title: Observation of an unusual electronically distorted semiquinone radical of PCB metabolites in the active site of prostaglandin H synthase-2.
abstract: The activation of the metabolites of airborne polychlorinated biphenyls (PCBs) into highly reactive radicals is of fundamental importance. We found that human recombinant prostaglandin H synthase-2 (hPGHS-2) biotransforms dihydroxy-PCBs, such as 4-chlorobiphenyl-2',5'-hydroquinone (4-CB-2',5'-H(2)Q), into semiquinone radicals via one-electron oxidation. Using electron paramagnetic resonance (EPR) spectroscopy, we observed the formation of the symmetric quartet spectrum (1:3:3:1 by area) of 4-chlorobiphenyl-2',5'-semiquinone radical (4-CB-2',5'-SQ()(-)) from 4-CB-2',5'-H(2)Q. This spectrum changed to an asymmetric spectrum with time: the change can be explained as the overlap of two different semiquinone radical species. Hindered rotation of the 4-CB-2',5'-SQ()(-) appears not to be a major factor for the change in lineshape because increasing the viscosity of the medium with glycerol produced no significant change in lineshape. Introduction of a fluorine, which increases the steric hindrance for rotation of the dihydroxy-PCB studied, also produced no significant changes. An in silico molecular docking model of 4-CB-2',5'-H(2)Q in the peroxidase site of hPGHS-2 together with ab initio quantum mechanical studies indicate that the close proximity of a negatively charged carboxylic acid in the peroxidase active site may be responsible for the observed perturbation in the spectrum. This study provides new insights into the formation of semiquinones from PCB metabolites and underscores the potential role of PGHS-2 in the metabolic activation of PCBs.
authors.affiliation: Department of Occupational and Environmental Health, The University of Iowa, 100 Oakdale Campus, Iowa City, IA 52242-5000, USA.
authors.forename: Orarat
authors.initials: O
authors.lastname: Wangpradit
authors.forename: Edelmiro
authors.initials: E
authors.lastname: Moman
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Nolan
authors.forename: Garry R
authors.initials: GR
authors.lastname: Buettner
authors.forename: Larry W
authors.initials: LW
authors.lastname: Robertson
authors.forename: Gregor
authors.initials: G
authors.lastname: Luthe
mesh_terms: D016718:Arachidonic Acid / Q000032:analysis / Q000737:chemistry; D016227:Benzoquinones / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D003198:Computer Simulation; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D004785:Environmental Pollutants / Q000737:chemistry* / Q000378:metabolism; D005480:Flurbiprofen / Q000737:chemistry / Q000378:metabolism; D006427:Hemin / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008956:Models, Chemical; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000378:metabolism; D011402:Pronase / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D004785:Environmental Pollutants; D016718:Arachidonic Acid; C025232:semiquinone radicals; D005480:Flurbiprofen; D006427:Hemin; D011078:Polychlorinated Biphenyls; D051546:Cyclooxygenase 2; D011402:Pronase