Sirtuin

Although the localisation patterns of some of the Sirtuins (class III HDACs) and their unique NAD-dependent deacetylation mechanism are known [58], less is understood about their functions and targets when compared to other HDACs [59]. The field of small molecule Sirtuin modulators is also correspondingly less advanced, because this alternative mechanism renders the zinc-dependent... 

A large number of patent applications has been filed, most recently describing imidazothiazoles [70], oxazolopyridines [71], benzimidazoles [72], benzothiazoles [73] and imidazopyridines [74] as sirtuin modulators, however it is not yet possible to determine which compound classes will prove most promising. Overall, due to their potential applications as new drug candidates for various indications, the class III HDAC inhibitors are currently a rapidly growing field of interest. 

Of note, a very recent report shows that SIRTl (sirtuin class of HDAC), that was shown to participate in axonal protection (Araki et al, 2004), could be acting in a neuroprotective way in ALS (Fischer et al, 2005). As noted earlier, this class of HDAC is insensitive to classical HDAC inhibitors, but it should be kept in mind reinstating acetylation homeostasis with classical HDACi might indirectly biased sirtuin s regulations as well. 

Gray SG, Ekstrom TJ (2001) The human histone deacetylase family. Exp Cell Res 262 75—83 Greiner D, Bonaldi T, Eskeland R, Roemer E, Imhof A (2005) Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9. Nat Chem BioH 143-145 Grozinger CM, Chao ED, Blackwell HE, Moazed D, Schreiber SL (2001) Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J Biol Chem 276(42) 38837-38843... 

Resveratrol (76) Triphenolic SRT-501 Against diabetes Activates sirtuins.by Phase II Sirtris 608-614... 

Small molecule activators of sirtuins extend Saccharomyces cere-visiae lifespan. Nature 425 191-196. 

Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430 686-689. 

SIRTl sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)... 

Michan, S. and Sinclair, D. (2007) Sirtuins in mammals insights into their biological function. The Biochemical Journal,... 

The sirtuins (silent information regulator 2-related proteins class III HDACs) form a specific class of histone deacetylases. First, they do not share any sequence or structural homology with the other HDACs. Second, they do not require zinc for activity, but rather use the oxidized form of nicotinamide adenine dinucleotide (NAD ) as cofactor. The reaction catalyzed by these enzymes is the conversion of histones acetylated at specific lysine residues into deacetylated histones, the other products of the reaction being nicotinamide and the metabolite 2 -0-acetyl-adenosine diphosphate ribose (OAADPR) [51, 52]. As HATs and other HDACs, sirtuins not only use acetylated histones as substrates but can also deacetylate other proteins. Intriguingly, some sirtuins do not display any deacetylase activity but act as ADP-ribosyl transferases. 

Sirtuins have been conserved from bacteria to eukaryotes. Notably, they all possess a conserved catalytic core domain flanked by sequence-divergent N- and C-terminal regions. If bacteria and archaebacteria generally possess one or two sirtuins, this number is higher in eukaryotes, with five sirtuins in Saccharomyces cerevisiae and seven in human. The presence of sirtuins in all phyla of life led to a wealth of structural data, not only on eukaryotic enzymes but also on bacterial and archaebacteria enzymes. 

Figure 2.4 Structures of histone deacetylases from the sirtuin family. Ribbon representation of the structures of the conserved catalytic domain of histone deacetylases (a) Homo sapiens SirT2 (PDB code IjSf) and (b) Thermotoga maritima Sir2 bound to NAD and an acetylated p53 peptide (PDB code 2h4f).

Despite the large amount of biochemical and structural studies of sirtuins in complex with various substrates, cofactors and reaction products, the catalytic mechanism of this class of enzymes is still a matter of debate. SN -like [56] and SN -like [60] mechanisms have been inferred from structural studies but further biochemical and possibly structural studies will be required to clarify which mechanism is used by sirtuins. It should also be noted that another matter of debate concerns the mode of noncompetitive inhibition of sirtuins by the reaction product nicotinamide [62], various structural studies having highlighted different binding pockets for this molecule [63, 64]. 

Hoff, K.G., Avalos, J.L., Sens, K. and Wolberger, C. (2006) Insights into the sirtuin mechanism from ternary complexes containing NAD + and acetylated peptide. Structure (London, England 1993), 14 (8), 1231-1240. 

Avalos, J.L., Bever, K.M. and Wolberger, C. (2005) Mechanism of sirtuin inhibition by nicotinamide altering the NAD( + ) cosubstrate specificity of a Sir2 enzyme. Molecular Cell, 17 (6), 855-868. 

So far 18 different members of HDACs have been discovered in humans and classified into four classes based on their homology to yeast histone deacetylases [33]. Class I includes four different subtypes (HDACl, 2, 3, 8), class II contains six subtypes tvhich are divided into two subclasses class Ila with subtypes HDAC4, 5, 7, 9 and class Ilb with HDAC6, 10. Class I and class II HDAC share significant structural homology, especially within the highly conserved catalytic domains. HDACs 6 and 10 are unique as they have two catalytic domains. HDACll is referred to as class IV. While the activity of class I, II and IV HDACs depends on a zinc based catalysis mechanism, the class III enzymes, also called sirtuins, require nicotinamide adenine dinucleotide as a cofactor for their catalysis. 

The class III deacetylases, named sirtuins, are structurally and functionally different from other HDACs. In contrast to the zinc-dependent deacetylation of classic HDACs, sirtuins depend on NAD" to carry out catalytic reactions. A variety of sirtuin crystal structures have been published over the past few years. The structures of human Sirt2 and SirtS as well as several bacterial Sir2 proteins could be derived, whereas no 3D structure is available for Sirtl and the other subtypes [69]. All solved sirtuin structures contain a conserved 270-amino-acid catalytic domain with variable N- and C-termini. The structure of the catalytic domain consists of a large classic Rossmann fold and a small zinc binding domain. The interface between the large and the small subdomain is commonly subdivided into A, B and C pockets. This division is based on the interaction of adenine (A), ribose (B) and nicotinamide (C) which are parts of the NAD" cofactor. (Figure 3.5) Whereas the interaction of adenine and... 

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