Monti Maria Chiara, Casapullo Agostino, Cavasotto Claudio N, Tosco Alessandra, Dal Piaz Fabrizio, Ziemys Arturas, Margarucci Luigi, Riccio Raffaele
Dipartimento di Scienze Farmaceutiche, Università di Salerno, Via Ponte Don Melillo, 84084 Fisciano, Italy.
Chemistry. 2009;15(5):1155-63. doi: 10.1002/chem.200801512.
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.
我们报告了对天然抗炎倍半萜岩海绵内酯M（PM）抑制人IIA组分泌型磷脂酶A2（sPLA(2)-IIA）机制的分析。两亲性的PM是一种γ-羟基丁烯内酯海洋萜类化合物，它选择性地与位于酶-膜界面结合表面附近的sPLA(2)-IIA Lys67残基反应，并通过形成亚胺共价修饰该酶。此外，PM能够通过几种范德华力/静电互补作用靶向sPLA(2)-IIA的活性位点。这两个事件不能在单个PLA(2)分子上同时发生，因此它们可能分别对酶抑制起作用。一个更有趣的假设提出PM与两个酶分子存在双重相互作用，其中一个被共价修饰，另一个通过其活性位点与抑制剂接触。我们探索了这种导致PM诱导的PLA(2)超分子复合物的异常结合模式的存在情况。这些见解可能为基于PLA(2)抑制的新治疗策略提供思路。
