Cell wall‐anchored 5′‐nucleotidases in Gram‐positive cocci

Abstract

5′‐nucleotidases (5′‐NTs) are enzymes that catalyze the hydrolysis of nucleoside monophosphates to produce nucleosides and phosphate. Since the identification of adenosine synthase A (AdsA) in Staphylococcus aureus in 2009, several other 5′‐NTs have been discovered in Gram‐positive cocci, mainly in streptococci. Despite some differences in substrate specificity, pH range and metal ion requirements, all characterized 5′‐NTs use AMP and ADP, and in some cases ATP, to produce the immunosuppressive adenosine, which dampens pro‐inflammatory immune responses. Several 5′‐NTs are also able to use dAMP as substrate to generate deoxy‐adenosine which is cytotoxic for macrophages. A synergy between 5′‐NTs and exonucleases which are commonly expressed in Gram‐positive cocci has been described, where the nucleases provide dAMP as a cleavage product from DNA. Some of these nucleases produce dAMP by degrading the DNA backbone of neutrophil extracellular traps (NETs) resulting in a “double hit” strategy of immune evasion. This Micro Review provides an overview of the biochemical properties of Gram‐positive cell wall‐anchored 5′‐NTs and their role as virulence factors. A potential use of 5′‐NTs for vaccine development is also briefly discussed.

Staphylococcus aureus induces neutrophil extracellular traps (NETs) and neutralizes their bactericidal potential

“…In a study performed to examine the potential role of S. aureus nuclease in NET degradation and virulence in a murine respiratory tract infection model, Berends et al showed that an isogenic deficient-nuclease mutant lacked the ability to degrade NETs compared with the parental strain and consequently appeared to be more susceptible to extracellular killing by activated neutrophils. On the contrary, nuclease expression by S. aureus enhanced the escape of bacteria from NETs in an in vivo mouse model of S. aureus respiratory tract injection [51] . In a more detailed study Thammavongsa and colleagues found that S. aureus escapes host defenses by converting DNA in NETs to deoxyadenosine (dAdo) through the concerted action of two enzymes, nuclease and adenosine synthase (AdsA).…”

Microbial 5′-nucleotidases: their characteristics, roles in cellular metabolism, and possible practical applications

“…Vaccines act as a tool to prevent life-threatening diseases caused by pathogenic bacteria, to reduce the use of antibiotics, and to alleviate the problem of antimicrobial resistance. Cell wall–anchored 5′-nucleotidases from gram-positive cocci, many of which are the most significant human bacterial pathogens, have characteristics that make them promising candidates for vaccine development (Soh et al 2020 ). These characteristics are the high level of sequence conservation among 5′-nucleotidase-encoding genes, the accessibility of the enzymes at the cell surface, the presence of these pathogens in a wide variety of clinical isolates, and their important role as virulence factors in immune evasions.…”

Staphylococcus aureus nt5 gene contributes to bacterial infection ability to form kidney abscess

“…The copyright holder for this preprint this version posted February 10, 2022. ; https://doi.org/10.1101/2022.02.09.479838 doi: bioRxiv preprint 4 genes py (gi 487015361) and adk (gi 488431505) are essential in nt5-mediated adenine metabolism of S. aureus (7). DAP disrupts kinase activity of py-encoding pyruvate kinase (PY, protein ID: ODV52833.1) and ADK (protein ID: WP_002500890.1) to mediate adenine metabolism pathway (6).…”

“…The downregulation of nt 5 (gi 446956624) upon DAP exposure leads to decrease of bacterial membrane potential and disruption of cell membrane, which contributes to bacterial DNA rapid release and finally causes bacteria death (6). Both genes py (gi 487015361) and adk (gi 488431505) are essential in nt 5-mediated adenine metabolism of S. aureus (7). DAP disrupts kinase activity of py- encoding pyruvate kinase (PY, protein ID: ODV52833.1) and ADK (protein ID: WP_002500890.1) to mediate adenine metabolism pathway (6).…”