Ricerc@Sapienza

The mammalian sirtuins (SIRTs) are evolutionally highly conserved proteins
and belong to class III histone deacetylases (HDACs). Its seven family members
(SIRT1–7) share a NAD+-dependent catalytic protein lysine deacetylase and/or
mono-ADP-ribosylase mechanism and are involved in various biological
processes acting on diverse substrates. SIRTs vary in length and sequence at
their N- and C-termini. This might explain in part their diverse functions and
localizations. To date, their protein lysine deacetylation is the most studied
function; however recent studies revealed that several SIRTs also are able to
cleave other types of acyl groups, e.g. succinyl, malonyl, glutaryl, and long-chain
fatty acyl residues .
In recent years, there is a growing body of literature highlighting the association
of SIRTs with various pathologies: SIRT inhibition might be beneficial in cancer
treatment, viral infections, muscular diseases, and neurodegenerative disorders,
whereas SIRT activationmay have a positive impact onmetabolic and age-related
disorders.Thus, the discovery of SIRT modulators via screening of chemical
libraries and catalytic mechanism-based design approaches, often in combination
with structure–activity relationship (SAR) investigations, is nowadays a field
of active research. In this book chapter, wewould like to illustrate themost important
SIRT functions and SIRT modulators discovered so far.