title: Unusual regioselectivity and active site topology of human cytochrome P450 2J2.
abstract: 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.
authors: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR 8601, Université Paris Descartes, 45 Rue des Saints Pères, 75270 Paris Cedex 06, France.
authors: Pierre
authors: P
authors: Lafite
authors: François
authors: F
authors: André
authors: Darryl C
authors: DC
authors: Zeldin
authors: Patrick M
authors: PM
authors: Dansette
authors: Daniel
authors: D
authors: Mansuy
mesh_terms: D000818:Animals; D001665:Binding Sites; D002244:Carbon; D002384:Catalysis; D000090762:Cytochrome P-450 CYP2J2; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D006634:Histamine H1 Antagonists / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D007313:Insecta; D007501:Iron; D007659:Ketones / Q000737:chemistry; D007700:Kinetics; D013058:Mass Spectrometry; D008958:Models, Molecular; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000737:chemistry* / Q000378:metabolism*; D040681:Structural Homology, Protein; D013379:Substrate Specificity
chemical_list: C000717350:CYP2J2 protein, human; D006634:Histamine H1 Antagonists; D007659:Ketones; D002244:Carbon; D003577:Cytochrome P-450 Enzyme System; D007501:Iron; D010105:Oxygenases; D000090762:Cytochrome P-450 CYP2J2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
references: Drug Metab Dispos. 2005 Mar;33(3):466-73
references: 15608133
references: J Biol Chem. 2004 Dec 3;279(49):50949-55
references: 15456790
references: Nat Struct Mol Biol. 2005 Sep;12(9):822-3
references: 16086027
references: Arch Biochem Biophys. 2007 Mar 1;459(1):59-69
references: 17222385
references: Drug Metab Dispos. 2006 Nov;34(11):1793-7
references: 16896065
references: J Pharmacol Exp Ther. 2002 Jan;300(1):298-304
references: 11752129
references: J Biol Chem. 2006 Mar 3;281(9):5973-81
references: 16373351
references: J Mol Model. 2002 Nov;8(11):327-35
references: 12483228
references: Biochemistry. 1971 Dec 21;10(26):4858-66
references: 5134533
references: Mol Pharmacol. 2004 Dec;66(6):1607-16
references: 15361551
references: Mol Pharmacol. 2001 Aug;60(2):310-20
references: 11455018
references: Proteins. 2004 Jun 1;55(4):846-55
references: 15146483
references: J Pharmacol Exp Ther. 2005 Aug;314(2):522-32
references: 15840765
references: Trends Biochem Sci. 2005 Jan;30(1):5-7
references: 15653318
references: Mol Cell. 2000 Jan;5(1):121-31
references: 10678174
references: Acta Crystallogr D Biol Crystallogr. 1994 Mar 1;50(Pt 2):178-85
references: 15299456
references: J Biol Chem. 2004 Sep 10;279(37):38091-4
references: 15258162
references: J Biol Chem. 2006 Mar 17;281(11):7614-22
references: 16352597
references: J Med Chem. 2006 Nov 30;49(24):6987-7001
references: 17125252
references: Circulation. 2004 Oct 12;110(15):2132-6
references: 15466638
references: Circ Res. 2004 Sep 3;95(5):506-14
references: 15256482
references: J Physiol. 2006 Sep 1;575(Pt 2):627-44
references: 16793897
references: Science. 2004 Jul 30;305(5684):683-6
references: 15256616
references: Mol Pharmacol. 1996 Nov;50(5):1111-7
references: 8913342
references: Biochem Biophys Res Commun. 2005 Dec 9;338(1):331-6
references: 16157296
references: Bioorg Med Chem Lett. 2006 May 15;16(10):2777-80
references: 16495056
references: Biochem Pharmacol. 1973 Dec 1;22(23):3099-108
references: 4202581
references: Biochemistry. 2003 Jun 3;42(21):6370-9
references: 12767218
references: Proc Natl Acad Sci U S A. 2006 Sep 12;103(37):13682-7
references: 16954191
references: J Biol Chem. 1996 Feb 16;271(7):3460-8
references: 8631948
references: Nature. 2003 Jul 24;424(6947):464-8
references: 12861225
references: Pharmacol Ther. 2006 Sep;111(3):584-95
references: 16380164
references: J Biol Chem. 2004 Aug 20;279(34):35630-7
references: 15181000
references: Biochim Biophys Acta. 2007 Mar;1770(3):390-401
references: 16920266
references: J Theor Biol. 2005 Jun 21;234(4):479-85
references: 15808869
references: Drug Metab Dispos. 2002 Nov;30(11):1240-5
references: 12386130
references: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13196-201
references: 14563924
references: Biochemistry. 2003 Aug 12;42(31):9335-45
references: 12899620
references: Mol Pharmacol. 1997 Jun;51(6):931-43
references: 9187259
references: J Med Chem. 2005 Apr 21;48(8):2725-55
references: 15828810
references: Arch Biochem Biophys. 2007 Aug 15;464(2):155-68
references: 17470359
references: J Mol Biol. 1998 Apr 17;277(5):1141-52
references: 9571028
references: J Biol Chem. 2004 Jun 25;279(26):27294-301
references: 15100217
references: Am J Physiol Cell Physiol. 2007 Mar;292(3):C996-1012
references: 16987999
references: J Mol Biol. 2006 Dec 1;364(3):266-74
references: 17020766
references: Nature. 1996 May 23;381(6580):272
references: 8692262
references: Nucleic Acids Res. 2003 Jul 1;31(13):3381-5
references: 12824332
references: J Biol Chem. 2004 Mar 5;279(10):9497-503
references: 14676196
references: Cancer Res. 2005 Jun 1;65(11):4707-15
references: 15930289
references: Hypertension. 2006 Apr;47(4):629-33
references: 16490839
references: J Biol Chem. 2001 May 11;276(19):15983-9
references: 11279071
references: Science. 1999 Aug 20;285(5431):1276-9
references: 10455056