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Originally published In Press as doi:10.1074/jbc.M100628200 on March 14, 2001

J. Biol. Chem., Vol. 276, Issue 23, 19879-19888, June 8, 2001
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Peroxidase Self-inactivation in Prostaglandin H Synthase-1 Pretreated with Cyclooxygenase Inhibitors or Substituted with Mangano Protoporphyrin IX*

Gang WuDagger , Jennifer L. Vuletich§, Richard J. KulmaczDagger , Yoichi Osawa§, and Ah-Lim TsaiDagger

From the Dagger  Division of Hematology, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030 and the § Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109

Self-inactivation imposes an upper limit on bioactive prostanoid synthesis by prostaglandin H synthase (PGHS). Inactivation of PGHS peroxidase activity has been found to begin with Intermediate II, which contains a tyrosyl radical. The structure of this radical is altered by cyclooxygenase inhibitors, such as indomethacin and flurbiprofen, and by replacement of heme by manganese protoporphyrin IX (forming MnPGHS-1). Peroxidase self-inactivation in inhibitor-treated PGHS-1 and MnPGHS-1 was characterized by stopped-flow spectroscopic techniques and by chromatographic and mass spectrometric analysis of the metalloporphyrin. The rate of peroxidase inactivation was about 0.3 s-1 in inhibitor-treated PGHS-1 and much slower in MnPGHS-1 (0.05 s-1); as with PGHS-1 itself, the peroxidase inactivation rates were independent of peroxide concentration and structure, consistent with an inactivation process beginning with Intermediate II. The changes in metalloporphyrin absorbance spectra during inactivation of inhibitor-treated PGHS-1 were similar to those observed with PGHS-1 but were rather distinct in MnPGHS-1; the kinetics of the spectral transition from Intermediate II to the next species were comparable to the inactivation kinetics in each case. In contrast to the situation with PGHS-1 itself, significant amounts of heme degradation occurred during inactivation of inhibitor-treated PGHS-1, producing iron chlorin and heme-protein adduct species. Structural perturbations at the peroxidase site (MnPGHS-1) or at the cyclooxygenase site (inhibitor-treated PGHS-1) thus can influence markedly the kinetics and the chemistry of PGHS-1 peroxidase inactivation.

* This work was supported in part by United States Public Health Service Grants GM44911 (to A.-L. T.), GM52170 (to R. J. K.), and ES08365 (to Y. O.), Training Grant GM07767 (to J. L. V.), and CA165954 (to Paul F. Hollenberg.), and by a Burrow Wellcome Fund new investigator award in toxicology (to Y. O.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Division of Hematology, Dept. of Internal Medicine, University of Texas Health Science Center, P. O. Box 20708, Houston, TX 77225. Tel.: 713-500-6771; Fax: 713-500-6810; E-mail: ah-lim.tsai@uth.tmc.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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