The Sirtuins Class III HDACs

Compared to the zinc-dependent HDACs, the sirtuins act by a very different mechanism and require NAD+ as a cofactor. Unsurprisingly, they show no sequence similarity with the other HDACs and are structurally very distinct [97]. The size of most sirtuins (Sirt2 to Sirt7) varies from 310 to 400 amino acid residues, while Sirtl is larger (747 residues). Multiple crystal structures of eukaryotic and prokaryotic sirtuin proteins have been reported, which either are apo-forms or include ligands such as NAD+ derivatives, W-acetylated lysine substrates, and/or other small molecules [98-110]. These data have shed much light on the mode of action of this enzyme class. 

As illustrated in Fig. 9, sirtuins convert one equivalent of NAD+ to nicotinamide and 2/-0-acetyl-ADP-ribose (2 -OAADPr) to deacetylate an Ve-acetyl lysine group [111]. This mechanism requires a conformational change of NAD+ resulting in weakening of the Cl -N bond, which is induced upon binding of the substrate to the enzyme [109, 112]. A nucleophilic substitution at the anomeric 

All sirtuins share a catalytic NAD+ binding domain, which is fairly well conserved across the family [115] and a substrate-binding pocket. Structural data also provided insights to the substrate selectivity of sirtuins [108]. 

Several structurally diverse sirtuin inhibitors have been reported, some of which are illustrated in Fig. 10. Nicotinamide is a product of NAD+ degradation that occurs during sirtuin-mediated catalytic process. Its inhibitory function at high concentrations is a result of a reaction with the ribosyl oxycarbenium intermediate formed as part of the mechanism, thus reversing the catalytic process and preventing deacetylation. Sirtinol 26 and salermide 27 [116], cambinol 28 [117], the tenovins 29 [118], and splitomycin 30 all show moderate inhibitory activity in the micromolar range. 

The pseudo-spiro compound 31, a moderately active Sirt2 inhibitor, has been identified by an in silico approach [119]. A crystal structure of the poly-sulfony-lated symmetric urea suramin 32 bound to the catalytic site of Sirt5 has been elucidated [110] and demonstrated that the poly-aromatic compound covers the 

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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... 

The HDAC superfamily consists of 18 members originating from two different evolutionary starting points which exhibit a common lysine deacetylase activity. The classical HDAC family is characterized by a well-conserved Zn2+ catalytic domain (Table 1 classes I, Ha, lib, and IV). The sirtuins (class III HDACs) comprise a distinct subfamily of HDACs, which use NAD+ as cofactor. 

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