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  • Title: Thromboxane synthase catalyses hydroxylations of prostaglandin H2 analogs in the presence of iodosylbenzene.
    Author: Hecker M, Baader WJ, Weber P, Ullrich V.
    Journal: Eur J Biochem; 1987 Dec 15; 169(3):563-9. PubMed ID: 3691505.
    Abstract:
    Human platelet microsomes supplemented with iodosylbenzene converted the stable prostaglandin H2 analog 15(S)-hydroxy-11 alpha,9 alpha-epoxymethano-5(Z),13(E)-prostadienoic acid (U46619) into three metabolites (17.5% yield) which were not formed in the presence of specific thromboxane synthase inhibitors. The same three products were also formed among others by incubation of U46619 with liver microsomes from phenobarbital-pretreated rats with NADPH/O2 or with iodosylbenzene. The NADPH-supported metabolism of U46619 was suppressed in the presence of carbon monoxide. Combined gas chromatography/negative-ion chemical ionization mass spectrometry analysis revealed for all three compounds the incorporation of one oxygen atom which according to the electron impact fragmentation pattern had to be introduced either at the 9-methylene group or at the cyclopentane ring. The identification of these metabolites as 9 beta,15(S)-dihydroxy-11 alpha,9 alpha-epoxymethano-5(Z),13(E)-prostadienoic acid and the R and S isomer of 15(S)-hydroxy-11 alpha,9 alpha-(C-hydroxy-epoxymethano)-5(Z),13(E)-prostadienoic acid is only tentative since no reference compounds were available, but clearly thromboxane synthase was acting as an oxene transferase in this reaction. In contrast to U46619, its 9,11-epoxymethano isomer U44069 was found to be only a poor substrate for the oxene transferase activity of thromboxane synthase (1% yield) which indicates a preference for the 9-methylene group of U46619 which is orientated close to the heme iron of thromboxane synthase as evidenced by spectroscopic studies. Low-level chemiluminescence detected following incubation of iodosylbenzene with partly purified thromboxane synthase is in agreement with the formation of an activated (FeO)3+ oxygen species. In summary, these results point to a common role of the thiolate ligand in the oxygen activation mechanism by thromboxane and prostacyclin synthase and liver cytochrome P-450 monooxygenases.
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