Sirtuin catalytic mechanism

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]. 

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... 

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. 

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. 

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