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Sir2 family
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).
Identifiers
Symbol	SIR2
Pfam	PF02146
Pfam clan	CL0085
InterPro	IPR003000
PROSITE	PS50305
SCOP2	1j8f / SCOPe / SUPFAM
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary PDB 1ici​, 1j8f​, 1m2g​, 1m2h​, 1m2j​, 1m2k​, 1m2n​, 1ma3​, 1q14​, 1q17​, 1q1a​, 1s5p​, 1s7g​, 1szc​, 1szd​, 1yc2​, 1yc5​

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 Zn as a cofactor.

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 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).

Sirtuin family of proteins possess a highly conserved structure throughout all kingdoms of life.

Types

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.

Sirtuin list based on North/Verdin diagram.

Aging

Although preliminary studies with resveratrol, a possible SIRT1 activator, led some scientists to speculate that resveratrol may extend lifespan, there was no clinical evidence for such an effect, as of 2018.

A study performed on transgenic mice overexpressing SIRT6, showed an increased lifespan of about 15% in males. The transgenic males displayed lower serum levels of insulin-like growth factor 1 (IGF1) and changes in its metabolism, which may have contributed to the increased lifespan.

Tissue fibrosis

Along with aging, many organs in the body have the same molecular mechanisms. These organs include the heart, vascular wall, lungs, kidney, liver, and the skin. Pathways and molecules in tissue fibrosis are regulated by SIRTs. This is the result of a decline in SIRT levels, as well as restoration of SIRT. SIRT elevation protects against aging and tissue fibrosis, however, extreme levels of SIRT are destructive. This elevation is the outcome of the activation of SIRTs. Through regulation of fibrosis-mediating pathways, sirtuins apply antifibrotic effects. It becomes difficult to classify the mechanistic effects of sirtuins because they are diverse. SIRTs interact with specific pathways and intracellular signaling molecules. Some of these pathways and signaling molecules include adenosine monophosphate-activated protein kinase (AMPK)-angiotensin-converting enzyme 2 (ACE2) signaling, manganese superoxide dismutase (MnSOD), mammalian target of rapamycin, and more.

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.

These findings suggest that SIRT1, SIRT6 and SIRT7 facilitate DNA repair and that this repair slows the aging process (see DNA damage theory of aging).

Inhibitors

Sirtuin activity is inhibited by nicotinamide, which binds to a specific receptor site.

See also

• Biological immortality
• Histone deacetylases or HDACs
• Trichostatin A

References

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External links

• Sirtuins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Rice J (2008-11-26). "How Cells Age: Parallels between mice and yeast uncover a potentially universal aging mechanism". Technology Review. Massachusetts Institute of Technology. Retrieved 2008-12-20.

• Enzymes
• Aging-related enzymes
• Aging-related proteins