Lysine residues across the proteome are modified by posttranslational 
modifications (PTMs) that significantly enhance the structural and functional 
diversity of proteins. For lysine, the most abundant PTM is ɛ-N-acetyllysine 
(Kac), which plays numerous roles in regulation of important cellular functions, 
such as gene expression (epigenetic effects) and metabolism. A family of 
enzymes, namely histone deacetylases (HDACs), removes these PTMs. A subset of 
these enzymes, the sirtuins (SIRTs), represent class III HDAC and, unlike the 
rest of the family, these hydrolases are NAD+-dependent. Although initially 
described as deacetylases, alternative deacylase functions for sirtuins have 
been reported, which expands the potential cellular roles of this class of 
enzymes. Currently, sirtuins are investigated as therapeutic targets for the 
treatment of diseases that span from cancers to neurodegenerative disorders. In 
the present book chapter, we review and discuss the current literature on novel 
ɛ-N-acyllysine PTMs, targeted by sirtuins, as well as mechanism-based sirtuin 
inhibitors inspired by their substrates.