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Nitroarachidonic Acid, a Novel Peroxidase Inhibitor of Prostaglandin Endoperoxide H Synthases 1 and 2

Trostchansky, A., Bonilla, L., Thomas, Christopher P., O'Donnell, Valerie Bridget, Marnett, L. J., Radi, R. and Rubbo, H. 2011. Nitroarachidonic Acid, a Novel Peroxidase Inhibitor of Prostaglandin Endoperoxide H Synthases 1 and 2. Journal of Biological Chemistry 286 (15) , pp. 12891-12900. 10.1074/jbc.M110.154518

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Abstract

Prostaglandin endoperoxide H synthase (PGHS) catalyzes the oxidation of arachidonate to prostaglandin H2. We have previously synthesized and chemically characterized nitroarachidonic acid (AANO2), a novel anti-inflammatory signaling mediator. Herein, the interaction of AANO2 with PGHS was analyzed. AANO2 inhibited oxygenase activity of PGHS-1 but not PGHS-2. AANO2 exhibited time- and concentration-dependent inhibition of peroxidase activity in both PGHS-1 and -2. The plot of kobs versus AANO2 concentrations showed a hyperbolic function with kinact = 0.045 s−1 and Ki*app = 0.019 μM for PGHS-1 and kinact = 0.057 s−1 and Ki*app = 0.020 μM for PGHS-2. Kinetic analysis suggests that inactivation of PGHS by AANO2 involves two sequential steps: an initial reversible binding event (described by Ki) followed by a practically irreversible event (Ki*app) leading to an inactivated enzyme. Inactivation was associated with irreversible disruption of heme binding to the protein. The inhibitory effects of AANO2 were selective because other nitro-fatty acids tested, such as nitrooleic acid and nitrolinoleic acid, were unable to inhibit enzyme activity. In activated human platelets, AANO2 significantly decreased PGHS-1-dependent thromboxane B2 formation in parallel with a decrease in platelet aggregation, thus confirming the biological relevance of this novel inhibitory pathway.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > Q Science (General)
R Medicine > R Medicine (General)
Uncontrolled Keywords: Arachidonic Acid; Cyclooxygenase (COX)Pathway; Enzyme Inhibitors; Lipid Oxidation; Nitric Oxide; Platelet
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Last Modified: 04 Jun 2017 03:43
URI: http://orca.cf.ac.uk/id/eprint/25393

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