Structural Determinants of Haloenol Lactone-Mediated Suicide Inhibition of Canine Myocardial Calcium-Independent Phospholipase A₂

Haloenol lactones are potent mechanism-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.