Crystallographic structure of yeast sir2 (rainbow colored cartoon, N-terminus = blue, C-terminus = red) complexed with ADP (space-filling model, carbon = white, oxygen = red, nitrogen = blue, phosphorus = orange) and a histone H4 peptide (magenta) containing an acylated lysine residue (displayed as spheres).
|SCOPe||1j8f / SUPFAM|
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.
From in vitro studies, sirtuins are implicated in influencing cellular processes like aging, transcription, apoptosis, inflammation and stress resistance, as well as energy efficiency and alertness during low-calorie situations. As of 2018, there was no clinical evidence that sirtuins affect human aging.
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.
Actions and species distribution
Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. 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 was started in 1991 by Leonard Guarente of MIT. Mammals possess seven sirtuins (SIRT1–7) that occupy different subcellular compartments: SIRT1, SIRT6 and SIRT7 are predominantly in the nucleus, SIRT2 in the cytoplasm, and SIRT3, SIRT4 and SIRT5 in the mitochondria.
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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).
|I||a||Sir2 or Sir2p,
Hst1 or Hst1p
|Sirt1||SIRT1||Nucleus, cytoplasm||Deacetylase||Metabolism inflammation|
|b||Hst2 or Hst2p||Sirt2||SIRT2||Nucleus and cytoplasm||Deacetylase||Cell cycle, tumorigenesis|
|c||Hst3 or Hst3p,
Hst4 or Hst4p
|II||Sirt4||SIRT4||Mitochondria||ADP-ribosyl transferase||Insulin secretion|
|III||Sirt5||SIRT5||Mitochondria||Demalonylase, desuccinylase and deacetylase||Ammonia detoxification|
|IV||a||Sirt6||SIRT6||Nucleus||Demyristoylase, depalmitoylase, ADP-ribosyl transferase and deacetylase||DNA repair, metabolism, TNF secretion|
|U||cobB||Regulation of acetyl-CoA synthetase||metabolism|
|M||SirTM||ADP-ribosyl transferase||ROS detoxification|
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.
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.
In vitro studies shown that calorie restriction regulates the plasma membrane redox system, involved in mitochondrial homeostasis, and the reduction of inflammation through cross-talks between SIRT1 and AMP-activated protein kinase (AMPK), but the role of sirtuins in longevity is still unclear, as calorie restriction in yeast could extend lifespan in the absence of Sir2 or other sirtuins, while the in vivo activation of Sir2 by calorie restriction or resveratrol to extend lifespan has been challenged in multiple organisms.
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.
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.
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