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

doi:10.1021/jm00053a012

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 journal › Article › peer-review

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 language	English
Pages (from-to)	95-100
Number of pages	6
Journal	Journal of Medicinal Chemistry
Volume	36
Issue number	1
DOIs	https://doi.org/10.1021/jm00053a012
State	Published - Jan 1 1993

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title = "Structural Determinants of Haloenol Lactone-Mediated Suicide Inhibition of Canine Myocardial Calcium-Independent Phospholipase A2",

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.",

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

year = "1993",

month = jan,

day = "1",

doi = "10.1021/jm00053a012",

language = "English",

volume = "36",

pages = "95--100",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

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Structural Determinants of Haloenol Lactone-Mediated Suicide Inhibition of Canine Myocardial Calcium-Independent Phospholipase A₂. / Zupan, Lori A.; Weiss, Randy H.; Hazen, Stanley L.; Parnas, Barry L.; Aston, Karl W.; Lennon, Patrick J.; Getman, Daniel P.; Gross, Richard W.

In: Journal of Medicinal Chemistry, Vol. 36, No. 1, 01.01.1993, p. 95-100.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Structural Determinants of Haloenol Lactone-Mediated Suicide Inhibition of Canine Myocardial Calcium-Independent Phospholipase A2

AU - Zupan, Lori A.

AU - Weiss, Randy H.

AU - Hazen, Stanley L.

AU - Parnas, Barry L.

AU - Aston, Karl W.

AU - Lennon, Patrick J.

AU - Getman, Daniel P.

AU - Gross, Richard W.

PY - 1993/1/1

Y1 - 1993/1/1

N2 - 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.

AB - 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.

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DO - 10.1021/jm00053a012

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JO - Journal of Medicinal Chemistry

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SN - 0022-2623

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

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