Observation of an unusual electronically distorted semiquinone radical of PCB metabolites in the active site of prostaglandin H synthase-2

Orarat Wangpradit; Edelmiro Moman; Kevin B Nolan; Garry R Buettner; Larry W Robertson; Gregor Luthe

doi:10.1016/j.chemosphere.2010.08.041

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Observation of an unusual electronically distorted semiquinone radical of PCB metabolites in the active site of prostaglandin H synthase-2

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Observation of an unusual electronically distorted semiquinone radical of PCB metabolites in the active site of prostaglandin H synthase-2

Orarat Wangpradit, Edelmiro Moman, Kevin B Nolan, Garry R Buettner, Larry W Robertson and Gregor Luthe

Chemosphere (Oxford), Vol.81(11), pp.1501-1508

2010

DOI: 10.1016/j.chemosphere.2010.08.041

PMCID: PMC3622869

PMID: 20843536

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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 2Q), 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 2Q. 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 2Q 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.

Human recombinant prostaglandin H synthase-2 (hPGHS-2)

Ab initio

Airborne polychlorinated biphenyls (PCBs)

Semiquinone radicals

In silico molecular docking model

Electron paramagnetic resonance (EPR) spectroscopy

Details

Title: Subtitle: Observation of an unusual electronically distorted semiquinone radical of PCB metabolites in the active site of prostaglandin H synthase-2
Creators: Orarat Wangpradit - Department of Occupational and Environmental Health, The University of Iowa, 100 Oakdale Campus, Iowa City, IA 52242-5000, USA
Edelmiro Moman - ProSciens, Computing & Molecular Sciences, 2-4 rue du Palais de Justice, L-1841, Luxembourg
Kevin B Nolan - Centre for Synthesis and Chemical Biology, Department of Pharmaceutical & Medicinal Chemistry, Royal College of Surgeons in Ireland, St Stephen’s Green, Dublin 2, Ireland
Garry R Buettner - Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, 100 Oakdale Campus, Iowa City, IA 52242-5000, USA
Larry W Robertson - Department of Occupational and Environmental Health, The University of Iowa, 100 Oakdale Campus, Iowa City, IA 52242-5000, USA
Gregor Luthe - Department of Occupational and Environmental Health, The University of Iowa, 100 Oakdale Campus, Iowa City, IA 52242-5000, USA
Resource Type: Journal article
Publication Details: Chemosphere (Oxford), Vol.81(11), pp.1501-1508
DOI: 10.1016/j.chemosphere.2010.08.041
PMID: 20843536
PMCID: PMC3622869
NLM abbreviation: Chemosphere
ISSN: 0045-6535
eISSN: 1879-1298
Publisher: Elsevier Ltd
Language: English
Date published: 2010
Academic Unit: Occupational and Environmental Health; Radiation Oncology
Record Identifier: 9984002435002771

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