Chapter 5 - Structural and Mechanistic Insights in Sirtuin Catalysis and Pharmacological Modulation

Abstract

Sirtuins are evolutionary conserved, NAD+-dependent protein lysine deacylases regulating functions such as energy metabolism and stress responses. They have been implicated in aging processes and the seven human isoforms, Sirt1–7, are considered therapeutic targets, e.g., for cancer and neurodegenerative disorders. Despite the shared catalytic core architecture of Sirt1–7, the development of small-molecule inhibitors and activators for them is at very different stages. We give here an overview of sirtuin modulation and discuss examples in more detail. Extensive efforts to develop sirtuin inhibitors have yielded many compounds with limited potency and/or selectivity, but also a few very promising substances. Most medical applications, however, demand for sirtuin activators. For Sirt1, activation is well established and a variety of small-molecule activators are available. For other isoforms, in particular Sirt6, the first activators are emerging. The increasingly available structural and mechanistic insights for sirtuin modulators promise to facilitate future drug development efforts.