Sirtuin

Actions and species distribution

Sirtuins are a family of signaling proteins involved in metabolic regulation. 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.

History

Research on sirtuin protein was started in 1991 by Leonard Guarente of MIT. Interest in the metabolism of NAD heightened after the year 2000 discovery by Shin-ichiro Imai and coworkers in the Guarente laboratory that sirtuins are NAD+-dependent protein deacetylases .

Types

The first sirtuin was identified in yeast (a fungus) 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 α-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, no clinical evidence for such an effect has been discovered, 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 in laboratory studies

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 stimulator in cells.

Activators

References

References

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5. (April 2013). "SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine". Nature.
6. (July 2015). "Identification of a Class of Protein ADP-Ribosylating Sirtuins in Microbial Pathogens". Molecular Cell.
7. {{EntrezGene. 23410
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13. (2000). "Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase". Nature.
14. (May 2003). "Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle". Molecular and Cellular Biology.
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17. (March 2004). "Structure and substrate binding properties of cobB, a Sir2 homolog protein deacetylase from Escherichia coli". Journal of Molecular Biology.
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22. (March 2018). "Sirtuins and accelerated aging in scleroderma". Current Rheumatology Reports.
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28. (July 2016). "SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair". The EMBO Journal.
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33. (21 June 2017). "The Identification of a SIRT6 Activator from Brown Algae Fucus distichus". Marine Drugs.
34. (28 March 2016). "Curcumin elevates sirtuin level but does not postpone in vitro senescence of human cells building the vasculature". Oncotarget.
35. (March 2020). "Pirfenidone Is an Agonistic Ligand for PPARα and Improves NASH by Activation of SIRT1/LKB1/pAMPK". Hepatology Communications.
36. (31 May 2018). "Rôle de la sirtuine 1 dans la modulation des réponses apoptotique et autophagique du coeur au stress du réticulum endoplasmique". Université Paris Saclay (COmUE).