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Silent information regulator 2 (Sir2) proteins, or sirtuins, are protein deacetylases/mono-ADP-ribosyltransferases found in organisms ranging from bacteria to humans. Named after the yeast silent mating type information regulation two1, the gene responsible for cellular regulation in yeast, sirtuins regulate important biological pathways in eubacteria, archaea and eukaryotes. 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, itself an inhibitor 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. Whereas bacteria and archaea encode either one or two sirtuins, eukaryotes encode several sirtuins in their genomes. 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). Sirtuins have been implicated in the regulation of aging, transcription, apoptosis and stress resistance. Regulation of metabolic processes as well as cellular defense mechanisms might ultimately be the key to a possible lifespan-extending role for sirtuins in mammals.
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Sirtuins in organisms
Sirtuins in lower eukaryotes
In yeast, roundworms, and fruitflies2, sir2 is the name of the sirtuin-type enzyme. This research started in 1991 by Leonard Guarente of the Massachusetts Institute of Technology 34.
Sirtuins as possible agents in retardation of the aging process
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Sirtuins may be able to control age-related disorders in various organisms and in humans. These disorders include the aging process, obesity, metabolic syndrome, type II diabetes mellitus5 and Parkinson's disease. Normally, sirtuin activity is inhibited by nicotinamide, which binds to a specific receptor site. Drugs that interfere with this binding should increase sirtuin activity. Several studies show that resveratrol, found in red wine, can inhibit this interaction and is a putative agent for slowing down the aging process6. However, the amount of resveratrol found naturally in red wine is too low to activate sirtuin, so potential therapeutic use would mandate purification and development of a therapeutic agent. Development of new agents that would specifically block the nicotinamide-binding site could provide an avenue to develop newer agents to treat degenerative diseases such as diabetes, atherosclerosis and gout.
Sirtuins 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 which 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.78
| Class | Human name | Yeast name | Mouse name |
|---|---|---|---|
| Ia | SIRT19 | Sir2 or Sir2p, Hst1 or Hst1p | Sir2-beta |
| Ib | SIRT2, SIRT3 | Hst2 or Hst2p | Sir2l2, Sir2l3 |
| Ic | Hst3 or Hst3p, Hst4 or Hst4p | ||
| II | SIRT4 | SIRT4 | |
| III | SIRT5 | SIRT5 | |
| IVa | SIRT6 10 | SIRT6 | |
| IVb | SIRT7 | SIRT7 | |
| U< | Found only in Gram-positive bacteria |
Sirtuin list based on North/Verdin diagram.11
See also
- Sir2
- Resveratrol
- Biological immortality
- Caloric restriction
- Trichostatin A
- Histone deacetylases or HDACs
References
- ^ EntrezGene 23410
- ^ Patient Care, "Do antiaging approaches promote longevity?" By: David A. Sinclair, PhD, Evan W. Kligman, MD.
- ^ "The quest for a way around aging", Nov. 8 2006, International Herald Tribune. By Nicholas Wade / The New York Times.
- ^ Massachusetts Institute of Technology, News Office: "MIT researchers uncover new information about anti-aging gene."
- ^ Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes; http://www.nature.com/nature/journal/v450/n7170/abs/nature06261.html
- ^ "New Hints Seen That Red Wine May Slow Aging" Jun. 4 2008, By Nicholas Wade, New York times
- ^ Frye R (2000). "Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins". Biochem Biophys Res Commun 273 (2): 793–8. doi:. PMID 10873683.
- ^ Dryden S, Nahhas F, Nowak J, Goustin A, Tainsky M (2003). "Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle". Mol Cell Biol 23 (9): 3173–85. doi:. PMID 12697818, http://mcb.asm.org/cgi/content/full/23/9/3173#T1.
- ^ FOCUS | September 2, 2005 | RESEARCH BRIEFS
- ^ Mostoslavsky R et al. (2006). "Genomic instability and aging-like phenotype in the absence of mammalian SIRT6". Cell 124 (2): 315–29. doi:. PMID 16439206.
- ^ North B, Verdin E (2004). "Sirtuins: Sir2-related NAD-dependent protein deacetylases". Genome Biol 5 (5): 224. doi:. PMID 15128440, http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=416462.
External links
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