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Suicide inhibition of canine myocardial cytosolic calcium-independent phospholipase A2. Mechanism-based discrimination between calcium-dependent and -independent phospholipases A2.
Open accessAbstract
The majority of phospholipase A2 activity in myocardium is calcium-independent and selective for hydrolysis of plasmalogen substrate (Wolf, R. A., and Gross, R. W. (1985) J. Biol. Chem. 260, 7295-7303; Hazen, S. L., Stuppy, R. J., and Gross, R. W. (1990) J. Biol. Chem. 265, 10622-10630). Accordingly, identification of an inhibitor which selectively targets calcium-independent phospholipases A2 would facilitate elucidation of the biologic significance of this class of intracellular phospholipases. We now report that the haloenol lactone, (E)-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (Compound 1), is a potent, irreversible, mechanism-based inhibitor of myocardial calcium-independent phospholipase A2 which is greater than 1000-fold specific for inhibition of myocardial calcium-independent phospholipase A2 in comparisons with multiple calcium-dependent phospholipases A2. Mechanism-based inhibition of myocardial cytosolic calcium-independent phospholipase A2 by Compound 1 was established by demonstrating: 1) time-dependent irreversible inactivation; 2) covalent binding of [3H]Compound 1 to the purified phospholipase A2; 3) ablation of covalent binding of [3H]Compound 1 after chemical inactivation of phospholipase A2 enzymic activity; 4) identical inhibition of myocardial phospholipase A2 by Compound 1 in the absence or presence of nucleophilic scavengers; 5) Compound 1 is a substrate for myocardial calcium-independent phospholipase A2 resulting in the generation of the electrophilic alpha-bromomethyl ketone; 6) phospholipase A2 inhibition requires the in situ generation of the reactive electrophile (i.e. neither the alpha-bromomethyl ketone nor the diproteoenol lactone analog are inhibitory); and 7) concomitant attenuation of the inhibitory potency and the extent of covalent adduct formation in the presence of saturating substrate. Collectively, these results demonstrate that the haloenol lactone, Compound 1, is a substrate for, covalently binds to, and irreversibly inhibits canine myocardial cytosolic calcium-independent phospholipase A2.
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Citations
Cited by
Dennis, E. A., Cao, J., Hsu, Y.-H., Magrioti, V., & Kokotos, G. (2011) · Chemical Reviews · doi:10.1021/cr200085w · Cited by 1,203
REGULATION AND INHIBITION OF PHOSPHOLIPASE A2
Balsinde, J., Balboa, M. A., Insel, P. A., & Dennis, E. A. (1999) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.39.1.175 · Cited by 566
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Self-citationCadas, H., di Tomaso, E., & Piomelli, D. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-04-01226.1997 · Cited by 396
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Metadata
- Authors
- Hazen, S. L., Zupan, L. A., Weiss, R. H., Getman, D. P., & Gross, R. W.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1991-04
- Volume
- 266
- Issue
- 11
- Pages
- 7227-7232
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1511017475
- Cited by
- 303
- References
- 0
- FWCI
- 3.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- CoChat. (2026). Citation check: Suicide inhibition of canine myocardial cytosolic calcium-independent phospholipase A2. Mechanism-based discrimination between calcium-dependent and -independent phospholipases A2. https://app.cochat.ai/papers/10.1016/s0021-9258(20)89634-3
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- Hazen, S. L., Zupan, L. A., Weiss, R. H., Getman, D. P., & Gross, R. W. (1991). Suicide inhibition of canine myocardial cytosolic calcium-independent phospholipase A2. Mechanism-based discrimination between calcium-dependent and -independent phospholipases A2. Journal of Biological Chemistry. https://doi.org/10.1016/s0021-9258(20)89634-3
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