The Full Wiki

Sirtuin: Wikis

Advertisements
  
  

Note: Many of our articles have direct quotes from sources you can cite, within the Wikipedia article! This article doesn't yet, but we're working on it! See more info or our list of citable articles.

Encyclopedia

From Wikipedia, the free encyclopedia

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
Symbol SIR2
Pfam PF02146
InterPro IPR003000
PROSITE PS50305
SCOP 1j8f

Silent Information Regulator Two (Sir2) proteins, or sirtuins, are a class of proteins which possess either histone deacetylase or mono-ribosyltransferase activity and are found in organisms ranging from bacteria to humans.[2][3] Named after the yeast silent mating type information regulation two,[4] 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.

Sirtuins have been implicated in influencing aging and regulating transcription, apoptosis and stress resistance.

Contents

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 is the name of the sirtuin-type protein.[5] This research started in 1991 by Leonard Guarente of MIT.[6][7] 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 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.[8][9]

Class Subclass Species Intracellular
location
Activity Function
Bacteria Yeast Mouse Human
I a Sir2 or Sir2p,
Hst1 or Hst1p
Sirt1 SIRT1 nucleus 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 deacetylase Ammonia detoxification
IV a Sirt6 SIRT6 nucleus ADP-ribosyl
transferase and deacetylase
DNA repair, metabolism
b Sirt7 SIRT7 nucleolus unknown rDNA
transcription
U cobB[10] regulation of
acetyl-CoA synthetase[11]
metabolism

Sirtuin list based on North/Verdin diagram.[12]

Clinical significance

Sirtuin activity is inhibited by nicotinamide, which binds to a specific receptor site,[13] 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 to develop newer agents to treat degenerative diseases such as diabetes, atherosclerosis and gout.[14][15]

Advertisements

Diabetes

Sirtuins have been proposed as a chemotherpeutic target for type II diabetes mellitus.[16]

Aging

Preliminary studies with resveratrol, a possible SIRT1 activator, have led some scientists to speculate that resveratrol may extend lifespan.[17] However, this hypothesis has not yet been borne out in experiments with mammals.[18]

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.[19] Adding resveratrol to the diet of mice inhibit gene expression profiles associated with muscle aging and age-related cardiac dysfunction.[20]

See also

References

  1. ^ PDB 1szd; Zhao K, Harshaw R, Chai X, Marmorstein R (June 2004). "Structural basis for nicotinamide cleavage and ADP-ribose transfer by NAD(+)-dependent Sir2 histone/protein deacetylases". Proc. Natl. Acad. Sci. U.S.A. 101 (23): 8563–8. doi:10.1073/pnas.0401057101. PMID 15150415. 
  2. ^ North BJ, Verdin E (2004). "Sirtuins: Sir2-related NAD-dependent protein deacetylases". Genome Biol. 5 (5): 224. doi:10.1186/gb-2004-5-5-224. PMID 15128440. 
  3. ^ Yamamoto H, Schoonjans K, Auwerx J (August 2007). "Sirtuin functions in health and disease". Mol. Endocrinol. 21 (8): 1745–55. doi:10.1210/me.2007-0079. PMID 17456799. 
  4. ^ EntrezGene 23410
  5. ^ Blander G, Guarente L (2004). "The Sir2 family of protein deacetylases". Annu. Rev. Biochem. 73: 417–35. doi:10.1146/annurev.biochem.73.011303.073651. PMID 15189148. 
  6. ^ Wade N (2006-11-08). "The quest for a way around aging". Health & Science. International Herald Tribune. http://www.iht.com/articles/2006/11/08/healthscience/snwonder.php. Retrieved 2008-11-30. 
  7. ^ "MIT researchers uncover new information about anti-aging gene". Massachusetts Institute of Technology, News Office. 2000-02-16. http://web.mit.edu/newsoffice/2000/guarente.html. Retrieved 2008-11-30. 
  8. ^ Frye R (2000). "Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins". Biochem Biophys Res Commun 273 (2): 793–8. doi:10.1006/bbrc.2000.3000. PMID 10873683. 
  9. ^ 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:10.1128/MCB.23.9.3173-3185.2003. PMID 12697818. http://mcb.asm.org/cgi/content/full/23/9/3173#T1. 
  10. ^ Zhao K, Chai X, Marmorstein R (March 2004). "Structure and substrate binding properties of cobB, a Sir2 homolog protein deacetylase from Escherichia coli". J. Mol. Biol. 337 (3): 731–41. doi:10.1016/j.jmb.2004.01.060. PMID 15019790. 
  11. ^ Schwer B, Verdin E (February 2008). "Conserved metabolic regulatory functions of sirtuins". Cell Metab. 7 (2): 104–12. doi:10.1016/j.cmet.2007.11.006. PMID 18249170. 
  12. ^ North B, Verdin E (2004). "Sirtuins: Sir2-related NAD-dependent protein deacetylases". Genome Biol 5 (5): 224. doi:10.1186/gb-2004-5-5-224. PMID 15128440. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=416462&blobtype=pdf. 
  13. ^ Avalos JL, Bever KM, Wolberger C (March 2005). "Mechanism of sirtuin inhibition by nicotinamide: altering the NAD(+) cosubstrate specificity of a Sir2 enzyme". Mol. Cell 17 (6): 855–68. doi:10.1016/j.molcel.2005.02.022. PMID 15780941. 
  14. ^ Adams JD Jr, Klaidman LK (2008). "Sirtuins, Nicotinamide and Aging: A Critical Review". Letters in Drug Design & Discovery 4 (1): 44–48. doi:10.2174/157018007778992892. http://www.bentham.org/lddd/sample/lddd4-1/009AJ.pdf. 
  15. ^ Taylor DM, Maxwell MM, Luthi-Carter R, Kazantsev AG (September 2008). "Biological and Potential Therapeutic Roles of Sirtuin Deacetylases". Cell. Mol. Life Sci. 65: 4000. doi:10.1007/s00018-008-8357-y. PMID 18820996. 
  16. ^ Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, Jin L, Boss O, Perni RB, Vu CB, Bemis JE, Xie R, Disch JS, Ng PY, Nunes JJ, Lynch AV, Yang H, Galonek H, Israelian K, Choy W, Iffland A, Lavu S, Medvedik O, Sinclair DA, Olefsky JM, Jirousek MR, Elliott PJ, Westphal CH (November 2007). "Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes". Nature 450 (7170): 712–6. doi:10.1038/nature06261. PMID 18046409. 
  17. ^ Wade N (2008-06-04). "New Hints Seen That Red Wine May Slow Aging". NYTimes.com. http://www.nytimes.com/2008/06/04/health/research/04aging.html. Retrieved 2008-11-30. 
  18. ^ Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R (August 2008). "Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span". Cell Metab. 8 (2): 157–68. doi:10.1016/j.cmet.2008.06.011. PMID 18599363. 
  19. ^ Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK, Hartlerode A, Stegmuller J, Hafner A, Loerch P, Wright SM, Mills KD, Bonni A, Yankner BA, Scully R, Prolla TA, Alt FW, Sinclair DA (November 2008). "SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging". Cell 135 (5): 907–18. doi:10.1016/j.cell.2008.10.025. PMID 19041753. 
  20. ^ Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, Allison DB, Saupe KW, Cartee GD, Weindruch R, Prolla TA (2008). "A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice". PLoS ONE 3 (6): e2264. doi:10.1371/journal.pone.0002264. PMID 18523577. 

External links


Advertisements






Got something to say? Make a comment.
Your name
Your email address
Message