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.
Zupan
L A
LA
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
Weiss
R H
RH
Hazen
S L
SL
Parnas
B L
BL
Aston
K W
KW
Lennon
P J
PJ
Getman
D P
DP
Gross
R W
RW
D000818:Animals; D004285:Dogs; D006321:Heart / Q000187:drug effects; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009206:Myocardium / Q000201:enzymology; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D007783:Lactones; D010741:Phospholipases A; D054467:Phospholipases A2