Sirtuin family

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... 

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).

S. L. Schreiber, Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening,... 

SIRTl belongs to the mammalian sirtuin family of NAD -dependent histone deacetylases (HDAGs) [198, 199]. Targets known to be deacetylated by SIRTl include histone 4 (H4), NFkB, and p53 [198, 199]. Through its deacetylase activity, SIRTl is considered to control cellular metabolic homeostasis, and to play important roles in the regulation of gene expression, cell proliferation, differentiation, survival, and senescence [198, 199]. SERTl activation has been considered to play a crucial role in calorie-restriction-induced longevity in several species [200]. 

Milne, J.C., and Denu, J.M. (2008) The Sirtuin family Therapeutic targets to treat diseases of aging. Current Opinion in Chemical Biology, 12,11-17. 

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. 

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]. 

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. 

Sirtuins represent a novel family of enzymes that are collectively well situated to help regulate nutrient sensing and utilization, metabolic rate, and ultimately metabolic disease. It was shown that resveratrol activated one of these enzymes, SIRTl [32]. The adivation of SIRTl leads to enhanced activity of multiple proteins, including peroxisomeprohferator-activated receptor coactivator-la (PGC-la), which helps mediate some of the in dtro and in invo effects of sirtuins. Resveratrol, given in a proprietary formulation SRT-501 (3 or 5 g), reached 5-8 times higher blood levels. 

Neugebauer RC, Uchiechowska U, Meier R, Hmby H, Valkov V, Verdin E, Sippl W, Jung M (2008) Structure-activity studies on splitomicin derivatives as sirtuin inhibitors and computational prediction of binding mode. J Med Chem 51 1203-1213 Costantini S, Sharma A, Raucci R, Costantini M, Autiero I, Colonna G (2013) Genealogy of an ancient protein family the Sirtuins, a family of disordered members. BMC Evol Biol 13 60... 

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