SIRT, Sirtuin

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... 

Although the Y3H studies reported by our laboratory have focused on the use of kinase inhibitors, a growing number of studies indicate that Y3H is equally suitable for use with other types of small molecules. For example, we have detected bona fide interactions of small molecules with phosphodiesterases (PDEs), histone deacetylases (HDACs), sirtuins (SIRTs), carbonic anhydrase, and various other proteins (manuscript in preparation). 

Recently, in an approach to explain the diverse actions of polyphenols, Howitz et al. suggested that the antiproliferative and oncosuppressive properties of resveratrol might be due to a mechanism that mimics caloric restriction and lifespan extension, and involves the sirtuin (SIRT) family of nicotinamide adenine dinucleotide (NAD) -dependent acety-lases (Howitz et al. 2003). More specifically, resveratrol was found to directly interact with SIRTl deacetylase, resulting in decreased acetylation of p53, increased DNA stability, and finally cell survival. Redox formation was implicated in the inhibition of histone deacetylase (HDAC) activity, leading to a chronic inflammatory-like response (Rahman et al. 2004). In this respect, resveratrol is a promising agent in the reversal of oxidative stress and rescue of mutant phenotypes. 

The human genome contains 18 HDACs that are classified according to their catalytic mechanism. The focus of this chapter is the eleven zinc-dependent HDACs 1-11, which contain a zinc cation as the active site catalyst. In addition, there are seven sirtuins, SIRTs 1-7, which instead employ the cofactor NAD for amide bond hydrolysis. The zinc-dependent HDACs are further subdivided into elass I (HDACs 1, 2, 3 and 8), class Ila (HDACs 4, 5, 7 and 9), class Ilb (HDACs 6 and 10) and class IV (HDAC 11) based on sequence homology and cellular loealization. The class I HDACs are ubiquitously expressed and primarily located in the cell nucleus, where... 

Mammalian sirtuins (SIRTs, silent information regulator transcript) were identified as conserved structural homologues to the yeast silent information regulator protein (Sir2), which has been shown to mediate longevity under calorie restriction conditions. The increased lifespan associated with calorie restriction in general has been attributed to reduced rates of cancer, diabetes, inflammation, and cardiovascular... 

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