Sirtuin 1

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Sirtuin 1
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols SIRT1 ; SIR2; SIR2L1; hSIR2
External IDs OMIM604479 MGI2135607 HomoloGene56556 ChEMBL: 4506 GeneCards: SIRT1 Gene
RNA expression pattern
PBB GE SIRT1 218878 s at tn.png
More reference expression data
Species Human Mouse
Entrez 23411 93759
Ensembl ENSG00000096717 ENSMUSG00000020063
UniProt Q96EB6 Q923E4
RefSeq (mRNA) NM_001142498 NM_001159589
RefSeq (protein) NP_001135970 NP_001153061
Location (UCSC) Chr 10:
67.88 – 67.92 Mb
Chr 10:
63.32 – 63.38 Mb
PubMed search [1] [2]

Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.[1][2][3]

SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae), referring to the fact that its sirtuin homolog (biological equivalent across species) in yeast (S. cerevisiae) is Sir2. SIRT1 is an enzyme that deacetylates proteins that contribute to cellular regulation (reaction to stressors, longevity).[4]


Sirtuin 1 is a member of the sirtuin family of proteins, homologs of the Sir2 gene in S. cerevisiae. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class I of the sirtuin family.[2]

Sirtuin 1 is downregulated in cells that have high insulin resistance and inducing its expression increases insulin sensitivity, suggesting the molecule is associated with improving insulin sensitivity.[5] Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of the PGC1-alpha/ERR-alpha complex, which are essential metabolic regulatory transcription factors.[6][7][8][9][10][11]

Selective ligands[edit]


  • Lamin A is a protein that had been identified as a direct activator of Sirtuin 1 during a study on Progeria.[12]
  • Resveratrol has been claimed to be an activator of Sirtuin 1,[13] but this effect has been disputed based on the fact that the initially used activity assay, using a non-physiological substrate peptide, can produce artificial results.[14][15] Resveratrol increases the expression of SIRT1, meaning that it does increase the activity of SIRT1, though not necessarily by direct activation.[5] However, resveratrol was later shown to directly activate Sirtuin 1 against non-modified peptide substrates.[16][17] Resveratrol also enhances the binding between Sirtuin 1 and Lamin A.[12]
  • SRT-1720 was also claimed to be an activator,[13] but this now has been questioned.[18]


Sirtuin 1 has been shown to interact with HEY2,[19] PGC1-alpha,[8] and ERR-alpha.[6] Mir-132 microRNA has been reported to interact with Sirtuin 1 mRNA, so as to reduce protein expression. This has been linked to insulin resistance in the obese.[20]

Human Sirt1 has been reported having 136 direct interactions in Interactomic studies involved in numerous processes.[21]


  1. ^ Frye RA (June 1999). "Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity". Biochem. Biophys. Res. Commun. 260 (1): 273–9. doi:10.1006/bbrc.1999.0897. PMID 10381378. 
  2. ^ a b "Entrez Gene: SIRT1 sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)". 
  3. ^ SIRT1 human gene location in the UCSC Genome Browser.
  4. ^ Sinclair DA, Guarente L (March 2006). "Unlocking the Secrets of Longevity Genes". Scientific American. 
  5. ^ a b Sun C, Zhang F, Ge X, Yan T, Chen X, Shi X, Zhai Q (October 2007). "SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B". Cell Metab. 6 (4): 307–19. doi:10.1016/j.cmet.2007.08.014. PMID 17908559. 
  6. ^ a b Wilson BJ, Tremblay AM, Deblois G, Sylvain-Drolet G, Giguère V (Jul 2010). "An acetylation switch modulates the transcriptional activity of estrogen-related receptor alpha". Mol. Endocrinol. 24 (7): 1349–58. doi:10.1210/me.2009-0441. PMID 20484414. 
  7. ^ Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P (Mar 2005). "Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1". Nature 434 (7029): 113–8. doi:10.1038/nature03354. PMID 15744310. 
  8. ^ a b Nemoto S, Fergusson MM, Finkel T (Apr 2005). "SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}". J. Biol. Chem. 280 (16): 16456–60. doi:10.1074/jbc.M501485200. PMID 15716268. 
  9. ^ Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J (Dec 2006). "Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha". Cell 127 (6): 1109–22. doi:10.1016/j.cell.2006.11.013. PMID 17112576. 
  10. ^ Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K, Schenk S, Milne J, Meyers DJ, Cole P, Yates J, Olefsky J, Guarente L, Montminy M (Nov 2008). "A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange". Nature 456 (7219): 269–73. doi:10.1038/nature07349. PMC 2597669. PMID 18849969. 
  11. ^ Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J (Apr 2009). "AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity". Nature 458 (7241): 1056–60. doi:10.1038/nature07813. PMC 3616311. PMID 19262508. 
  12. ^ a b Liu B, Ghosh S, Yang X, Zheng H, Liu X, Wang Z, Jin G, Zheng B, Kennedy BK, Suh Y, Kaeberlein M, Tryggvason K, Zhou Z (2012). "Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria". Cell Metab. 16 (6): 738–50. doi:10.1016/j.cmet.2012.11.007. PMID 23217256. 
  13. ^ a b Alcaín FJ, Villalba JM (April 2009). "Sirtuin activators". Expert Opin Ther Pat 19 (4): 403–14. doi:10.1517/13543770902762893. PMID 19441923. 
  14. ^ Kaeberlein M, McDonagh T, Heltweg B, Hixon J, Westman EA, Caldwell SD, Napper A, Curtis R, DiStefano PS, Fields S, Bedalov A, Kennedy BK (April 2005). "Substrate-specific activation of sirtuins by resveratrol". J. Biol. Chem. 280 (17): 17038–45. doi:10.1074/jbc.M500655200. PMID 15684413. 
  15. ^ Beher D, Wu J, Cumine S, Kim KW, Lu SC, Atangan L, Wang M (December 2009). "Resveratrol is not a direct activator of SIRT1 enzyme activity". Chem Biol Drug Des 74 (6): 619–24. doi:10.1111/j.1747-0285.2009.00901.x. PMID 19843076. 
  16. ^ Lakshminarasimhan M, Rauh D, Schutkowski M, Steegborn C (Mar 2013). "Sirt1 activation by resveratrol is substrate sequence-selective". Aging (Albany NY) 5 (3): 151–4. PMID 23524286. 
  17. ^ Hubbard BP, Gomes AP, Dai H, Li J, Case AW, Considine T, Riera TV, Lee JE, E SY, Lamming DW, Pentelute BL, Schuman ER, Stevens LA, Ling AJ, Armour SM, Michan S, Zhao H, Jiang Y, Sweitzer SM, Blum CA, Disch JS, Ng PY, Howitz KT, Rolo AP, Hamuro Y, Moss J, Perni RB, Ellis JL, Vlasuk GP, Sinclair DA (Mar 2013). "Evidence for a common mechanism of SIRT1 regulation by allosteric activators". Science 339 (6124): 1216–9. doi:10.1126/science.1231097. PMID 23471411. 
  18. ^ Pacholec M, Bleasdale JE, Chrunyk B, Cunningham D, Flynn D, Garofalo RS, Griffith D, Griffor M, Loulakis P, Pabst B, Qiu X, Stockman B, Thanabal V, Varghese A, Ward J, Withka J, Ahn K (January 2010). "SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1". J. Biol. Chem. 285 (11): 8340–51. doi:10.1074/jbc.M109.088682. PMC 2832984. PMID 20061378. 
  19. ^ Takata T, Ishikawa F (January 2003). "Human Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional repression". Biochem. Biophys. Res. Commun. 301 (1): 250–7. doi:10.1016/S0006-291X(02)03020-6. PMID 12535671. 
  20. ^ Strum JC, Johnson JH, Ward J, Xie H, Feild J, Hester A, Alford A, Waters KM (2009). "MicroRNA 132 regulates nutritional stress-induced chemokine production through repression of SirT1". Mol. Endocrinol. 23 (11): 1876–84. doi:10.1210/me.2009-0117. PMID 19819989. 
  21. ^ Sharma A, Gautam V, Costantini S, Paladino A, Colonna G (2012). "Interactomic and pharmacological insights on human sirt-1". Front Pharmacol 3: 40. doi:10.3389/fphar.2012.00040. PMC 3311038. PMID 22470339. 

Further reading[edit]

External links[edit]