title: Staphylococcus aureus lactate- and malate-quinone oxidoreductases contribute to nitric oxide resistance and virulence.
abstract: Staphylococcus aureus is a Gram-positive pathogen that resists many facets of innate immunity including nitric oxide (NO·). Staphylococcus aureus NO-resistance stems from its ability to evoke a metabolic state that circumvents the negative effects of reactive nitrogen species. The combination of l-lactate and peptides promotes S. aureus growth at moderate NO-levels, however, neither nutrient alone suffices. Here, we investigate the staphylococcal malate-quinone and l-lactate-quinone oxidoreductases (Mqo and Lqo), both of which are critical during NO-stress for the combined utilization of peptides and l-lactate. We address the specific contributions of Lqo-mediated l-lactate utilization and Mqo-dependent amino acid consumption during NO-stress. We show that Lqo conversion of l-lactate to pyruvate is required for the formation of ATP, an essential energy source for peptide utilization. Thus, both Lqo and Mqo are essential for growth under these conditions making them attractive candidates for targeted therapeutics. Accordingly, we exploited a modelled Mqo/Lqo structure to define the catalytic and substrate-binding residues.We also compare the S. aureus Mqo/Lqo enzymes to their close relatives throughout the staphylococci and explore the substrate specificities of each enzyme. This study provides the initial characterization of the mechanism of action and the immunometabolic roles for a newly defined staphylococcal enzyme family.
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors: Nicole A
authors: NA
authors: Spahich
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors: Nicholas P
authors: NP
authors: Vitko
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors: Lance R
authors: LR
authors: Thurlow
authors: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors: Brenda
authors: B
authors: Temple
authors: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors: Anthony R
authors: AR
authors: Richardson
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000596:Amino Acids / Q000378:metabolism; D002384:Catalysis; D019344:Lactic Acid / Q000737:chemistry* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010088:Oxidoreductases / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D013211:Staphylococcus aureus / Q000201:enzymology* / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity*; D013379:Substrate Specificity; D014774:Virulence
chemical_list: D000596:Amino Acids; D010455:Peptides; D009569:Nitric Oxide; D019344:Lactic Acid; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D010088:Oxidoreductases; C471971:malate dehydrogenase, FAD-dependent