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

Lori A. Zupan, Randy H. Weiss, Stanley L. Hazen, Barry L. Parnas, Karl W. Aston, Patrick J. Lennon, Daniel P. Getman, Richard W. Gross

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)95-100
Number of pages6
JournalJournal of Medicinal Chemistry
Volume36
Issue number1
DOIs
StatePublished - Jan 1 1993

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