Molecular features of the sortase enzyme family

Abstract

Bacteria possess complex and varying cell walls with many surface exposed proteins. Sortases are responsible for the covalent attachment of specific proteins to the peptidoglycan of the cell wall of Gram‐positive bacteria. Sortase A of Staphylococcus aureus, which is seen as the archetypal sortase, has been shown to be essential for pathogenesis and has therefore received much attention as a potential target for novel therapeutics. Being widely present in Gram‐positive bacteria, it is likely that other Gram‐positive pathogens also require sortases for their pathogenesis. Sortases have also been shown to be of significant use in a range of industrial applications. We review current knowledge of the sortase family in terms of their structures, functions and mechanisms and summarize work towards their use as antibacterial targets and microbiological tools.

Sortase Transpeptidases: Structural Biology and Catalytic Mechanism

“…Their important role in displaying virulence factors makes them promising drug targets (Bradshaw et al, 2015; Cascioferro et al, 2014; Clancy et al, 2010; Maresso & Schneewind, 2008; Suree et al, 2007), while their ability catalyze in vitro transpeptidation has made them useful bioconjugation reagents (Antos et al, 2016; Bentley et al, 2008; Maresso et al, 2006; Popp & Ploegh, 2011; Ritzefeld, 2014; Schmidt et al, 2017; Schmohl & Schwarzer, 2014; Tsukiji & Nagamune, 2009; Voloshchuk et al, 2016). Considerable effort has been put forth to elucidate the molecular mechanism of catalysis, class-specific structural features that dictate function, and the molecular basis of substrate recognition.…”

“…Sortases in pathogenic bacteria are frequently important virulence factors, as many of the proteins that they display have key roles in the infection process, such as promoting bacterial adhesion, nutrient acquisition, and the evasion and suppression of the immune response (Cascioferro, Totsika, & Schillaci, 2014; Schneewind & Missiakas, 2012, 2014; Siegel, Liu, & Ton-That, 2016; Spirig, Weiner, & Clubb, 2011). As a result, a significant amount of effort has been put forth to elucidate the mechanism of sortase-mediated catalysis and to discover small-molecule sortase inhibitors that could function as potent antiinfective agents (Bradshaw et al, 2015; Cascioferro et al, 2014; Clancy, Melvin, & McCafferty, 2010; Maresso & Schneewind, 2008; Suree, Jung, & Clubb, 2007). Moreover, sortases have been developed into valuable biochemical reagents to ligate distinct biomolecules together via a covalent peptide bond.…”

“…A number of excellent reviews have been written that describe the overall function of sortases in bacteria, their development as biochemical reagents, and efforts to discover therapeutically useful sortase inhibitors (Antos et al, 2016; Bradshaw et al, 2015; Cascioferro et al, 2014; Clancy et al, 2010; Maresso & Schneewind, 2008; Popp & Ploegh, 2011; Ritzefeld, 2014; Schmidt et al, 2017; Schmohl & Schwarzer, 2014; Schneewind & Missiakas, 2012, 2014; Siegel et al, 2016; Spirig et al, 2011; Suree et al, 2007; Voloshchuk et al, 2016). In this chapter, we review what is known about their atomic structures and the molecular basis of substrate recognition and catalysis.…”

Bacterial proteases, untapped antimicrobial drug targets

“…99 Sortases graft secreted proteins to the bacterial cell wall in Gram-positive bacteria, many of which are essential for infection and thus are potential targets for antivirulence compounds. 100 For example, synthetic 3,6-disubstituted triazolothiadiazole inhibitors of S. aureus sortase have shown efficacy in a mouse model of infection. 101 Indeed the role of proteases in bacterial virulence and infection is widespread across many species and here is an opportunity for antivirulence compounds that selectively target a narrow group of pathogens.…”

Етіологічна Терапія Бактеріальних Пневмоній Сьогодні Та В Майбутньому 3. Антибактеріальні Препарати, Що Розробляються

“…Таким образом, SrtA, катализируя закрепление факторов вирулентности на поверхности клеточной стенки стафилококков, энтерококков и стрепто-кокков, играет критическую роль в патогенезе ин-фекционного процесса, вызванного грамположи-тельными бактериями [6,10].…”