1. Free radical-dependent inhibition of prostaglandin endoperoxide H Synthase-2 by nitro-arachidonic acid.
- Author
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Wood I, Trostchansky A, Xu Y, Qian S, Radi R, and Rubbo H
- Subjects
- Anti-Inflammatory Agents metabolism, Anti-Inflammatory Agents pharmacology, Arachidonic Acid metabolism, Arachidonic Acid pharmacology, Biocatalysis, Cyclooxygenase 2 metabolism, Electron Spin Resonance Spectroscopy, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacology, Heme chemistry, Heme metabolism, Humans, Mass Spectrometry, Nitro Compounds metabolism, Nitro Compounds pharmacology, Prostaglandin H2 antagonists & inhibitors, Prostaglandin H2 biosynthesis, Protein Binding, Anti-Inflammatory Agents chemistry, Arachidonic Acid chemistry, Cyclooxygenase 2 chemistry, Enzyme Inhibitors chemistry, Nitro Compounds chemistry, Prostaglandin H2 chemistry
- Abstract
Prostaglandin endoperoxide H synthase (PGHS) is a heme-enzyme responsible for the conversion of arachidonic acid (AA) to prostaglandin H
2 (PGH2 ). PGHS have both oxygenase (COX) and peroxidase (POX) activities and is present in two isoforms (PGHS-1 and -2) expressed in different tissues and cell conditions. It has been reported that PGHS activity is inhibited by the nitrated form of AA, nitro-arachidonic acid (NO2 AA), which in turn could be synthesized by PGHS under nitro-oxidative conditions. Specifically, NO2 AA inhibits COX in PGHS-1 as well as POX in both PGHS-1 and -2, in a dose and time-dependent manner. NO2 AA inhibition involves lowering the binding stability and displacing the heme group from the active site. However, the complete mechanism remains to be understood. This review describes the interactions of PGHS with NO2 AA, focusing on mechanisms of inhibition and nitration. In addition, using a novel approach combining EPR-spin trapping and mass spectrometry, we described possible intermediates formed during PGHS-2 catalysis and inhibition. This literature revision as well as the results presented here strongly suggest a free radical-dependent inhibitory mechanism of PGHS-2 by NO2 AA. This is of relevance towards understanding the underlying mechanism of inhibition of PGHS by NO2 AA and its anti-inflammatory potential., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
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