Sirtuin

Sirtuin or Sir2 proteins are a class of proteins that possess either histone deacetylase or mono-ribosyltransferase activity. Sirtuins regulate important biological pathways in bacteria, archaea and eukaryotes. The name Sir2 comes from the yeast gene ' s ilent mating-type i nformation r egulation 2 ', the gene responsible for cellular regulation in yeast.

Sirtuins have been implicated in influencing aging and regulating transcription, apoptosis and stress resistance, as well as energy efficiency and alertness during low-calorie situations.

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, itself an inhibitor of sirtuin activity. 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.

Species distribution
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 the sirtuin-type protein. This research 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).

Types
Sirtuins are classed according to their sequence of amino acids. Prokaryotics are in class U. In yeast (a lower eukaryote), sirtuin was initially found and named sir2. In more complex mammals, there are seven known enzymes that act as on cellular regulation, as sir2 does in yeast. These genes are designated as belonging to different classes, depending on their amino acid sequence structure.

Sirtuin list based on North/Verdin diagram.

Clinical significance
Sirtuin activity is inhibited by nicotinamide, which binds to a specific receptor site, so it is thought that drugs that interfere with this binding should increase sirtuin activity. Development of new agents that would specifically block the nicotinamide-binding site could provide an avenue for development of newer agents to treat degenerative diseases such as cancer, Alzheimer's, diabetes, atherosclerosis, and gout. sitris

Alzheimer's
SIRT1 deacetylates and coactivates the retinoic acid receptor beta that upregulates the expression of alpha-secretase (ADAM10). Alpha-secretase in turn suppresses beta-amyloid production. Furthermore, ADAM10 activation by SIRT1 also induces the Notch signaling pathway, which is known to repair neuronal damage in the brain.

Diabetes
Sirtuins have been proposed as a chemotherapeutic target for type II diabetes mellitus.

Aging
Preliminary studies with resveratrol, a possible SIRT1 activator, have led some scientists to speculate that resveratrol may extend lifespan. However, this hypothesis has not yet been borne out in experiments with mammals.

Cell culture research into the behaviour of the human sirtuin SIRT1 shows that it behaves like the yeast sirtuin Sir2: SIRT2 assists in the repair of DNA and regulates genes that undergo altered expression with age. Adding resveratrol to the diet of mice inhibit gene expression profiles associated with muscle aging and age-related cardiac dysfunction.