PLA2-mediated catalytic activation of its inhibitor 25-acetyl-petrosaspongiolide M: serendipitous identification of a new PLA2 suicide inhibitor.
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.
Monti
M C
MC
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy.
Casapullo
A
A
Riccio
R
R
Gomez-Paloma
L
L
D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D054501:Group II Phospholipases A2; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008024:Ligands; D013058:Mass Spectrometry; D015394:Molecular Structure; D008970:Molecular Weight; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D011161:Porifera / Q000737:chemistry; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D021241:Spectrometry, Mass, Electrospray Ionization; D013696:Temperature
D004791:Enzyme Inhibitors; D008024:Ligands; C118309:petrosaspongiolide m; D009828:Oleanolic Acid; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2