Silent information regulator 2 (Sir2) enzymes or sirtuins are a family of intracellular protein deacetylases that can catalyze the beta-nicotinamide adenine dinucleotide (beta-NAD+)-dependent deacetylation of N(epsilon)-acetyl-lysine on protein substrates. 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, SIRT1-7, have been identified. Protein acetylation/deacetylation plays a critical role in biological processes such as metabolism, gene transcription, neurodegeneration, apoptosis, the cell-cycle, aging, cell fate, and cytoskeletal organization. The past few years have witnessed a tremendous interest in investigating the unique mechanism for the sirtuin-catalyzed deacetylation reaction. There has also been a great deal of effort invested in the employment of different strategies to identify different types of 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 as well as cancer.
This study discovered i) two potent, cell-permeable, and
proteolytically stable small molecule human sirtuin inhibitors that harbor the previously identified sirtuin inhibitory acetyl-lysine analog, thioacetyl-lysine; and ii) a novel sirtuin inhibitory warhead, L-2-amino-7-carboxamidoheptanoic acid, that may
function both to elucidate the sirtuin mechanism and in the development of new sirtuin inhibition therapies.