Dipartimento di Scienze Farmaceutiche e Biomediche, Università degli Studi di Salerno, Via Ponte Don Melillo, 84084 Fisciano, Italy.
Chembiochem. 2011 Nov 25;12(17):2686-91. doi: 10.1002/cbic.201100478. Epub 2011 Sep 27.
The molecular basis for human group IIA phospholipase A(2) inactivation by the marine natural product cladocoran A (CLD A) has been studied in order to elucidate its relevant anti-inflammatory properties. Indeed, secretory phospholipases A(2) are well-known to be implicated in the pathogenesis of inflammation, such as rheumatoid arthritis, septic shock, psoriasis and asthma, thus the understanding of their inactivation mechanism could be useful for the development of new chemical classes of selective inhibitors. Our results, collected by a combination of biochemical approaches, advanced mass spectrometry and molecular modeling, suggest a competitive inhibition mechanism guided by a noncovalent molecular recognition event, and disclose the key role of the CLD A γ-hydroxybutenolide ring in the chelation of the catalytic calcium ion inside the enzyme active site. Moreover, CLD A is able to react selectively with Ser82, although this covalent event seems to play a secondary role in terms of enzyme inhibition.
为了阐明其相关的抗炎特性，研究了海洋天然产物 cladocoran A (CLD A) 使人类 IIA 组磷脂酶 A(2)失活的分子基础。事实上，分泌型磷脂酶 A(2)被认为与炎症的发病机制有关，如类风湿性关节炎、败血症性休克、银屑病和哮喘，因此了解其失活机制可能有助于开发新的选择性抑制剂化学类别。我们的研究结果结合了生化方法、先进的质谱和分子建模，表明这是一种由非共价分子识别事件引导的竞争性抑制机制，并揭示了 CLD A γ-羟基丁烯内酯环在螯合酶活性位点内催化钙离子中的关键作用。此外，CLD A 能够选择性地与 Ser82 反应，尽管这一共价事件在酶抑制方面似乎起着次要作用。
