by this, we tested the activity of HDAC8 using a variety of different acyl lysine peptides. Screening a panel of peptides with different acyl lysine modifications, we found that HDAC8 can catalyze the removal of acyl groups with 2–16 carbons from lysine 9 of the histone H3 peptide (H3K9). Interestingly, the catalytic efficiencies (kcat/Km) of HDAC8 on octanoyl, dodecanoyl, and my...