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). SIRT3, a mitochondrial protein deacetylase, plays a role in the regulation of multiple metabolic proteins like isocitrate dehydrogenase of the TCA cycle. It also plays a role in skeletal muscle as a metabolic adaptive response. Since glutamine is a source of a-ketoglutarate used to replenish the TCA cycle, SIRT4 is involved in glutamine metabolism. Ageing Although preliminary studies with resveratrol, an activator of deacetylases such as SIRT1, led some scientists to speculate that resveratrol may extend lifespan, there was no clinical evidence for such an effect, as of 2018. Tissue fibrosis A 2018 review indicated that SIRT levels are lower in tissues from people with scleroderma, and such reduced SIRT levels may increase risk of fibrosis through modulation of the TGF-β signaling pathway. DNA repair SIRT1, SIRT6 and SIRT7 proteins are employed in DNA repair. SIRT1 protein promotes homologous recombination in human cells and is involved in recombinational repair of DNA breaks. SIRT6 is a chromatin-associated protein and in mammalian cells is required for base excision repair of DNA damage. SIRT6 deficiency in mice leads to a degenerative aging-like phenotype. In addition, SIRT6 promotes the repair of DNA double-strand breaks. Furthermore, over-expression of SIRT6 can stimulate homologous recombinational repair. SIRT7 knockout mice display features of premature aging. SIRT7 protein is required for repair of double-strand breaks by non-homologous end joining. Inhibitors Certain sirtuin activity is inhibited by nicotinamide, which binds to a specific receptor site. It is an inhibitor in vitro of SIRT1, but can be a stiumlator in cells. Activators See also Biological immortality Histone deacetylases or HDACs Trichostatin A References External links Enzymes Aging-related enzymes Aging-related proteins