HDACs Discovered to Create New Protein Modifications Beyond Removing Acetyl Groups

This groundbreaking study reveals that histone deacetylases (HDACs) have a dual function beyond their well-known role in gene regulation. While HDACs are famous for removing acetyl groups from histones, researchers discovered they can also catalyze the addition of β-hydroxybutyrate modifications to proteins.

The research team investigated how β-hydroxybutyrate, a ketone body that accumulates during fasting and low-carb diets, gets attached to proteins. They found that class I HDACs unexpectedly catalyze this process, creating lysine β-hydroxybutyrylation modifications through a condensation reaction between lysine amino groups and β-hydroxybutyrate's carboxylic acid.

Mutational analysis revealed that the same active site amino acids required for traditional deacetylation are also essential for this newly discovered acylation activity. This suggests HDACs evolved as versatile enzymes capable of both adding and removing protein modifications based on metabolic conditions.

The implications extend beyond β-hydroxybutyrate, as researchers demonstrated this mechanism works with multiple short-chain fatty acids. This creates a direct link between cellular metabolism and protein function, potentially explaining how dietary changes influence gene expression and cellular behavior at the molecular level.

This discovery opens new avenues for understanding how metabolic states like ketosis affect cellular function and may inform therapeutic approaches targeting HDAC activity.