Reversible histone deacetylase activity catalyzes lysine acylation

Area of Science:

• Biochemistry
• Molecular Biology
• Metabolomics

Background:

• Starvation and low-carbohydrate diets elevate blood β-hydroxybutyrate (BHB) levels.
• BHB accumulation induces lysine β-hydroxybutyrylation (Kbhb) of proteins, a post-translational modification (PTM).
• Histone deacetylases (HDACs) are known to remove lysine acylation marks.

Approach:

• Investigated the enzymatic activity of class I HDACs on protein lysine residues.
• Utilized mutational analyses of the HDAC2 active site to probe catalytic mechanisms.
• Examined the influence of substrate availability and mass action on Kbhb formation.

Key Points:

• Class I HDACs unexpectedly catalyze the addition of β-hydroxybutyrate (BHB) to lysine residues, forming Kbhb.
• HDAC2 active site residues are crucial for both deacetylation and non-canonical β-hydroxybutyrylation.
• Kbhb formation is a reversible PTM driven by mass action and substrate availability.
• This reverse HDAC activity extends to other short-chain fatty acids.

Conclusions:

• Class I HDACs possess a novel reverse catalytic activity, depositing BHB modifications onto proteins.
• This finding reveals a new mechanism for PTM deposition in response to metabolic states.
• The reversible nature of Kbhb is relevant to understanding metabolically-sensitive proteome modifications.