homologin mammals is known as SIRT1, SIR2L1 or Sir2α) is the namesake of a family of closely related enzymes, the sirtuins (sir-too-ins).Members of this family have been found in nearly all organisms studied. [Frye RA. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. "Biochem Biophys Res Commun". 2000 Jul 5;273(2):793-8. PMID: 10873683] Sirtuins are hypothesized to play a key role in an organism's response to stresses (such as heat or starvation) and to be responsible for the lifespan-extending effects of calorie restriction.Sinclair DA, Guarente L. Unlocking the Secrets of Longevity Genes. " Scientific American", March 2006, pp 48-57, [http://www.sciam.com/article.cfm?chanID=sa006&colID=1&articleID=000B73EB-3380-13F6-B38083414B7F0000 full text] ]
Nomenclature in various organisms
Sir stands for Silent information regulator genes. [Jasper Rine and Ira Herskowitz.(1987).Four Genes Responsible for a Position Effect on Expression from HML and HMR in Saccharomyces cerevisiae. Genetics. 116(1): 9–22. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=3297920 ] Sir2 is short for Silent mating type Information Regulation-2 and sirtuin stands for Sir2-homolog [ [http://www.ihop-net.org/UniPub/iHOP/gismo/142188.html Sirt1] , from iHOP database] .
The name Sir2 is used for the enzyme in the yeast "
Saccharomyces cerevisiae" (where it was first discovered), in the fruit fly " Drosophila melanogaster" and in the roundworm " Caenorhabditis elegans". [ [http://mediwire.skyscape.com/main/Default.aspx?P=Content&ArticleID=174239 Skyscape Content: Do antiaging approaches promote longevity? ] ]
The various sirtuins in mammals are named SIRT1-SIRT7, and SIRT1 is the mammalian homolog (sometimes claimed to be
ortholog) of Sir2. [ [http://mcb.asm.org/cgi/content/full/23/9/3173 Role for Human SIRT2 NAD-Dependent Deacetylase Activity in Control of Mitotic Exit in the Cell Cycle - Dryden et al. 23 (9): 3173 - Molecular and Cellular Biology ] ] [cite journal |author=Frye R |title=Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins |journal=Biochem Biophys Res Commun |volume=273 |issue=2 |pages=793–8 |year=2000 |pmid=10873683 |doi=10.1006/bbrc.2000.3000]
Method of action and observed effects
Sirtuins act by removing
acetylgroups from proteins in the presence of NAD+; they are thus classified as "NAD+-dependent deacetylases" and have EC number3.5.1. [ [http://www.ebi.ac.uk/interpro/IEntry?ac=IPR003000 The Sir2 protein family] from EMBL's InterPro database] They add the acetyl group from the protein to the ADP- ribosepart of NAD+ to form O-acetyl-ADP-ribose.
yeast" Saccharomyces cerevisiae", overexpression of the Sir2 generesults in a lifespan extension of about 30%, if the lifespan is measured as the number of cell divisions the cell can undergo before dying. This is due to Sir2 deacetylating (removing an acetyl group from) histonemolecules, which results in tighter packaging and lower level of transcription of the cell's DNAFact|date=March 2008. Sir2 is thus classified as a histone deacetylase.
Starving of yeast cells leads to a similarly extended lifespan, and indeed starving increases the available amount of NAD+ and reduces
nicotinamide, both increasing the activity of Sir2. Furthermore, removing the Sir2 gene eliminates the life-extending effect of calorie restriction. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=34708 Drosophilia Sir2] from NCBI's Entrez Gene database] Experiments in the nematode" Caenorhabditis elegans" and in the fruit fly " Drosophila melanogaster" [Rogina B, Helfand SL. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. "Proc Natl Acad Sci U S A." 2004 Nov 9;101(45):15998-6003. PMID 15520384] support these findings. As of 2006, experiments in mice are underway.
However, some other findings call the above interpretation into question. If one measures the lifespan of a yeast cell as the amount of time it can live in a non-dividing stage, then silencing the Sir2 gene actually "increases" lifespan [Fabrizio P "et al." Sir2 blocks extreme life-span extension. "Cell". 2005 Nov 18;123(4):655-67. PMID 16286010] Furthermore, calorie restriction can substantially prolong reproductive lifespan in yeast even in the absence of Sir2. [Kaeberlein M "et al." Sir2-independent life span extension by calorie restriction in yeast. "PLoS Biol." 2004 Sep;2(9):E296. PMID 15328540]
In organisms more complicated than yeast, it appears that Sir2 acts by deacetylation of several other proteins besides histones.
Resveratrolis a substance which experiments have shown to have a number of life-extending and health benefits in various species; it also increases the activity of Sir2 and this is the postulated reason for its beneficial effects. Resveratrol is produced by plants when they are stressed, and it is possible that plants use the substance to increase their own Sir2 activity in order to survive periods of stress. However, these claims are controversial: it has been reported that the observed effect of resvertatrol on Sir2 activity is likely an artifact of the experimental setup and does not reflect biological reality. [Kaeberlein "et al." Substrate-specific activation of sirtuins by resveratrol. "J Biol Chem." 2005 Apr 29; 280(17):17038-45. PMID 15684413.] [Borra MT "et al." Mechanism of human SIRT1 activation by resveratrol. "J Biol Chem." 2005 Apr 29; 280(17):17187-95. PMID 15749705.]
In mammals, SIRT1 (the mammalian homolog of Sir2) has been shown to deacetylate and thereby deactivate the
p53protein. [ [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=23411 Human Sirt1] from NCBI's Entrez Gene database] SIRT1 also stimulates autophagy by preventing acetylation of proteins required for autophagy in cultured cells and embryonic and neonatal tissues. This function provides a link between sirtuin expression and the cellular response to limited nutrients due to caloric restriction. [ [Lee IH, Cao L, Mostoslavsky R, et.al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci U S A. 2008 Feb 22 (Epub ahead of print)] ]
In the fruit fly "Drosophilia melanogaster" the Sir2 gene does not seem to be essential; loss of a sirtuin gene only has very subtle effects. However mice lacking the SIRT1 gene (the sir2 biological equivalent) were smaller than normal at birth, often died early or became sterile. [McBurney "et al." The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis. Mol Cell Biol. 2003 Jan;23(1):38-54. PMID 12482959]
Seven sirtuins are known in mammals.
* (also known as Sir2α) is the mammal
homologof Sir2. Mice that overexpress SIRT1 show eight properties of calorie restriction, including low cholesterol, low blood glucose, and low insulinlevels. They also show increased numbers of mitochondriain their neurons.
* is mainly expressed in the
*, Gene|SIRT4, and Gene|SIRT5 are active in mitochondria, the energy producing organelles that are a part of every cell.
* is active in the nucleus of the cell.
* is active in the
nucleolus, a compartment of the nucleus reserved for the assembly of ribosomes. Sirt7 has been shown to activate RNA Polymerase I transcription [Genes Dev. 2006 May 1;20(9):1075-80. Epub 2006 Apr 17. PMID:16618798]
Histone deacetylases, the class of enzymes yeast Sir2 belongs to.
* [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=23411 Human Sirt1] from NCBI's Entrez Gene database
* [http://genomics.senescence.info/genes/entry.php?hugo=SIRT1 Human Sirt1] in the GenAge database
* [http://www.ihop-net.org/UniPub/iHOP/gismo/142188.html Sirt1] in the iHOP database
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