We report an analysis of the mechanism of human group IIA secretory phospholipase A2 (sPLA2-IIA) inhibition by the natural anti-inflammatory sesterterpene petrosaspongiolide M (PM). The amphiphilic PM, a ghydroxybutenolide marine terpenoid, selectively reacts with the sPLA2-IIA Lys67 residue, located near the enzyme–membrane interfacial binding surface, and covalently modifies the enzyme through imine formation. Furthermore, PM is able to target the active site of sPLA2-IIA through several van der Waals/electrostatic complementarities. The two events cannot cooccur on a single PLA2 molecule, so they may contribute separately to enzyme inhibiton. A more intriguing hypothesis suggests a double interaction of PM with two enzyme molecules, one of them covalently modified and the other contacting the inhibitor through its active site. We have explored the occurrence of this unusual binding mode leading to PM-induced PLA2 supramolecular complexes. These insights could suggest new PLA2-inhibition-based therapeutic strategies.
The Binding Mode of Petrosaspongiolide M to the Human Group IIA Phospholipase A2: Exploring the Role of Covalent and Noncovalent Interactions in the Inhibition Process
MONTI, Maria Chiara;CASAPULLO, Agostino;TOSCO, ALESSANDRA;DAL PIAZ, FABRIZIO;MARGARUCCI, LUIGI;RICCIO, Raffaele
2009-01-01
Abstract
We report an analysis of the mechanism of human group IIA secretory phospholipase A2 (sPLA2-IIA) inhibition by the natural anti-inflammatory sesterterpene petrosaspongiolide M (PM). The amphiphilic PM, a ghydroxybutenolide marine terpenoid, selectively reacts with the sPLA2-IIA Lys67 residue, located near the enzyme–membrane interfacial binding surface, and covalently modifies the enzyme through imine formation. Furthermore, PM is able to target the active site of sPLA2-IIA through several van der Waals/electrostatic complementarities. The two events cannot cooccur on a single PLA2 molecule, so they may contribute separately to enzyme inhibiton. A more intriguing hypothesis suggests a double interaction of PM with two enzyme molecules, one of them covalently modified and the other contacting the inhibitor through its active site. We have explored the occurrence of this unusual binding mode leading to PM-induced PLA2 supramolecular complexes. These insights could suggest new PLA2-inhibition-based therapeutic strategies.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
