Mechanisms and molecular probes of sirtuins

Abstract

Sirtuins are critical regulators of many cellular processes, including insulin secretion, the cell cycle, and apoptosis. Sirtuins are associated with a variety of age-associated diseases such as type II diabetes, obesity, and Alzheimer's disease. A thorough understanding of sirtuin chemical mechanisms will aid toward developing novel therapeutics that regulate metabolic disorders and combat associated diseases. In this review, we discuss the unique deacetylase mechanism of sirtuins and how this information might be employed to develop inhibitors and other molecular probes for therapeutic and basic research applications. We also cover physiological regulation of sirtuin activity and how these modes of regulation may be exploited to manipulate sirtuin activity in live cells. Development of molecular probes and drugs that specifically target sirtuins will further understanding of sirtuin biology and potentially afford new treatments of several human diseases.

Figure 1

The proposed mechanism of Sir2 protein deacetylases.

Figure 2

Known post-translational modifications, interacting proteins, and binding sites of the human Sir2 homologs Sirt1, Sirt2, and Sirt3.

Figure 3

An example application of the mechanism-based inhibition displayed by thioacetyl-lysine peptides. (A) Proposed inhibition mechanism of thioacetyl-lysine peptides. (B) Modular design of a sirtuin activity-based photolabeling probe. (C) Example experiment utilizing sirtuin activity-based photolabeling probe to identify disease specific sirtuin activities.