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ETUDE du CYTOCHROME P450 2J2 HUMAIN :
Recherche de substrats et d'inhibiteurs sélectifs ;
Détermination de la topologie de son site actif

Abstract : This manuscript deals with the functional and structural study of human cytochrome P450 2J2 (CYP2J2), an enzyme mainly expressed in cardiovascular tissues, whose biological roles are not wellknown. We used terfenadone, regioselectively oxydized by CYP2J2, as a starting point for design and synthesis of several compounds, which revealed to be affine and selective inhibitors of this P450. In particular, one affine and selective inhibitor (Ki = 160 nM) and two efficient mechanism-based inactivators (kinact/Ki 3000 L/mol/s) of CYP2J2 were identified. The study of the CYP2J2-catalyzed oxidation of some of these compounds revealed a surprising regioselectivity, favoring a less reactive position, regarding the reactivity towards oxidation. The characterization of the active site and the identification of important residues for terfenadone derivatives recognition by CYP2J2 was achieved using an homology 3D model of this enzyme, and docking of several substrates in the active site. Finally, a preliminary study of the potential biological roles of CYP2J2 was performed by looking at the inhibitory effect of several compounds involved in the vascular relaxation pathways. In conclusion, this work provides the characterization of the first biochemical tools to study the biological roles of CYP2J2, the first description of the active site topology and a study on CYP2J2 biological roles.
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https://tel.archives-ouvertes.fr/tel-00192090
Contributor : Patrick Dansette <>
Submitted on : Monday, November 26, 2007 - 3:34:06 PM
Last modification on : Friday, April 10, 2020 - 5:24:05 PM
Long-term archiving on: : Monday, April 12, 2010 - 5:11:29 AM

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  • HAL Id : tel-00192090, version 1

Citation

Pierre Lafite. ETUDE du CYTOCHROME P450 2J2 HUMAIN :
Recherche de substrats et d'inhibiteurs sélectifs ;
Détermination de la topologie de son site actif. Autre. Université René Descartes - Paris V, 2007. Français. ⟨tel-00192090⟩

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