Sirtuin

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Sir2 family
1SZD.png
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
SCOP1j8f
SUPERFAMILY1j8f

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][5][6] The name Sir2 comes from the yeast gene 'silent mating-type information regulation 2',[7] 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[8] and stress resistance, as well as energy efficiency and alertness during low-calorie situations.[9] 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.

Species distribution[edit]

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).[10] Research on sirtuin protein started in 1991 by Leonard Guarente of MIT.[11][12] 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).

Types[edit]

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.[13][14] 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.[13] 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).[6] Most notable, the latter have an altered catalytic residue, which make them exclusive ADP-ribosyl transferases.

Class Subclass Species Intracellular
location
Activity Function
Bacteria Yeast Mouse Human
I a Sir2 or Sir2p,
Hst1 or Hst1p
Sirt1 SIRT1 nucleus, cytoplasm deacetylase metabolism
inflammation
b Hst2 or Hst2p Sirt2 SIRT2 cytoplasm deacetylase cell cycle,
tumorigenesis
Sirt3 SIRT3 nucleus and
mitochondria
deacetylase metabolism
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
b Sirt7 SIRT7 nucleolus deacetylase rRNA
transcription
U cobB[15] regulation of
acetyl-CoA synthetase[16]
metabolism
M SirTM[6] ADP-ribosyl transferase ROS detoxification

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.[17]

Since glutamine is a source of a-ketoglutarate used to replenish the TCA cycle, SIRT4 is important for its role in glutamine metabolism.[17]

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.[17]

Sirtuin list based on North/Verdin diagram.[2]

Clinical significance[edit]

Sirtuin activity is inhibited by nicotinamide, which binds to a specific receptor site,[18] so it is thought that drugs that interfere with this binding should increase sirtuin activity. Development of new agents that would specifically block the nicotinamide-binding site could provide an avenue for development of newer agents to treat degenerative diseases such as cancer, diabetes, atherosclerosis, and gout.[19][20]

Diabetes[edit]

Sirtuins have been proposed as a therapeutic target for type II diabetes mellitus.[21]

Aging[edit]

Preliminary studies with resveratrol, a possible SIRT1 activator, have led some scientists to speculate that resveratrol may extend lifespan.[22] Research has shown that resveratrol can reproduce the effects of exercise and caloric restriction such as lowered blood pressure, sugar levels, and metabolic rate.[23] These findings aid scientists to come to the reasoning that it can slow down the metabolism and increase lifespan. Further experiments conducted by Rafael de Cabo et al. showed that resveratrol-mimicking drugs such as SRT1720 could extend the lifespan of obese mice by 44%.[24] Comparable molecules are now undergoing clinical trials in humans.

Cell culture research into the behaviour of the human sirtuin SIRT1 shows that it behaves like the yeast sirtuin Sir2: SIRT2 assists in the repair of DNA and regulates genes that undergo altered expression with age.[25] Adding resveratrol to the diet of mice inhibit gene expression profiles associated with muscle aging and age-related cardiac dysfunction.[26]

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.[27]

Tissue Fibrosis[edit]

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.[28]

DNA repair[edit]

SIRT1, SIRT6 and SIRT7 proteins are employed in DNA repair.[29] SIRT1 protein promotes homologous recombination in human cells and is involved in recombinational repair of DNA breaks.[30]

SIRT6 is a chromatin-associated protein and in mammalian cells is required for base excision repair of DNA damage.[31] SIRT6 deficiency in mice leads to a degenerative aging-like phenotype.[31] In addition, SIRT6 promotes the repair of DNA double-strand breaks.[32] Furthermore, over-expression of SIRT6 can stimulate homologous recombinational repair.[33]

SIRT7 knockout mice display features of premature aging.[34] SIRT7 protein is required for repair of double-strand breaks by non-homologous end joining.[34]

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).

See also[edit]

References[edit]

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External links[edit]