Slow- and tight-binding inhibitors of the 85-kDa human phospholipase A2

A trifluoromethyl ketone analogue of arachidonic acid in which the COOH group is replaced with COCF 3 (AACOCF 3 ) was prepared and found to be a tight- and slow-binding inhibitor of the 85-kDa cytosolic human phospholipase A 2 (cPLA 2 ). Enzyme inhibition was observed when AACOCF 3 was tested in assays using either phospholipid vesicles or phospholipid/Triton X-100 mixed micelles. The fact that the inhibition developed over several minutes in both assays establishes that AACOCF 3 inhibits by direct binding to the enzyme rather than by decreasing the fraction of enzyme bound to the substrate interface