SIRTUINS 2º parte

20.07.2018

Sirtuins are NAD-dependent deacetylases that are highly conserved from bacteria to human and SIR2 was originally shown to extend lifespan in budding yeast (Imai et al., 2000; Kaeberlein et al., 1999). Since then, sirtuins have been shown to also regulate longevity in other lower organisms, such as flies and worms (Tissenbaum and Guarente, 2001; Rogina and Helfand, 2004). In mammals, there are seven sirtuins (SIRT1-7). All mammalian sirtuins contain a conserved NAD-binding and catalytic domain, termed the sirtuin core domain, but differ in their N- and C-terminal domains (Frye, 2000). They have different specific substrates and biological functions, and are found in various cell compartments. The fact that sirtuins require NAD for their enzymatic activity connects metabolism to aging and aging-related diseases. In this Cell Science at a Glance article, we summarize the recent data related to the role of sirtuins in aging and aging-related diseases, and describe the underlying molecular mechanisms.

Enzymatic activity of sirtuins and NAD biosynthesis

Sirtuins belong to the class III protein deacetylase family, which are the only histone deactyalses (HDACs) that require NAD for their enzymatic activity (Imai et al., 2000). NAD is an important co-factor for the electron transport chain and is also involved in many enzymatic reactions (Houtkooper et al., 2010). Owing to the characteristic NAD requirement for their enzymatic reaction, the activity of sirtuins is directly linked to the metabolic state in the cell. Initially, yeast SIR2 was discovered as a histone deacetylase, but mammalian sirtuins have also various non-histone protein substrates. The deacetylation reaction of sirtuins consists of two steps. In the first, sirtuins cleave NAD and produce nicotinamide (NAM), and in the second step the acetyl group is transferred from the substrate to the ADP-ribose moiety of NAD to generate O-acetyl-ADP ribose and the deacetylated substrate (Tanner et al., 2000). Although most of sirtuins have deacetylase activity, SIRT4 has been shown to have only ADP-ribosyltransferase activity, whereas SIRT1 and SIRT6 have both deacetylation and a relatively weak ADP-ribosyltransferase activity (Haigis et al., 2006; Imai et al., 2000; Liszt et al., 2005; Michishita et al., 2008). Interestingly, the generated NAM is an endogenous inhibitor of sirtuins and is usually converted to nicotinamide mononucleotide (NMN) by the NAD salvage pathway enzyme, nicotinamide phosphoribosyl-transferase (Nampt). Subsequently, nicotinamide mononucleotide adenyltransferase (Nmnat) regenerates NAD from NMN (Houtkooper et al., 2010) (see poster). Recent studies suggest that NAD biosynthesis critically regulates the activity of sirtuins. For example, Nampt-mediated NAD biosynthesis controls SIRT1 activity in several tissues; and SIRT3, SIRT4 and SIRT5 are also regulated by NAD biosynthesis in response to nutrient stress (Nakagawa et al., 2009; Revollo et al., 2007; Yang et al., 2007). Nampt also mediates the production of tumor necrosis factor α (TNFα) in a SIRT6 dependent manner (Van Gool et al., 2009). Additionally, NAD biosynthesis is linked to the circadian clock cycle, because Nampt is regulated by a complex consisting of the circadian locomotor output cycles kaput (CLOCK), brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1) and SIRT1, and in turn regulates SIRT1 activity through NAD (Nakahata et al., 2009; Ramsey et al., 2009).