Abstract
BackgroundStaphylococcus aureus is a human pathogen that produces extracellular adenosine to evade clearance by the host immune system, an activity attributed to the 5'-nucleotidase activity of adenosine synthase (AdsA). In mammals, conversion of adenosine triphosphate to adenosine is catalyzed in a two-step process: ecto-nucleoside triphosphate diphosphohydrolases (ecto-NTDPases) hydrolyze ATP and ADP to AMP, whereas 5'-nucleotidases hydrolyze AMP to adenosine. NTPDases harbor apyrase conserved regions (ACRs) that are critical for activity.ResultsNTPDase ACR motifs are absent in AdsA, yet we report here that recombinant AdsA hydrolyzes ADP and ATP in addition to AMP. Competition assays suggest that hydrolysis occurs following binding of all three substrates at a unique site. Alanine substitution of two amino acids, aspartic acid 127 and histidine 196 within the 5'-nucleotidase signature sequence, leads to reduced AMP or ADP hydrolysis but does not affect the binding of these substrates.ConclusionCollectively, these results provide insight into the unique ability of AdsA to produce adenosine through the consecutive hydrolysis of ATP, ADP and AMP, thereby endowing S. aureus with the ability to modulate host immune responses.
Highlights
Staphylococcus aureus is a human pathogen that produces extracellular adenosine to evade clearance by the host immune system, an activity attributed to the 5’-nucleotidase activity of adenosine synthase (AdsA)
We recently reported that S. aureus AdsA, a cell wall anchored protein, is a 5’-nucleotidase that catalyzes the conversion of adenosine monophosphates (AMP) to adenosine
AdsA hydrolyzes adenosine nucleoside tri- and diphosphates We have previously shown that S. aureus AdsA hydrolyzes AMP to produce adenosine [31]
Summary
Staphylococcus aureus is a human pathogen that produces extracellular adenosine to evade clearance by the host immune system, an activity attributed to the 5’-nucleotidase activity of adenosine synthase (AdsA). S. aureus produces numerous virulence factors that contribute to its ability to cause disease [2,3,4]. These include several toxins that are known for their detrimental effects on host cells [5,6], in particular cells of the immune system [7,8]. Excessive inflammation can be detrimental to the host due to the prolonged presence of activated immune cells as well as the leakage of proteases and other noxious agents that damage surrounding tissues. A delicate balance of proand anti-inflammatory mediators is critical to prevent extensive inflammation
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