Identification of a class of protein ADP-ribosylating sirtuins in microbial pathogens

Sirtuins are a diverse enzyme family of NAD+-dependent protein deacylases that control a variety of cellular processes including cell cycle progression, maintenance of genome integrity, and metabolic homeostasis (Asher and Schibler, 2011, Choi and Mostoslavsky, 2014). The overall structure of sirtuins is comprised of a highly conserved Rossmann fold and a more diverse zinc coordinating domain (Yuan and Marmorstein, 2012). The reaction mechanism is initialized by activation of NAD+, followed by a nucleophilic attack and release of nicotinamide. In the case of deacylation, a reactive imidate intermediate is formed that can undergo base-exchange with nicotinamide, thereby inhibiting reaction progression (reviewed in Sauve, 2010). Phylogenetically, the sirtuin family can be divided into five classes (I–IV and U, see Figure 1A) (Frye, 2000, Greiss and Gartner, 2009), and a correlation between sirtuin class and substrate preference was recently suggested (Dölle et al., 2013, He et al., 2012). For example, human SIRT1, a class I sirtuin, is most efficient at deacetylation, whereas SIRT5, belonging to class III, has highest activity toward succinylation (Du et al., 2011, Feldman et al., 2013). Although sirtuins appear to be primarily deacylases, several studies have suggested that some also possess protein ADP-ribosyltransferase activity (Haigis et al., 2006, Kowieski et al., 2008). Posttranslational ADP-ribosylation influences various cellular processes, such as transcription, chromatin organization, nitrogen fixation, and DNA repair, via modification of different acceptor proteins (Barkauskaite et al., 2013, Feijs et al., 2013, Nordlund and Högbom, 2013)