title: The inactivation mechanism of human group IIA phospholipase A(2) by Scalaradial.
abstract: Secretory phospholipases A(2) (sPLA(2)s) are implicated in the pathogenesis of several inflammation diseases, such as rheumatoid arthritis, septic shock, psoriasis, and asthma. Thus, an understanding of their inactivation mechanisms could be useful for the development of new classes of chemical selective inhibitors. In the marine environment, several bioactive terpenoids possess interesting anti-inflammatory activity, often through covalent and/or noncovalent inactivation of sPLA(2). Herein, we report the molecular mechanism of human group IIA phospholipase A(2) (sPLA(2)-IIA) inactivation by Scalaradial (SLD), a marine 1,4-dialdehyde terpenoid isolated from the sponge Cacospongia mollior and endowed with a significant anti-inflammatory profile. Our results have been collected by a combination of biochemical approaches, advanced mass spectrometry, surface plasmon resonance, and molecular modeling. These suggest that SLD acts as a competitive inhibitor. Indeed, the sPLA(2)-IIA inactivation process seems to be driven by the noncovalent recognition process of SLD in the enzyme active site and by chelation of the catalytic calcium ion. In contrast, covalent modification of the enzyme by the SLD dialdehyde moiety emerges as only a minor side event in the ligand-enzyme interaction. These results could be helpful for the rational design of new PLA(2) inhibitors that would be able to selectively target the enzyme active site.
authors.affiliation: Dipartimento di Scienze Farmaceutiche e Biomediche, Università degli Studi di Salerno, Via Ponte Don Melillo, 84084 Fisciano, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Margarucci
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Monti
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Chini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tosco
authors.forename: Raffaele
authors.initials: R
authors.lastname: Riccio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
authors.forename: Agostino
authors.initials: A
authors.lastname: Casapullo
mesh_terms: D000818:Animals; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D054501:Group II Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006718:Homosteroids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D013058:Mass Spectrometry; D008958:Models, Molecular; D011161:Porifera / Q000737:chemistry*; D054830:Sesterterpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001688:Biological Products; D006718:Homosteroids; D054830:Sesterterpenes; C071197:scalaradial; D054501:Group II Phospholipases A2; C516287:PLA2G2A protein, human