Sirtuin mechanism and inhibition: explored with N(ε)-acetyl-lysine analogs.
Silent information regulator 2 (Sir2) enzymes or sirtuins are a family of intracellular protein deacetylases that can catalyze the β-nicotinamide adenine dinucleotide (β-NAD(+))-dependent deacetylation of N(ε)-acetyl-lysine on protein substrates, with the formation of lysine N(ε)-deacetylated protein species and small molecule products, i.e. nicotinamide and 2'-O-acetyl-ADP-ribose (2'-O-AADPR). These enzymes are evolutionarily conserved among all the three kingdoms of life, with the yeast Sir2 being the founding family member. In humans, seven sirtuins, i.e. SIRT1-7, have been identified. The past a few years have witnessed a tremendous interest in investigating the unique mechanism for the sirtuin-catalyzed deacetylation reaction. We have also seen a lot of research employing different strategies to identify different types of the inhibitors for this enzymatic deacetylation reaction. These inhibitors hold great potential toward a fuller exploration of sirtuin biology and pharmacology as well as toward developing novel therapeutics for metabolic and age-related diseases and cancer. Here we would like to review the significant contributions that the judicious use of a variety of N(ε)-acetyl-lysine analogs has been able to make toward our enhanced mechanistic understanding and capability of pharmacological exploitation of the sirtuin-catalyzed deacetylation reaction.
Hirsch
Brett M
BM
Department of Chemistry, University of Akron, 190 E. Buchtel Commons, Akron, OH 44325, USA.
Zheng
Weiping
W
D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D037761:Sirtuins / Q000737:chemistry / Q000378:metabolism*
D037761:Sirtuins; D008239:Lysine