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sirtuin 1; NAD-dependent deacetylase sirtuin 1; silent mating type information regulation 2 homolog 1 (SIRT1)

Function: 1) NAD-dependent deacetylase 2) regulates processes including apoptosis & muscle differentiation by deacetylating key proteins 3) deacetylates Lys-382 of p53/TP53 & impairs its ability to induce apoptosis & modulate cell senescence 4) deacetylates TAF1B, thus represses rDNA transcription by RNA polymerase 1 5) role in HES1- & HEY2-mediated transcriptional repression 6) inhibits skeletal muscle differentiation by deacetylating PCAF & MYOD1 (found in a complex with PCAF & MYOD1) 7) role as sensor of the cytosolic ratio of NAD+/NADH, essential in skeletal muscle cell differentiation 8) despite some ability to deacetylate histones in vitro, unlikely to play role in vivo 9) interacts with MLLT7/FOXO4, PML 10) forms complex with FOXO transcription factor FOXO3 in response to oxidative stress 11) SIRT1 deacetylates FOXO3 which a) increases its ability to effect cell cycle arrest b) increases resistance to oxidative stress c) inhibits ability to induce cell death [4] 12) SIRT1 deacetylates FOXO4 13) SIRT1 inhibits PPAR-gamma, induces lipolysis [5] 14) SIRT1 inhibits ROCK1, which in turn, increases APP alpha-secretase activity [6] 15) SIRT1 regulates acetylation of HSF1 [8] 16) may decrease deposition of amyloid beta-peptide in the brain & boost repair of damaged neurons through deacetylating transcription factor RARB [9] a) RARB, in turn, induces ADAM10 (an APP alpha-secretase, activity of which precludes formation of beta-peptide b) ADAM10 also induces the notch pathway involved in repair of damaged neurons 17) component of the eNoSC complex NAD+ + acetylprotein nicotinamide + O-acetyl-ADP-ribose + protein Cofactor: binds 1 Zn+2 per subunit Inhibition: 1) nicotinamide 2) 6-chloro-2,3,4,9-tetrahydro-1-H-carbazole-1-carboxamide 3) > 16 miRNAs modulate SIRT1 expression, including miR-34a [10] Activated by: (see SIRT1 activator) 1) resveratrol (component of red wine), 2) butein 3) piceatannol 4) isoliquiritigenin 5) fisetin 6) quercetin 7) SRT1720 (most potent), SRT1460 [7] Structure: - belongs to the sirtuin family - contains 1 deacetylase sirtuin-type domain Compartment: - nucleus - recruited to the nuclear bodies via interaction with PML Expression: - widely expressed, including expression within the brain - expressed in hypothalamus (mice) - induced by calorie restriction Polymorphism: - polymorphism(s) in SIRT1 may be associated with longevity [10] Comparative biology: - mediates longevity effect of caloric restriction in mice through actions in the hypothalamus - increases cellular response of orexin receptor type 2 in the dorsomedial hypothalamus & lateral hypothalamus [11]

Related

SIRT1 activator sirtinol

General

sirtuin (silent mating type information regulation 2 homolog)

Properties

SIZE: MW = 82 kD entity length = 747 aa COMPARTMENT: cell nucleus MOTIF: alanine-rich region {54-98} MOTIF: alanine residue (SEVERAL) POLY-ASP {122-127} glutamate residue {128-134} (6) DEACETYLASE SIRTUIN-TYPE {244-498} MOTIF: histidine residue {H363} Zn+2-binding site SITE: 371-371 Zn+2-binding site SITE: 374-374 Zn+2-binding site SITE: 395-395 Zn+2-binding site SITE: 398-398

Database Correlations

OMIM 604479 UniProt Q96EB6 Pfam PF02146 Entrez Gene 23411

References

  1. OMIM :accession 604479 UniProt :accession Q96EB6
  2. Luo et al. Cell 107:137-148, 2001
  3. Vaziri et al. Cell 107:149-159, 2001
  4. Brunet A et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004, 303:2011-2015 PMID: 14976264
  5. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004 Jul 16;305(5682):390-2. Epub 2004 Jun 17. PMID: 15205477 Wolf G Calorie restriction increases life span: a molecular mechanism. Nutr Rev 2006, 64:89 PMID: 16536186
  6. Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve AA, Pasinetti GM. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem. 2006 Aug 4;281(31):21745-54. Epub 2006 Jun 2. PMID: 16751189
  7. 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. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007 Nov 29;450(7170):712-6. PMID: 18046409
  8. Morimoto R, Northwestern University Proceedings of the 38th Annual Meeting of the American Aging Association: Integrative Biology: Hormones, Signaling, and Aging. May 29-June 1, 2009, Scottsdale, AZ
  9. Donmez G et al. SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10. Cell 2010 Jul 23; 142:320 PMID: 20655472 - Wolfe MS and Selkoe DJ. Giving Alzheimer's the old one-two. Cell 2010 Jul 23; 142:194 PMID: 20655461
  10. Yamakuchi M MicroRNA Regulation of SIRT1. Front Physiol. 2012;3:68. Epub 2012 Mar 30. PMID: 22479251
  11. Satoh A, Brace CS, Rensing N et al Sirt1 Extends Life Span and Delays Aging in Mice through the Regulation of Nk2 Homeobox 1 in the DMH and LH. Cell Metab. 2013 Sep 3;18(3):416-30 PMID: 24011076

Component-of

energy-dependent nucleolar silencing complex (eNoSC complex)