The binding mode of petrosaspongiolide M to the human group IIA phospholipase A(2): exploring the role of covalent and noncovalent interactions in the inhibition process.

We report an analysis of the mechanism of human group IIA secretory phospholipase A(2) (sPLA(2)-IIA) inhibition by the natural anti-inflammatory sesterterpene petrosaspongiolide M (PM). The amphiphilic PM, a gamma-hydroxybutenolide marine terpenoid, selectively reacts with the sPLA(2)-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 sPLA(2)-IIA through several van der Waals/electrostatic complementarities. The two events cannot co-occur on a single PLA(2) 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 PLA(2) supramolecular complexes. These insights could suggest new PLA(2)-inhibition-based therapeutic strategies.