Sirtuin

Sirtuins are a class of proteins that possess either mono-ADP-ribosyltransferase, or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity.[2][3][4] The name Sir2 comes from the yeast gene 'silent mating-type information regulation 2',[5] the gene responsible for cellular regulation in yeast.

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).[1]
Identifiers
SymbolSIR2
PfamPF02146
Pfam clanCL0085
InterProIPR003000
PROSITEPS50305
SCOP21j8f / SCOPe / SUPFAM

From in vitro studies, sirtuins are implicated in influencing cellular processes like aging, transcription, apoptosis, inflammation[6] and stress resistance, as well as energy efficiency and alertness during low-calorie situations.[7] As of 2018, there was no clinical evidence that sirtuins affect human aging.[8]

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.[9] This hydrolysis yields O-acetyl-ADP-ribose, the deacetylated substrate and nicotinamide, which is an inhibitor of sirtuin activity itself. These proteins utilize NAD+ to maintain cellular health and turn NAD+ to nicotinamide (NAM).[10] 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 NAM 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.[11][12]

Actions and species distribution

Sirtuins are a family of signaling proteins involved in metabolic regulation.[13][14] They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life.[13] 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).[15] 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.[13]

History

Research on sirtuin protein was started in 1991 by Leonard Guarente of MIT.[16][17] 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 .[18]

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.[19] 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).[4]

Class Subclass Species Intracellular
location		 Activity Function
BacteriaYeastMouseHuman
IaSir2 or Sir2p,
Hst1 or Hst1p		Sirt1SIRT1Nucleus, cytoplasmDeacetylaseMetabolism inflammation
bHst2 or Hst2pSirt2SIRT2Nucleus and cytoplasmDeacetylaseCell cycle, tumorigenesis
Sirt3SIRT3MitochondriaDeacetylaseMetabolism
cHst3 or Hst3p,
Hst4 or Hst4p
IISirt4SIRT4MitochondriaADP-ribosyl transferaseInsulin secretion
IIISirt5SIRT5MitochondriaDemalonylase, desuccinylase and deacetylaseAmmonia detoxification
IVaSirt6SIRT6NucleusDemyristoylase, depalmitoylase, ADP-ribosyl transferase and deacetylaseDNA repair, metabolism, TNF secretion
bSirt7SIRT7NucleolusDeacetylaserRNA transcription
UcobB[20] Regulation of acetyl-CoA synthetase[21]metabolism
M SirTM[4] 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.[22]

Aging

Although preliminary studies with resveratrol, an activator of deacetylases such as SIRT1,[23] led some scientists to speculate that resveratrol may extend lifespan, there was no clinical evidence for such an effect, as of 2018.[8] Although resveratrol has been shown to extend the lifespan of mice made obese with a high-fat diet, resveratrol has not been shown to extend the lifespan of normal mice fed resveratrol from four months of age.[24]

Whether or not sirtuin activators can extend lifespan, genetically modified mice with enhanced sirtuin gene expression have shown extended lifespan.[25] Moreover, supplementation with a molecule called nicotinamide mononucleotide (NMN) that increases NAD+ levels in aged rodents has been touted as a sirtuin activator with anti-aging properties.[26]

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),[27][28][29] but the role of sirtuins in longevity is still unclear,[23][27][29] 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.[30]

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.[31]

DNA repair

SIRT1, SIRT6 and SIRT7 proteins are employed in DNA repair.[32] SIRT1 protein promotes homologous recombination in human cells and is involved in recombinational repair of DNA breaks.[33]

SIRT6 is a chromatin-associated protein and in mammalian cells is required for base excision repair of DNA damage.[34] SIRT6 deficiency in mice leads to a degenerative aging-like phenotype.[34] In addition, SIRT6 promotes the repair of DNA double-strand breaks.[35] Furthermore, over-expression of SIRT6 can stimulate homologous recombinational repair.[36]

SIRT7 knockout mice display features of premature aging.[37] SIRT7 protein is required for repair of double-strand breaks by non-homologous end joining.[37]

Inhibitors

Sirtuin activity is inhibited by nicotinamide, which binds to a specific receptor site.[38]

See also

References
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