Metallopeptidase (Sapep) Staphylococcus Aureus

Abstract

Abstract Proteases belonging to the M20 family are characterized by diverse substrate specificity. This feature can be rationalized by the conformational adaptability of the active site in these enzymes. The Staphylococcus aureus metallodipeptidase, Sapep, is a member of the aminoacylase‐I/M20 family. These enzymes play a role in the final steps of intracellular protein degradation. The crystal structure of Sapep was determined in the apo form and in complex with a manganese cofactor. These structures reveal large interdomain movements between the apo (inactive) and the manganese‐bound (active) conformation. The conformational changes between the catalytic and lid domains could potentially regulate the activity of this enzyme. This interdomain reorientation between the catalytic and lid domains on substrate binding is also seen in other proteins of the M20 family and related enzymes. A noteworthy difference between Sapep and other homologues is the finding that the inactive conformation is stabilized by a disulfide bond between two cysteine residues, Cys155 and Cys178. Although these cysteines are not part of the active site, the reduced form of this enzyme is more active as a peptidase. The catalytic activity of Sapep is thus likely to be regulated by redox stimuli. These findings are relevant as it has been observed that this enzyme is active only in methicillin resistant Staphylococcus aureus Methicillin Resistant Staphylococcus Aureus (MRSA) and demonstrates β‐lactamase activity in these strains.