Sirtuin 

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, phosphorous = orange) and a histone H4 peptide (magenta) containing an acylated lysine residue (displayed as spheres).1
Sir2 family
Identifiers
Symbol SIR2
Pfam PF02146
InterPro IPR003000
PROSITE PS50305
SCOP 1j8f
Available PDB structures:

1ici, 1j8f, 1m2g, 1m2h, 1m2j, 1m2k, 1m2n, 1ma3, 1q14, 1q17, 1q1a, 1s5p, 1s7g, 1szc, 1szd, 1yc2, 1yc5

Silent information regulator 2 (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.23 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 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.

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.67 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.89

Class Subclass Yeast Mouse Human Intracellular location Activity Function
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
mitrochondira		 deacetylase metabolism
c Hst3 or Hst3p, Hst4 or Hst4p
II Sirt4 SIRT4 mitochondria ADP-ribosyl
transferase		 insulin secretion
III Sirt5 SIRT5 mitochondria deacetylase unknown
IV a Sirt6 SIRT6 nucleus ADP-ribosyl
transferase		 DNA repair
b Sirt7 SIRT7 nucleus unknown rDNA
transcription
U Found only in gram-positive bacteria

Sirtuin list based on North/Verdin diagram.10

Clinical significance

Sirtuin activity is inhibited by nicotinamide, which binds to a specific receptor site,11 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.1213

Diabetes

Sirtuins may be of therapeutic utility for type II diabetes mellitus.14

Aging

Several studies show that resveratrol, found in red wine, can inhibit this interaction and is a putative agent for slowing down the aging process.15 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.

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 connected with aging.16 The researchers found that increasing SIRT1 expression improved gene regulation and propose that the negative effects of aging may be the result of loss of regulation of detrimental genes by SIRT2 as the protein is increasingly diverted to repair DNA damage.

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. Retrieved on 2008-11-30.
  7. ^ "MIT researchers uncover new information about anti-aging gene". Massachusetts Institute of Technology, News Office (2000-02-16). Retrieved on 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. ^ 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/articlerender.fcgi?artid=416462. 
  11. ^ 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. 
  12. ^ Adams JD Jr, Klaidman LK (2008). "Sirtuins, Nicotinamide and Aging: A Critical Review". Letters in Drug Design & Discovery 4 (1): 44-48, http://www.bentham.org/lddd/sample/lddd4-1/009AJ.pdf. 
  13. ^ Taylor DM, Maxwell MM, Luthi-Carter R, Kazantsev AG (September 2008). "Biological and Potential Therapeutic Roles of Sirtuin Deacetylases". Cell. Mol. Life Sci.. doi:10.1007/s00018-008-8357-y. PMID 18820996. 
  14. ^ 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. 
  15. ^ Wade N (2008-06-04). "New Hints Seen That Red Wine May Slow Aging". NYTimes.com. Retrieved on 2008-11-30.
  16. ^ Oberdoerffer P et al. (2008). "SIRT1 Redistribution on Chromatin Promotes Genome Stability but Alters Gene Expression during Aging". Cell 135: 907-918. doi:10.1016/j.cell.2008.10.025. 

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