Sirtuins and Pyridine Nucleotides

The silencer information regulator (Sir) family of proteins has attracted much attention during the past decade due to its prominent role in metabolic homeostasis in mammals. The Sir1-4 proteins were first discovered in yeast as nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylases, which through a gene silencing effect promoted longevity. The subsequent discovery of a homologous sirtuin (Sirt) family of proteins in the mammalian systems soon led to the realization that these molecules have beneficial effects in metabolism-and aging-related diseases. Through their concerted functions in the central nervous system, liver, pancreas, skeletal muscle, and adipose tissue, they regulate the body's metabolism. Sirt1, -6, and -7 exert their functions, predominantly, through a direct effect on nuclear transcription of genes involved in metabolism, whereas Sirt3-5 reside in the mitochondrial matrix and regulate various enzymes involved in the tricarboxylic acid and urea cycles, oxidative phosphorylation, as well as reactive oxygen species production. An interesting aspect of the functionality of sirtuin involves their regulation by the circadian rhythm, which affects their function via cyclically regulating systemic NAD(+) availability, further establishing the link of these proteins to metabolism. In this review, we will discuss the relation of sirtuins to NAD(+) metabolism, their mechanism of function, and their role in metabolism and mitochondrial functions. In addition, we will describe their effects in the cardiovascular and central nervous systems. (Circ Res. 2012;111:642-656.)