Silent information regulator 2 (Sir2) enzymes or sirtuins are a family of evolutionarily conserved intracellular
protein deacetylases that can catalyze the acetyl group removal from the specific Nε-acetyl-lysine (AcK) side chains on a
variety of proteins from all kingdoms of life. Yeast Sir2 was the first sirtuin identified, and so far seven sirtuins (i.e.
SIRT1-7) have been found in mammals including humans. The sirtuin-catalyzed deacetylation reaction has captured
tremendous interest during the past a few years because of (i) its increasingly demonstrated importance in many crucial
biological processes such as gene transcription, metabolism, and aging, and thus its therapeutic potential for metabolic and
age-related diseases and cancer, and (ii) its unique deacetylation chemistry. Specifically, the sirtuin-catalyzed AcK side
chain deacetylation is not merely an amide hydrolysis reaction, instead is coupled to the nicotinamide cleavage from β-
nicotinamide adenine dinucleotide (β-NAD+ or NAD+) with the generation of three enzymatic products, i.e. the
deacetylated protein species, nicotinamide, and 2’-O-acetyl-ADP-ribose (2’-O-AADPR). Here the author would like to
review the past endeavors on developing mechanism-based sirtuin modulators (inhibitors and activators). The first part of
this article will provide an updated mechanistic picture of the sirtuin-catalyzed deacetylation reaction. The second part
will be focused on how the mechanistic knowledge has been exploited for the design of effective sirtuin modulators.