MECHANISMS THAT REGULATE ENZYMES THAT METABOLIZE CIS UNSATURATED FATTY ACIDS

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Summary of Work: The goal is to develop an understanding of the biochemical mechanisms responsible for the metabolism of arachidonic acid and linoleic acid. Studies with PGHS-1 indicate that a tyrosyl radical is formed which could be the reactive intermediate that initiates arachidonic acid oxygenation. Recently, we have shown that NO reacts with the tyrosyl radical converting the radical to a new radical characterized by ESR analysis as an iminoxyl radical. The iminoxyl radical decays to nitrotyrosine resulting in the nitration of the tyrosine moiety on PHS. In addition, its formation of nitrotyrosine is often used as an indicator of oxidative stress. We have identified the specific tyrosine moiety in PHS nitrated by the reaction of NO with tyrosyl radical as Tyrosine-385. This indicates that tyrosine-385 is oxidized to tyrosyl radical during catalysis and suggests this residue is a likely active site or is the site of enzyme inactivation. Future studies will focus on understanding the interaction of Cox tyrosine radical with NO and its effect on Cox activity. In addition, we are currently testing the hypothesis that measurement of nitrotyrosine, a marked for oxidative stress, occur mainly by the interaction of metabolically active Cox-2 and NO formed by iNOS. Understanding the biochemical mechanisms which regulate the activities and expression of these enzymes will provide new insights into potentially controlling or preventing these disease conditions. - Prostaglandin-H-synthase, COX-1, COX-2, tyrosyl radical