Finding the gas pedal on a slow sirtuin

Area of Science:

• Biochemistry
• Molecular Biology
• Epigenetics

Background:

• Sirtuin 6 (SIRT6) is a class III histone deacetylase.
• SIRT6 deacetylates histone lysine residues, regulating cellular functions.
• SIRT6 exhibits higher in vitro activity on fatty acylated substrates compared to acetylated ones.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying SIRT6 activation.
• To identify novel activators of SIRT6.
• To provide a foundation for developing therapeutic SIRT6 activators.

Main Methods:

• Utilized a novel activator for SIRT6.
• Performed thorough kinetic investigations.
• Conducted mutagenesis studies to understand activation requirements.

Main Results:

• Demonstrated that SIRT6 activity is significantly enhanced by long-chain fatty acyl modifications on lysine residues.
• Identified specific molecular requirements for SIRT6 activation through mutagenesis.
• Showcased the stimulatory effect of fatty acids and small-molecule modulators on SIRT6 deacetylase activity.

Conclusions:

• The study explains the puzzling activation of SIRT6, particularly its preference for fatty acylated substrates.
• Elucidated the molecular basis for SIRT6 activation.
• Provides a basis for the rational design of therapeutic activators targeting SIRT6.