Sirtuin/Sir2 phylogeny, evolutionary considerations and structural conservation

Abstract

The sirtuins are a protein family named after the first identified member, S. cerevisiae Sir2p. Sirtuins are protein deacetylases whose activity is dependent on NAD(+) as a cosubstrate. They are structurally defined by two central domains that together form a highly conserved catalytic center, which catalyzes the transfer of an acetyl moiety from acetyllysine to NAD(+), yielding nicotinamide, the unique metabolite O-acetyl-ADP-ribose and deacetylated lysine. One or more sirtuins are present in virtually all species from bacteria to mammals. Here we describe a phylogenetic analysis of sirtuins. Based on their phylogenetic relationship, sirtuins can be grouped into over a dozen classes and subclasses. Humans, like most vertebrates, have seven sirtuins: SIRT1-SIRT7. These function in diverse cellular pathways, regulating transcriptional repression, aging, metabolism, DNA damage responses and apoptosis. We show that these seven sirtuins arose early during animal evolution. Conserved residues cluster around the catalytic center of known sirtuin family members.

Fig. 1

Unrooted phylogenetic tree of all aligned sirtuin sequences. The tree was constructed using SplitsTree 4 (Huson and Bryant, 2006). Classes defined by Frye (2000) are shown in black, classes added in this review are shown in red. Branches for which bootstrap values are shown are also in red. The SplitsTree file with all bootstrap values can be down-loaded as Supplementary File 2.

Fig. 2

Structural context of conserved residues. Structure of budding yeast Hst2p catalytic domain in complex with acetyllysine histone H4 peptide (yellow) and a non-hydrolyzable NAD⁺ analogue (yellow) (Zhao et al., 2004). Amino acids 4 to 204 and 213 to 287 of the structure were used. Amino acids 205 to 212 (WLREKITT) were excluded because they are unique to Hst2p and not conserved in any other sirtuin. Conserved residues were visualized using Chimera software (Meng et al., 2006; Pettersen et al., 2004); highly conserved residues are shown in red. A rotational 360° view of the structure is shown in Supplementary File 5 (ribbon view, Fig. 1A) and Supplementary File 6 (surface view, Fig. 1B).

Fig. 3

Deacetylation mechanism catalyzed by sirtuins. Sirtuin-mediated deacetylation proceeds in two steps. In the first step nicotinamide is cleaved, yielding an O-alkylamidate intermediate. In the second step the nicotinamide ribose 2′OH group attacks the intermediate, yielding deacetylated lysine and O-acetyl-ADP-ribose.