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

Maria Chiara Monti, Agostino Casapullo, Claudio N. Cavasotto, Alessandra Tosco, Fabrizio Dal Piaz, Arturas Ziemys, Luigi Margarucci, Raffaele Riccio

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

We report an analysis of the mechanism of human group HA secretory phospholipase A2 (sPLA2-IIA) inhibition by the natural anti-inflammatory sesterterpene petrosaspongiolide M (PM). The amphiphilic PM, a λ-hydroxybutenolide marine terpenoid, selectively reacts with the sPLA,-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 PLA 2 supramolecular complexes. These insights could suggest new PLA,-inhibition-based therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)1155-1163
Number of pages9
JournalChemistry - A European Journal
Volume15
Issue number5
DOIs
StatePublished - Jan 19 2009

Keywords

  • Enzymes
  • Inhibitors
  • Natural products
  • Phospholipases
  • Protein interactions

ASJC Scopus subject areas

  • Chemistry(all)

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