PLA2-mediated catalytic activation of its inhibitor 25-acetyl-petrosaspongiolide M: serendipitous identification of a new PLA2 suicide inhibitor

FEBS Lett. 2004 Dec 17;578(3):269-74. doi: 10.1016/j.febslet.2004.10.100.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Binding Sites
  • Catalysis
  • Chromatography, High Pressure Liquid
  • Circular Dichroism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Group II Phospholipases A2
  • Hydrogen-Ion Concentration
  • Hydrolysis
  • Kinetics
  • Ligands
  • Mass Spectrometry
  • Molecular Structure
  • Molecular Weight
  • Oleanolic Acid / analogs & derivatives*
  • Oleanolic Acid / chemistry
  • Oleanolic Acid / pharmacology*
  • Phospholipases A / metabolism*
  • Phospholipases A2
  • Porifera / chemistry
  • Protein Conformation
  • Protein Structure, Secondary
  • Spectrometry, Mass, Electrospray Ionization
  • Temperature

Substances

  • Enzyme Inhibitors
  • Ligands
  • petrosaspongiolide m
  • Oleanolic Acid
  • Phospholipases A
  • Group II Phospholipases A2
  • Phospholipases A2