Sirtuin or Sir2 proteins are a class of protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s that possess either histone deacetylase

Histone deacetylase

Histone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...

 or mono-ribosyltransferase

ADP-ribosylation

ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. These reactions are involved in cell signaling and the control of many cell processes, including DNA repair and apoptosis.-ADP-ribosylation enzymes:...

 activity. Sirtuins regulate important biological pathways in bacteria

Bacteria

Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

, archaea

Archaea

The Archaea are a group of single-celled microorganisms. A single individual or species from this domain is called an archaeon...

 and eukaryote

Eukaryote

A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...

s. The name Sir2 comes from the yeast gene 'silent mating-type information regulation 2', the gene responsible for cellular regulation in yeast

Yeast

Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...

.

Sirtuins have been implicated in influencing aging and regulating transcription

Transcription (genetics)

Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...

, apoptosis

Apoptosis

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

 and stress resistance, as well as energy efficiency and alertness during low-calorie situations.

Yeast Sir2 and some, but not all, sirtuins are protein deacetylase

Protein deacetylase

Protein deacetylase; any enzyme that removes acetyl groups from lysine amino acids in proteins.The main ones are histone deacetylases and sirtuins ....

s. Unlike other known protein deacetylases, which simply hydrolyze acetyl-lysine

Lysine

Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....

 residues, the sirtuin-mediated deacetylation reaction couples lysine

Lysine

Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....

 deacetylation to NAD

Nicotinamide adenine dinucleotide

Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...

 hydrolysis. This hydrolysis yields O-acetyl-ADP-ribose

Ribose

Ribose is an organic compound with the formula C5H10O5; specifically, a monosaccharide with linear form H––4–H, which has all the hydroxyl groups on the same side in the Fischer projection....

, the deacetylated substrate and nicotinamide

Nicotinamide

Nicotinamide, also known as niacinamide and nicotinic acid amide, is the amide of nicotinic acid . Nicotinamide is a water-soluble vitamin and is part of the vitamin B group...

, itself an inhibitor

Enzyme inhibitor

An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...

 of sirtuin activity. 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

Whereas bacteria and archaea encode either one or two sirtuins, eukaryotes encode several sirtuins in their genomes. In yeast, roundworms, and fruitflies, sir2

Sir2

Sir2 was the first gene of the sirtuin genes to be found. It was found in budding yeast, and, since then, members of this highly conserved family have been found in nearly all organisms studied...

 is the name of the sirtuin-type protein. This research started in 1991 by Leonard Guarente of MIT

Massachusetts Institute of Technology

The Massachusetts Institute of Technology is a private research university located in Cambridge, Massachusetts. MIT has five schools and one college, containing a total of 32 academic departments, with a strong emphasis on scientific and technological education and research.Founded in 1861 in...

. 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

Sirtuins are classed according to their sequence of amino acids. Prokaryotics are in class U. In yeast (a lower eukaryote), sirtuin was initially found and named sir2. In more complex mammals, there are seven known enzymes that act as on cellular regulation, as sir2 does in yeast. These genes are designated as belonging to different classes, depending on their amino acid sequence structure.

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 SIRT2 NAD-dependent deacetylase sirtuin-2 is an enzyme that in humans is encoded by the SIRT2 gene.-Model organisms:The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA.-Further...	cytoplasm	deacetylase	cell cycle tumorigenesis
				Sirt3	SIRT3 SIRT3 NAD-dependent deacetylase sirtuin-3, mitochondrial also known as SIRT3 is a protein that in humans is encoded by the SIRT3 gene [sirtuin 3 ]. SIRT3 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein...	nucleus and mitochondria	deacetylase	metabolism
	c		Hst3 or Hst3p, Hst4 or Hst4p
II				Sirt4	SIRT4 SIRT4 Sirtuin 4, also known as SIRT4 is a protein which in humans is encoded by the SIRT4 gene.-Function:This gene encodes a member of the sirtuin family of proteins which are homologs of the Sir2 gene in budding yeast. Members of the sirtuin family are characterized by a sirtuin core domain and grouped...	mitochondria	ADP-ribosyl transferase	insulin secretion
III				Sirt5	SIRT5 SIRT5 Sirtuin 5 , also known as SIRT5 is a protein which in humans in encoded by the SIRT5 gene and in other species by the Sirt5 gene....	mitochondria	deacetylase	Ammonia detoxification
IV	a			Sirt6	SIRT6 SIRT6 Mono-ADP-ribosyltransferase sirtuin-6 is an enzyme that in humans is encoded by the SIRT6 gene.-External links:...	nucleus	ADP-ribosyl transferase and deacetylase	DNA repair, metabolism
	b			Sirt7	SIRT7 SIRT7 NAD-dependent deacetylase sirtuin-7 is an enzyme that in humans is encoded by the SIRT7 gene.-Further reading:...	nucleolus	unknown	rDNA Ribosomal RNA Ribosomal ribonucleic acid is the RNA component of the ribosome, the enzyme that is the site of protein synthesis in all living cells. Ribosomal RNA provides a mechanism for decoding mRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity... transcription
U		cobB CobB CobB is a bacterial protein that belongs to the sirtuin family, a broadly conserved family of NAD+-dependent protein deacetylases....					regulation of acetyl-CoA Acetyl-CoA Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...  synthetase	metabolism

Sirtuin list based on North/Verdin diagram.

Clinical significance

Sirtuin activity is inhibited by nicotinamide

Nicotinamide

Nicotinamide, also known as niacinamide and nicotinic acid amide, is the amide of nicotinic acid . Nicotinamide is a water-soluble vitamin and is part of the vitamin B group...

, which binds to a specific receptor site, 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, Alzheimer's, diabetes, atherosclerosis, and gout.sitris

Alzheimer's

SIRT1 deacetylates and coactivates the retinoic acid receptor beta

Retinoic acid receptor beta

Retinoic acid receptor beta , also known as NR1B2 is a nuclear receptor that in humans is encoded by the RARB gene.- Function :...

 that upregulates the expression of alpha-secretase (ADAM10

ADAM10

Disintegrin and metalloproteinase domain-containing protein 10, also known as ADAM10 or CDw156 or CD156c is a protein that in humans is encoded by the ADAM10 gene.- Function :...

). Alpha-secretase in turn suppresses beta-amyloid production. Furthermore, ADAM10 activation by SIRT1 also induces the Notch signaling pathway, which is known to repair neuronal damage in the brain.

Diabetes

Sirtuins have been proposed as a chemotherapeutic target for type II diabetes mellitus.

Aging

Preliminary studies with resveratrol

Resveratrol

Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....

, a possible SIRT1 activator, have led some scientists to speculate that resveratrol may extend lifespan. However, this hypothesis has not yet been borne out in experiments with mammals.

Cell culture

Cell culture

Cell culture is the complex process by which cells are grown under controlled conditions. In practice, the term "cell culture" has come to refer to the culturing of cells derived from singlecellular eukaryotes, especially animal cells. However, there are also cultures of plants, fungi and microbes,...

 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. Adding resveratrol to the diet of mice inhibit gene expression profiles associated with muscle aging and age-related cardiac dysfunction.

See also

• Ageing
  Ageing
  Ageing or aging is the accumulation of changes in a person over time. Ageing in humans refers to a multidimensional process of physical, psychological, and social change. Some dimensions of ageing grow and expand over time, while others decline...
  
  
• Sir2
  Sir2
  Sir2 was the first gene of the sirtuin genes to be found. It was found in budding yeast, and, since then, members of this highly conserved family have been found in nearly all organisms studied...
  
  
• Resveratrol
  Resveratrol
  Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
  
  
• Biological immortality
  Biological immortality
  Biological immortality refers to a stable rate of mortality as a function of chronological age. Some individual cells and entire organisms in some species achieve this state either throughout their existence or after living long enough. This requires that death occur from injury or disease rather...
  
  
• Caloric restriction
• Trichostatin A
  Trichostatin A
  Trichostatin A is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase families of enzymes, but not class III HDACs . TSA inhibits the eukaryotic cell cycle during the beginning of the growth stage...
  
  
• Histone deacetylases or HDACs

External links