Sirtuin


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. Chemically, 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.
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.
Sirtuins that deacetylate histones are structurally and mechanistically distinct from other classes of histone deacetylases, 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. Mammals possess seven sirtuins 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 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, 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.
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

CompoundTarget/SpecificityReferences
PiceatannolSIRT1
SRT-1720SIRT1
SRT-2104SIRT1
Beta-LapachoneSIRT1
CilostazolSIRT1
Quercetin and rutin derivativesSIRT6
LuteolinSIRT6
FisetinSIRT6
Phenolic acidSIRT6
FucoidanSIRT6
CurcuminSIRT1, SIRT6
PirfenidoneSIRT1
MyricetinSIRT6
CyanidinSIRT6
DelphinidinSIRT6
ApigeninSIRT6
ButeinSIRT6
IsoliquiritigeninSIRT6
Ferulic acidSIRT1
BerberineSIRT1
CatechinSIRT1
MalvidinSIRT1
PterostilbeneSIRT1
TyrosolSIRT1