Unusual Regioselectivity and Active Site Topology of Human Cytochrome P450 2J2
| Autor: | Pierre Lafite, Patrick M. Dansette, François André, Darryl C. Zeldin, Daniel Mansuy |
|---|---|
| Přispěvatelé: | Protéines membranaires transductrices d'énergie (PMTE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Stress Oxydants et Détoxication (LSOD), Département Biochimie, Biophysique et Biologie Structurale (B3S), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), National Institutes of Health (NIEHS), NIEHS, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques ( LCBPT - UMR 8601 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Stress Oxydants et Détoxication ( LSOD ), Département Biochimie, Biophysique et Biologie Structurale ( B3S ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), National Institutes of Health ( NIEHS ), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay |
| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular MESH: Oxidation-Reduction Insecta MESH : Cytochrome P-450 Enzyme System MESH: Ketones [CHIM.THER]Chemical Sciences/Medicinal Chemistry MESH : Carbon Cytochrome P-450 CYP2J2 Biochemistry Mass Spectrometry MESH : Iron Substrate Specificity Hydroxylation chemistry.chemical_compound 0302 clinical medicine MESH: Insects Cytochrome P-450 Enzyme System Cytochrome P-450 CYP3A MESH : Catalysis MESH: Animals [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] Heme ComputingMilieux_MISCELLANEOUS MESH: Structural Homology Protein 0303 health sciences MESH: Iron MESH : Substrate Specificity MESH : Insects biology MESH: Kinetics [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Structural Biology [q-bio.BM] Regioselectivity MESH: Oxygenases [ CHIM.THER ] Chemical Sciences/Medicinal Chemistry Ketones [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] 030220 oncology & carcinogenesis MESH: Cytochrome P-450 Enzyme System Histamine H1 Antagonists Oxygenases MESH: Histamine H1 Antagonists MESH : Kinetics Oxidation-Reduction MESH: Models Molecular MESH : Models Molecular Stereochemistry Iron MESH : Oxygenases MESH: Hydroxylation MESH: Carbon MESH : Ketones Catalysis Article 03 medical and health sciences MESH : Mass Spectrometry [ INFO.INFO-BI ] Computer Science [cs]/Bioinformatics [q-bio.QM] Animals Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Homology modeling Binding site [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry Molecular Biology 030304 developmental biology MESH : Oxidation-Reduction MESH: Mass Spectrometry Binding Sites MESH: Humans MESH : Humans Cytochrome P450 Active site MESH : Histamine H1 Antagonists MESH: Catalysis Carbon Kinetics chemistry MESH: Binding Sites Structural Homology Protein Docking (molecular) biology.protein MESH : Structural Homology Protein MESH : Hydroxylation MESH: Substrate Specificity MESH : Animals [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] MESH : Binding Sites |
| Zdroj: | Biochemistry Biochemistry, American Chemical Society, 2007, pp.10237-10247 Biochemistry, American Chemical Society, 2007, 46 (36), pp.10237-47. ⟨10.1021/bi700876a⟩ Biochemistry, American Chemical Society, 2007, 46 (36), pp.10237-47. 〈10.1021/bi700876a〉 Biochemistry, 2007, pp.10237-10247 Biochemistry, 2007, 46 (36), pp.10237-47. ⟨10.1021/bi700876a⟩ |
| ISSN: | 0006-2960 1520-4995 |
| DOI: | 10.1021/bi700876a⟩ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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