Sirtuin

Sir2 family
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
SymbolSIR2
PfamPF02146
Pfam clanCL0085
InterProIPR003000
PROSITEPS50305
SCOP21j8f / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1ici​, 1j8f​, 1m2g​, 1m2h​, 1m2j​, 1m2k​, 1m2n​, 1ma3​, 1q14​, 1q17​, 1q1a​, 1s5p​, 1s7g​, 1szc​, 1szd​, 1yc2​, 1yc5

Sirtuins are a family of signaling proteins involved in metabolic regulation.[2][3] They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life.[2] Chemically, sirtuins are a class of proteins that possess either mono-ADP-ribosyltransferase or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity.[4][5][6] The name Sir2 comes from the yeast gene 'silent mating-type information regulation 2',[7] the gene responsible for cellular regulation in yeast.

From in vitro studies, sirtuins were thought to be implicated in influencing cellular processes like aging, transcription, apoptosis, inflammation[8] and stress resistance, as well as energy efficiency and alertness during low-calorie situations.[9] As of 2018, there was no clinical evidence that sirtuins affect human aging,[10] and a 2022 review criticized researchers who propagate this claim.[11]

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.[12] This hydrolysis yields O-acetyl-ADP-ribose, the deacetylated substrate and nicotinamide, which is an inhibitor of sirtuin activity itself. These proteins utilize NAD+ to maintain cellular health and turn NAD+ to nicotinamide (NAM).[13] 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 NAM or a combination of these variables.

Sirtuins that deacetylate histones are structurally and mechanistically distinct from other classes of histone deacetylases (classes I, IIA, IIB and IV), which have a different protein fold and use Zn2+ as a cofactor.[14][15]

  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". Proceedings of the National Academy of Sciences of the United States of America. 101 (23): 8563–8. Bibcode:2004PNAS..101.8563Z. doi:10.1073/pnas.0401057101. PMC 423234. PMID 15150415.
  2. ^ a b Ye X, Li M, Hou T, Gao T, Zhu WG, Yang Y (3 January 2017). "Sirtuins in glucose and lipid metabolism". Oncotarget (Review). 8 (1): 1845–1859. doi:10.18632/oncotarget.12157. PMC 5352102. PMID 27659520.
  3. ^ Yamamoto H, Schoonjans K, Auwerx J (August 2007). "Sirtuin functions in health and disease". Molecular Endocrinology. 21 (8): 1745–55. doi:10.1210/me.2007-0079. PMID 17456799.
  4. ^ Du J, Zhou Y, Su X, Yu JJ, Khan S, Jiang H, Kim J, Woo J, Kim JH, Choi BH, He B, Chen W, Zhang S, Cerione RA, Auwerx J, Hao Q, Lin H (November 2011). "Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase". Science. 334 (6057): 806–9. Bibcode:2011Sci...334..806D. doi:10.1126/science.1207861. PMC 3217313. PMID 22076378.
  5. ^ Jiang H, Khan S, Wang Y, Charron G, He B, Sebastian C, Du J, Kim R, Ge E, Mostoslavsky R, Hang HC, Hao Q, Lin H (April 2013). "SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine". Nature. 496 (7443): 110–3. Bibcode:2013Natur.496..110J. doi:10.1038/nature12038. PMC 3635073. PMID 23552949.
  6. ^ Rack JG, Morra R, Barkauskaite E, Kraehenbuehl R, Ariza A, Qu Y, Ortmayer M, Leidecker O, Cameron DR, Matic I, Peleg AY, Leys D, Traven A, Ahel I (July 2015). "Identification of a Class of Protein ADP-Ribosylating Sirtuins in Microbial Pathogens". Molecular Cell. 59 (2): 309–20. doi:10.1016/j.molcel.2015.06.013. PMC 4518038. PMID 26166706.
  7. ^ EntrezGene 23410
  8. ^ Preyat N, Leo O (May 2013). "Sirtuin deacylases: a molecular link between metabolism and immunity". Journal of Leukocyte Biology. 93 (5): 669–80. doi:10.1189/jlb.1112557. PMID 23325925. S2CID 3070941.
  9. ^ Satoh A, Brace CS, Ben-Josef G, West T, Wozniak DF, Holtzman DM, Herzog ED, Imai S (July 2010). "SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus". The Journal of Neuroscience. 30 (30): 10220–32. doi:10.1523/JNEUROSCI.1385-10.2010. PMC 2922851. PMID 20668205.
  10. ^ Shetty AK, Kodali M, Upadhya R, Madhu LN (2018). "Emerging anti-aging strategies - scientific basis and efficacy (Review)". Aging and Disease. 9 (6): 1165–1184. doi:10.14336/ad.2018.1026. ISSN 2152-5250. PMC 6284760. PMID 30574426.
  11. ^ Brenner C (2022-09-22). "Sirtuins are not conserved longevity genes". Life Metabolism. 1 (2): 122–133. doi:10.1093/lifemeta/loac025. ISSN 2755-0230. PMC 10081735. PMID 37035412.
  12. ^ Klein MA, Denu JM (2020). "Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators". Journal of Biological Chemistry. 295 (32): 11021–11041. doi:10.1074/jbc.REV120.011438. PMC 7415977. PMID 32518153.
  13. ^ "NMN vs NR: The Differences Between These 2 NAD+ Precursors". www.nmn.com. Retrieved 2021-01-04.
  14. ^ Bürger M, Chory J (2018). "Structural and chemical biology of deacetylases for carbohydrates, proteins, small molecules and histones". Communications Biology. 1: 217. doi:10.1038/s42003-018-0214-4. PMC 6281622. PMID 30534609.
  15. ^ Marks PA, Xu WS (July 2009). "Histone deacetylase inhibitors: Potential in cancer therapy". Journal of Cellular Biochemistry. 107 (4): 600–8. doi:10.1002/jcb.22185. PMC 2766855. PMID 19459166.