PLA2-mediated catalytic activation of its inhibitor 25-acetyl-petrosaspongiolide M: serendipitous identification of a new PLA2 suicide inhibitor |
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Authors: | Monti M C Casapullo A Riccio R Gomez-Paloma L |
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Affiliation: | Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy. |
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Abstract: | 25-Acetyl-petrosaspongiolide M (PMAc) (1), a mild non-covalent PLA(2) inhibitor, unexpectedly recovers, after incubation with bvPLA(2), the ability to covalently modify the enzyme target. This study demonstrates the catalytic effect of bvPLA(2) in converting 1 in its deacetylated congener petrosaspongiolide M (PM) (2), a strong covalent PLA(2) inhibitor whose molecular mechanism of inhibition has already been clarified. Moreover, our findings outline the potential role of PMAc as anti-inflammatory pro-drug, by virtue of its ability of delivering the active PM agent at the site of inflammation, functioning as a suicide inhibitor. |
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Keywords: | PLA2, Phospholipase A2 bvPLA2, bee venom PLA2 (PDB code: 1POC) DOPG, dioleoylphosphatidylglycerol SUV’s, small unilamellar vesicles RP-HPLC, Reverse Phase-High Performance Liquid Cromatography ESI-MS, electrospray mass spectrometry TFA, trifluoroacetic acid CD, circular dichroism |
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