STRUCTURAL DETERMINANTS OF HALOENOL LACTONE-MEDIATED SUICIDE INHIBITION OF CANINE MYOCARDIAL CALCIUM-INDEPENDENT PHOSPHOLIPASE-A2

Haloenol lactones are potent mechanism im-based inhibitors of a novel class of calcium-independent phospholipases A2 Which have been implicated as the enzymic mediators of membrane dysfunction during myocardial ischemia (Hazen, S. L.; et al. J. Biol. Chem. 1991, 266,7227-7232). Herein we demonstrate that the ring size, hydrophobic group, and cryptic electrophile in the haloenol lactone moiety are important and modifiable determinants of the inhibitory potency of haloenol lactone-mediated inhibition of calcium-independent phospholipase A2. Direct comparisons between haloenol lactone-mediated inhibition of calcium-independent phospholipase A2 and the absence of inhibition with calcium-dependent phospholipase A2 further underscore the marked differences in the catalytic strategy employed by these two classes of intracellular phospholipases A2.