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Unusual Regioselectivity and Active Site Topology of Human Cytochrome P450 2J2

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Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR 8601, Université Paris Descartes, 45 Rue des Saints Pères, 75270 Paris Cedex 06, France, Laboratoire Stress Oxydant et Détoxication, CNRS URA 2096 DSV/iBiTec-S/SB2SM, CEA Saclay, 91191 Gif-sur-Yvette Cedex, France, and National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709
Cite this: Biochemistry 2007, 46, 36, 10237–10247
Publication Date (Web):August 17, 2007
https://doi.org/10.1021/bi700876a
Copyright © 2007 American Chemical Society

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    Abstract

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    The oxidation of six derivatives of terfenadone by recombinant human CYP2J2 (CYP = cytochrome P450) was studied by high-performance liquid chromatography coupled to mass spectrometry (MS) using tandem MS techniques and by 1H NMR spectroscopy. CYP2J2 exhibited a surprising regioselectivity in favor of the hydroxylation of the substrate terminal chain at the weakly reactive homobenzylic position. In contrast, hydroxylation of the same substrates by CYP3A4 mainly occurred on the most chemically reactive sites of the substrates (N-oxidation and benzylic hydroxylation). A 3D homology model of CYP2J2 was constructed using recently published structures of CYP2A6, CYP2B4, CYP2C8, CYP2C9, and CYP2D6 as templates. In contrast with other CYP2 structures, it revealed an active site cavity with a severely restricted access of substrates to the heme through a narrow hydrophobic channel. Dynamic docking of terfenadone derivatives in the CYP2J2 active site allowed one to interpret the unexpected regioselectivity of the hydroxylation of these substrates by CYP2J2, which is mainly based on this restricted access to the iron. The structural features that have been found to be important for recognition of substrates or inhibitors by CYP2J2 were also interpreted on the basis of CYP2J2−substrate interactions in this model.

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     This work was supported by the CNRS (Centre National de la Recherche Scientifique), Ministère de la Recherche (France), and Intramural Research Program of the NIH, National Institute of Environmental Health Sciences.

     Université Paris Descartes.

    §

     CEA Saclay.

     National Institutes of Health.

    *

     To whom correspondence should be addressed. Phone:  +33 (0)1 42 86 40 62. Fax:  +33 (0)1 42 86 83 87. E-mail:  daniel.mansuy@ univ-paris5.fr.

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