SIRTUINS

Sirtuins are enzymes which catalyze the NAD⁺-dependent deacylation of acyl-lysine residues, producing O-acyl-ADP-ribose and nicotinamide. Humans encode seven sirtuins (Sirt1-7) that are considered pro-survival proteins. Decreased sirtuin activity promotes inflammation and aging-related diseases. However, how sirtuin activity is inhibited during aging is largely unknown. We seek to define the physiological mechanisms regulating sirtuin activity and develop chemical tools and probes to monitor their activity.

It is known oxidative stress increases with age and inflammation. We have sought to define the effects of cellular oxidants on the regulation of sirtuin activity. We demonstrated that Sirt1 can be post-translationally modified by cystein S-nitrosation by the small molecule S-nitrosoglutathione (Kalous et al, 2016).  Sirt1 S-nitrosation correlated with Zn²⁺-release and loss of α-helical structure, suggesting the target of nitrosation is the Zn²⁺-tetrathiolate domain conserved among sirtuins. Sirt1 S-nitrosation was reversed upon exposure to thiol-based reducing-agents, resulting in restoration of Sirt1 activity. This restoration was dependent on the presence of Zn²⁺, consistent with Zn²⁺-tetrathiolate nitrosation as the source of Sirt1 inhibition. A follow up study broadened the scope to include other Sirtuin family members (including Sirt1, 2, 3, 5, and 6) to examine their susceptibility to S-nitrosation and other oxidative post-translational modifications (Kalous et al, 2020). Our review (Kalous et al, 2021) highlighted the state of the knowledge of the field regarding oxidative modifications of sirtuins.