Sirtuin

Sirtuins are a class of proteins that possess either mono-ADP-ribosyltransferase, or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity. The name Sir2 comes from the yeast gene 'silent mating-type information regulation 2', the gene responsible for cellular regulation in yeast. Sirtuins are a class of proteins that possess either mono-ADP-ribosyltransferase, or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity. The name Sir2 comes from the yeast gene 'silent mating-type information regulation 2', the gene responsible for cellular regulation in yeast. Sirtuins have been implicated in influencing a wide range of cellular processes like aging, transcription, apoptosis, inflammation and stress resistance, as well as energy efficiency and alertness during low-calorie situations. Sirtuins can also control circadian clocks and mitochondrial biogenesis. Yeast Sir2 and some, but not all, sirtuins are protein deacetylases. Unlike other known protein deacetylases, which simply hydrolyze acetyl-lysine residues, the sirtuin-mediated deacetylation reaction couples lysine deacetylation to NAD hydrolysis. This hydrolysis yields O-acetyl-ADP-ribose, the deacetylated substrate and nicotinamide, which is an inhibitor of sirtuin activity itself. The dependence of sirtuins on NAD links their enzymatic activity directly to the energy status of the cell via the cellular NAD:NADH ratio, the absolute levels of NAD, NADH or nicotinamide or a combination of these variables. Sirtuins that deacetylate histones are structurally and mechanistically distinct from other classes of histone deacetylases (classes I, IIA, IIB and IV), which have a different protein fold and use Zn2+ as a cofactor. Whereas bacteria and archaea encode either one or two sirtuins, eukaryotes encode several sirtuins in their genomes. In yeast, roundworms, and fruitflies, sir2 is the name of one of the sirtuin-type proteins (see table below). Research on sirtuin protein started in 1991 by Leonard Guarente of MIT. Mammals possess seven sirtuins (SIRT1–7) that occupy different subcellular compartments such as the nucleus (SIRT1, -2, -6, -7), cytoplasm (SIRT1 and SIRT2) and the mitochondria (SIRT3, -4 and -5). The first sirtuin was identified in yeast (a lower eukaryote) and named sir2. In more complex mammals, there are seven known enzymes that act in cellular regulation, as sir2 does in yeast. These genes are designated as belonging to different classes (I-IV), depending on their amino acid sequence structure. Several Gram positive prokaryotes as well as the Gram negative hyperthermophilic bacterium Thermotoga maritima possess sirtuins that are intermediate in sequence between classes and these are placed in the 'undifferentiated' or 'U' class. In addition, several Gram positive bacteria, including Staphylococcus aureus and Streptococcus pyogenes, as well as several fungi carry macrodomain-linked sirtuins (termed 'class M' sirtuins). Most notable, the latter have an altered catalytic residue, which make them exclusive ADP-ribosyl transferases. SIRT3, a mitochondrial protein deacetylase, plays a major role in the regulation of multiple metabolic proteins like isocitrate dehydrogenase of the TCA cycle. It also plays a major role in skeletal muscle as a metabolic adaptive response. Recent studies have shown that decreased levels of SIRT3 result in oxidative stress, as well as an increase in insulin resistance. Since glutamine is a source of a-ketoglutarate used to replenish the TCA cycle, SIRT4 is important for its role in glutamine metabolism. SIRT6 is shown in previous studies to be a critical epigenetic regulator of glucose metabolism. In a study, mice knockout with SIRT6 showed a fatal hypoglycemic phenotype. This resulted in death in a few weeks after birth and showed that hypoglycemia resulted mainly from increase of glucose uptake in brown adipose tissue and muscle.