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Papers In Press, published online ahead of print February 9, 2006
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Center of Vascular Biology, Weill Medical College of Cornell University, New York City, NY 10021
Corresponding Author: rsdeeb{at}med.cornell.edu
The mechanism by which the inflammatory enzyme prostaglandin H2 synthase-1 (PGHS-1) deactivates remains undefined. This study aimed to determine stabilizing parameters of PGHS-1 and identify factors leading to deactivation by nitrogen oxide species (NOx). Purified PGHS-1 was stabilized when solubilized in ß-octylglucoside (rather than Tween-20 or CHAPS) and when reconstituted with hemin chloride (rather than hematin). Peroxynitrite (ONOO- ) activated the peroxidase site of PGHS-1 independently of the cyclooxygenase site. Following ONOO- exposure, holoPGHS-1 could not metabolize arachidonic acid and was structurally compromised, whereas apoPGHS-1 retained full activity once reconstituted with heme. After incubation of holoPGHS-1 with ONOO-, heme absorbance was diminished but to a lesser extent than the loss in enzymatic function, suggesting the contribution of more than one process to enzyme inactivation. Hydroperoxide scavengers improved enzyme activity, whereas hydroxyl radical (•OH) scavengers provided no protection from the effects of ONOO-. Mass spectral analyses revealed that Tyr 385 is a target for nitration by ONOO- only when heme is present. Multimer formation was also observed and required heme but could be attenuated by arachidonic acid substrate. We conclude that the heme plays a role in catalyzing Tyr 385 nitration by ONOO- and the demise of PGHS-1.
Revised on January 20, 2006
Accepted on February 9, 2006
Heme catalyzes Tyr385 nitration and inactivation of prostaglandin H2 synthase-1 by peroxynitrite
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