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Review Biological and Potential Therapeutic Roles of Sirtuin Cell. Mol. Life Sci. 65 (2008) 4000 – 4018 1420-682X/08/244000-19 Cellular and Molecular Life Sciences DOI 10.1007/s00018-008-8357-y Birkhuser Verlag, Basel, 2008 Review Biological and Potential Therapeutic Roles of Sirtuin Deacetylases D. M. Taylora, M. M. Maxwellb, R. Luthi-Cartera, A. G. Kazantsevb, * a Brain Mind Institute, Ecole Polytechnique Fdrale de Lausanne (EPFL), 1015 Lausanne (Switzerland) b Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, 114 16th Street, Charlestown, MA 02129 (USA), Fax: 617-724-1480, e-mail: [email protected] Received 25 June 2008; received after revision 20 August 2008; accepted 29 August 2008 Online First 27 September 2008 Abstract. Sirtuins comprise a unique class of nicoti- mammalian sirtuins in less than a decade. The namide adenine dinucleotide (NAD+)-dependent de- implication of sirtuins in medically important areas acetylases that target multiple protein substrates to such as diabetes, cancer, cardiovascular dysfunction execute diverse biological functions. These enzymes and neurodegenerative disease has further catapulted are key regulators of clinically important cellular and them to a prominent status as potential targets for organismal processes, including metabolism, cell di- nutritional and therapeutic development. Here, we vision and aging. The desire to understand the present a review of published results on sirtuin biology important determinants of human health and lifespan and its relevance to human disease. has resulted in a firestorm of work on the seven Keywords. Sirtuin, deacetylase, longevity, human disease, therapeutics. Introduction lated research has placed a great emphasis on the study of post-translational modification cascades. The biological function of most proteins relies on The post-translational addition of an acetyl moiety to reversible post-translational modification. Recent the e-amino group of a lysine residue, known as years have linked regulation of nearly every cellular protein acetylation, can have varying effects on signaling pathway to phosphorylation, acetylation, protein function [2]. The most prominently studied methylation, O-GlcNacylation, and/or ubiquitination substrates are histones, whose deacetylation typically of one or many of its contributors. Although crosstalk results in decreased gene expression [2]. Nonetheless, between post-translational modifications can regulate numerous other proteins such as transcription factors, multiple aspects of a particular biological pathway, a cytoskeletal proteins, metabolic enzymes and other singular modification, when applied to a crucial signaling mediators can also be modified by acetyla- mediator, can lead to dramatic effects that modify tion. Historically, enzymes that perform acetylation health at the organism level [1]. For this reason, as well have been known as histone acetyltransferases as the fact that enzymes are among the most tractable (HATs), whereas enzymes providing the counterbal- targets for pharmaceutical intervention, disease-re- ancing activity are known as histone deacetylases (HDACs). This nomenclature remains in common use, despite the fact that histones are not exclusive * Corresponding author. substrates for HDAC enzymes [3]. Cell. Mol. Life Sci. Vol. 65, 2008 Review Article 4001 Enzymes belonging to the HDAC superfamily play extends lifespan, while limited information exists as to critical roles in the regulation of cellular metabolism, the biological function of the other three [20, 21]. and constitute promising drug targets for treatment Similarly, increased expression of the well-studied D. of a broad range of human diseases. The classical melanogaster Sir2 has shown a positive effect on fly HDACs are grouped into three subfamilies (termed lifespan, while four other Drosophila sirtuins remain class I, II, and IV), comprised of eleven enzymes that largely uncharacterized [20, 22]. Mammals have seven share sequence homology and require Zn2+ for sirtuins, SIRTs1–7 [19, 23], which are described in deacetylase activity [2]. Although the sirtuins detail below. (SIRTs) nominally comprise the class III HDACs, they possess unique NAD+-dependent enzymatic activities and share no sequence similarity with the Sirtuin enzymatic activities classical enzymes [4]. The present review will focus on the class III HDACs, summarizing current knowl- The sirtuin-mediated deacetylation reaction involves edge of the biology of the mammalian sirtuins and hydrolysis of one NAD+ and formation of both highlighting their potential utility as therapeutic nicotinamide and a unique byproduct called O- targets. acetyl-ADP-ribose (OAADPr) [24]; OAADPr is formed by transfer of the removed acetyl group to ADP ribose [25]. Evidence is emerging that OAADPr Sirtuin family homologs and orthologs may have a biological function of its own, including delaying cell division [26], gene silencing [27] and The first known members of the sirtuin family were regulation of the cationic channel TRPM2 in a manner discovered in yeast. Among these was the nucleolar S. that could influence cell death [28]. Kinetically, cerevisiae protein Sir2p, which was shown to interact sirtuins bind to the acetylated substrate, resulting in with histones and effect transcriptional silencing at a conformational change and subsequent formation of telomeres [5–8]. Although early studies showed that a ternary complex with NAD+ [29]. A very detailed overexpression of Sir2p resulted in histone deacety- mechanism for this reaction is reviewed in [30]. lation [9], this enzymatic activity was not immediately Deacetylation activity has now been demonstrated attributed to Sir2p itself. In 1995, a mutation in the for six of seven mammalian SIRTs, with evidence of gene encoding the Sir2p interactor Sir4p was shown to this activity lacking only for SIRT4 [31–37]. Although extend replicative lifespan in S. cerevisiae [10], of lesser-understood biological significance, ADP- reinforcing an earlier hypotheses that transcriptional ribosyltransferase activity has been demonstrated for control and telomere maintenance are crucial regu- all mammalian SIRTs except SIRT5 and SIRT7 [23, lators of aging [11]. Further investigation revealed 38–41]. that Sir2p regulates the rate of ribosomal DNA Sirtuin enzymatic action depends on steady avail- (rDNA) recombination and formation of toxic ex- ability of reduced NAD+, and the enzyme pyrazina- trachromosomal rDNA circles (ERCs), which accu- midase/nicotinamidase 1 (PNC1) is crucial for recy- mulate with replicative age in yeast [12]. Deletion of cling of NAD+ in yeast [42]. A protective effect of SIR2 results in increased ERC levels, thereby reduc- elevated nicotinamide/nicotinic acid mononucleotide ing replicative lifespan, while overexpression of Sir2p adenylyltransferase (Nmnat1) expression in mouse has the expected opposite effect [13]. neurons was attributed to increased NAD+ biosyn- The discovery that the longevity-enhancing deacety- thesis and subsequent SIRT1 activation, suggesting an lase activity of Sir2p was dependent on the nutrient analogous system in mammals [43]. Further studies of NAD+ sparked interest in a possible relationship with this pathway revealed that nicotinamide phosphor- cellular metabolism, especially in light of the previ- ibosyltransferase (Nampt) is the rate-limiting enzyme ously ascribed benefit of calorie restriction on lifespan in NAD+ recycling [44]. [14–16]. Indeed, a 75% reduction in glucose signifi- It has been suggested recently that increasing sirtuin cantly increases the yeast replicative lifespan, and activities globally by boosting NAD+ levels could deletion of SIR2 abrogates this beneficial effect [17]. provide one strategy for tapping into the beneficial The intense interest in discovering longevity genes in effects of the SIRTs. However, given that both higher species prompted a search for additional Sir2p beneficial and detrimental effects of sirtuin activation homologs and orthologs (Fig. 1). S. cerevisiae was can be envisaged (as discussed below), it is difficult to found to express five sirtuins: SIR2 and four homologs predict whether their manipulation via an upstream termed HST1–4. All are implicated in transcriptional cofactor would be successful in achieving only desir- silencing at mating type loci and at telomeres [18]. C. able results. Interestingly, the recent description of elegans has four sirtuins [19]; one of these (SIR-2.1) conditions where increased levels of Nampt may have 4002 D. M. Taylor et al. Sirtuin Biology and Therapeutics Figure 1. (A) Amino acid sequence alignment of metazoan sirtuins ranked from highest to lowest homology with yeast Sir2p in the conserved sirtuin domain (aa. 255–526). (B) Enlarged section of sequence alignment containing the largest active site loop. (C) Homology of invertebrate and mammalian sirtuins to yeast Sir2p. Values represent percent amino acid homology. * – hypothetical proteins; ^ – representative of both isoforms. Cell. Mol. Life Sci. Vol. 65, 2008 Review Article 4003 Figure 2. Subcellular localization of mammalian sirtuins. a negative impact on cellular health reinforces this synthases 1 and 2 [59], and the PGC-1a [41, 60] and skepticism [45, 46]. LXR [61] transcriptional co-regulators, all of which play central roles in cellular lipid and carbohydrate metabolism. Regulation of PGC-1a function is also an Functional classes of sirtuin substrates important determinant of mitochondrial energetics and biogenesis [41, 60, 62]. The enzymatic activities
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