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Association of Cytochrome P450 Enzymes is a Determining Factor in their Catalytic Activity

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Abstract

Previously, our laboratory demonstrated that one cytochrome P450 isoenzyme can influence the catalytic properties of another P450 isoenzyme when combined in a reconstituted system. Moreover, our data and that of other investigators indicate that P450 interaction is required for catalytic activity even when one isoenzyme is present. The goal of the current study was to examine the possible mechanism of these interactions in more detail. Analyzing recently published X-ray data of microsomal P450 enzymes and protein docking studies, four types of dimer formations of P450 enzymes were examined in more detail. In case of two dimer types, the aggregating partner was shown to contribute to NADPH cytochrome P450 reductase (CPR) binding-a flavoprotein whose interaction with P450 is required for expressing P450 functional activity of the neighboring P450 moiety. Thus, it was shown that dimerization of P450 enzymes might result in an altered affinity towards the CPR. Two dimer types were shown to exist only in the presence of a substrate, while the other two types exist also without a substrate present. The molecular basis was established for the fact that the presence of a substrate and other P450 enzymes simultaneously determine the catalytic activity. Furthermore, a kinetic model was improved describing the catalytic activity of P450 enzymes as a function of CPR concentration based on equilibrium between different supramolecular organizations of P450 enzymes. This model was successfully applied in order to explain our experimental data and that of other investigators.

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References

  1. P.P. Tamburini I. Jansson L.V. Favreau W.L. Backes J.B. Schenkman (1986) Biochem. Biophys. Res. Commun. 137 437–442 Occurrence Handle10.1016/0006-291X(86)91229-5 Occurrence Handle3087359

    Article  PubMed  Google Scholar 

  2. J. Blaisdell H. Mohrenweiser J. Jackson S. Ferguson S. Coulter B. Chanas T. Xi B. J.A. Ghanayem Goldstein (2002) Pharmacogenetics 12 703–711 Occurrence Handle10.1097/00008571-200212000-00004 Occurrence Handle12464799

    Article  PubMed  Google Scholar 

  3. W.L. Backes C.S. Eyer (1989) J. Biol. Chem. 264 6252–6259 Occurrence Handle2495281

    PubMed  Google Scholar 

  4. C.S. Eyer W.L. Backes (1992) Arch. Biochem. Biophys. 293 231–240 Occurrence Handle10.1016/0003-9861(92)90390-I Occurrence Handle1536561

    Article  PubMed  Google Scholar 

  5. J.S. French F.P. Guengerich M.J. Coon (1980) J. Biol. Chem. 255 4112–4119 Occurrence Handle6768748

    PubMed  Google Scholar 

  6. S.J. Pernecky J.R. Larson R.M. Philpot M.J. Coon (1993) Proc. Natl. Acad. Sci. USA 90 2651–2655 Occurrence Handle8464872

    PubMed  Google Scholar 

  7. I.F. Sevrioukova I.P. Kanaeva Y.M. Koen N.F. Samenkova G.I. Bachmanova A.I. Archakov (1994) Arch. Biochem. Biophys. 311 133–143 Occurrence Handle10.1006/abbi.1994.1218 Occurrence Handle8185310

    Article  PubMed  Google Scholar 

  8. W.L. Dean R.D. Gray (1982) J. Biol. Chem. 257 14679–14685 Occurrence Handle6816797

    PubMed  Google Scholar 

  9. S.L. Wagner W.L. Dean R.D. Gray (1984) J. Biol. Chem. 259 2390–2395 Occurrence Handle6421810

    PubMed  Google Scholar 

  10. K. Alston R.C. Robinson S.S. Park H.V. Gelboin F.K Friedman (1991) J. Biol. Chem. 266 735–739 Occurrence Handle1985961

    PubMed  Google Scholar 

  11. G.F. Cawley C.J. Batie W.L. Backes (1995) Biochemistry 34 1244–1247 Occurrence Handle10.1021/bi00004a018 Occurrence Handle7827074

    Article  PubMed  Google Scholar 

  12. W.L. Backes C.J. Batie G.F. Cawley (1998) Biochemistry 37 12852–12859 Occurrence Handle10.1021/bi980674a Occurrence Handle9737863

    Article  PubMed  Google Scholar 

  13. L.S. Kaminsky F.P. Guengerich (1985) Eur. J. Biochem. 149 479–489 Occurrence Handle10.1111/j.1432-1033.1985.tb08950.x Occurrence Handle3924614

    Article  PubMed  Google Scholar 

  14. G.F. Cawley S. Zhang R.W. Kelley W.L. Backes (2001) Drug Metab. Dispos. 29 1529–1534 Occurrence Handle11717170

    PubMed  Google Scholar 

  15. E. Hazai D. Kupfer (2005) Drug Metab. Dispos. 33 157–164 Occurrence Handle10.1124/dmd.104.001578 Occurrence Handle15486075

    Article  PubMed  Google Scholar 

  16. H.M. Berman J. Westbrook Z. Feng G. Gillilandv T.N. Bhat H. Weissig I.N. Shindyalov P.E. Bourne (2000) Nucleic Acids Res. 28 235–242 Occurrence Handle10.1093/nar/28.1.235 Occurrence Handle10592235

    Article  PubMed  Google Scholar 

  17. N. Guex M.C. Peitsch (1997) Electrophoresis 18 2714–2723 Occurrence Handle9504803

    PubMed  Google Scholar 

  18. G. Ausiello G. Cesareni M. Helmer Citterich (1997) Proteins 28 556–567 Occurrence Handle10.1002/(SICI)1097-0134(199708)28:4<556::AID-PROT9>3.0.CO;2-7 Occurrence Handle9261871

    Article  PubMed  Google Scholar 

  19. R.A. Laskowski M.W. MacArthur D.S. Moss J.M. Thornton (1993) J. Appl. Cryst. 26 283–291 Occurrence Handle10.1107/S0021889892009944

    Article  Google Scholar 

  20. E.E. Scott M.A. White Y.A. He E.F. Johnson C.D. Stout J.R. Halpert (2004) J. Biol. Chem. 279 27294–27301 Occurrence Handle10.1074/jbc.M403349200 Occurrence Handle15100217

    Article  PubMed  Google Scholar 

  21. P.A. Williams J. Cosme V. Sridhar E.F. Johnson D.E. McRee (2000) Mol. Cell 5 121–131 Occurrence Handle10.1016/S1097-2765(00)80408-6 Occurrence Handle10678174

    Article  PubMed  Google Scholar 

  22. G.A. Schoch J.K. Yano M.R. Wester K.J. Griffin C.D. Stout E.F Johnson (2004) J. Biol. Chem. 279 9497–9503 Occurrence Handle10.1074/jbc.M312516200 Occurrence Handle14676196

    Article  PubMed  Google Scholar 

  23. P.A. Williams J. Cosme A. Ward H.C. Angove M.D. Vinkovic H Jhoti (2003) Nature 424 464–468 Occurrence Handle10.1038/nature01862 Occurrence Handle12861225

    Article  PubMed  Google Scholar 

  24. I.F. Sevrioukova H. Li H. Zhang J.A. Peterson T.L Poulos (1999) Proc. Natl. Acad. Sci. USA 96 1863–1868 Occurrence Handle10.1073/pnas.96.5.1863 Occurrence Handle10051560

    Article  PubMed  Google Scholar 

  25. Q. Zhao S. Modi G. Smith M. Paine P.D. McDonagh C.R. Wolf D. Tew L.Y. Lian G.C. Roberts H.P Driessen (1999) Proteins 8 298–306

    Google Scholar 

  26. S. Shen H.W Strobel (1992) Arch. Biochem. Biophys. 294 83–90 Occurrence Handle10.1016/0003-9861(92)90140-R Occurrence Handle1550361

    Article  PubMed  Google Scholar 

  27. T. Shimizu T. Tateishi M. Hatano Y Fujii-Kuriyama (1991) J. Biol. Chem. 266 3372–3375 Occurrence Handle1899862

    PubMed  Google Scholar 

  28. D.F.V. Lewis P.J. Lee-Robichaud (1998) Steroid Biochem. Mol. Biol. 66 217–233 Occurrence Handle10.1016/S0960-0760(98)00032-6

    Article  Google Scholar 

  29. P.S. Stayton S.G. Sligar (1990) Biochemistry 29 7381–7386 Occurrence Handle10.1021/bi00484a005 Occurrence Handle2223769

    Article  PubMed  Google Scholar 

  30. H. Mayuzumi C. Sambongi K. Hiroya T. Shimizu T. Tateishi M Hatano. (1993) Biochemistry 32 5622–5628 Occurrence Handle10.1021/bi00072a018 Occurrence Handle8504082

    Article  PubMed  Google Scholar 

  31. Y. Omata H. Sakamoto R.C. Robinson M.R. Pincus F.K. Friedman (1994) Biochem. Biophys. Res. Commun. 201 1090–1095 Occurrence Handle10.1006/bbrc.1994.1817 Occurrence Handle8024550

    Article  PubMed  Google Scholar 

  32. A. Bridges L. Gruenke Y.T. Chang I.A. Vakser G. Loew L Waskell (1998) J. Biol. Chem. 273 17036–17049 Occurrence Handle10.1074/jbc.273.27.17036 Occurrence Handle9642268

    Article  PubMed  Google Scholar 

  33. F.S. Millett L.M. Geren (1991) Methods Enzymol. 206 49–56 Occurrence Handle1784234

    PubMed  Google Scholar 

  34. H. Shimada S. Nagano H. Hori Y Ishimura (2001) J. Inorg. Biochem. 83 255–260 Occurrence Handle10.1016/S0162-0134(00)00173-2 Occurrence Handle11293545

    Article  PubMed  Google Scholar 

  35. R.O. Juvonen M. Iwasaki M Negishi (1992) Biochemistry 31 11519–11523 Occurrence Handle10.1021/bi00161a033 Occurrence Handle1445886

    Article  PubMed  Google Scholar 

  36. P. Honkakoski A.L. Kankkunen S.A. Usanov M.A Lang (1992) Biochim. Biophys. Acta 1122 6–14 Occurrence Handle1633197

    PubMed  Google Scholar 

  37. T.B. Adamovich I.A. Pikuleva V.L. Chashchin S.A Usanov (1989) Biochim. Biophys. Acta 996 247–253 Occurrence Handle2502182

    PubMed  Google Scholar 

  38. S. Shen H.W Strobel (1993) Arch. Biochem. Biophys. 304 257–265 Occurrence Handle10.1006/abbi.1993.1347 Occurrence Handle8323289

    Article  PubMed  Google Scholar 

  39. H. Furuya T. Shimizu K. Hirano M. Hatano Y. Fujii-Kuriyama (1989) Biochemistry 28 6848–6857 Occurrence Handle10.1021/bi00443a011 Occurrence Handle2819037

    Article  PubMed  Google Scholar 

  40. P. Hlavica J. Schulze D.F.V. Lewis (2003) J. Inorg. Biochem. 96 279–297 Occurrence Handle10.1016/S0162-0134(03)00152-1 Occurrence Handle12888264

    Article  PubMed  Google Scholar 

  41. E.E. Scott Y.A. He M.R. Wester M.A. White C.C. Chin J.R. Halpert E.F. Johnson C.D. Stout (2003) Proc. Natl. Acad. Sci. USA 100 13196–13201 Occurrence Handle10.1073/pnas.2133986100 Occurrence Handle14563924

    Article  PubMed  Google Scholar 

  42. L. Podust Y. Kim M. Arase B. Neely B. Beck H. Bach D. Sherman D. Lamb S. Kelly M. Waterman (2003) J. Biol. Chem. 278 12214–12221 Occurrence Handle10.1074/jbc.M212210200 Occurrence Handle12519772

    Article  PubMed  Google Scholar 

  43. H. Li T.L Poulos (1995) Acta Crystallogr. D 51 21–32 Occurrence Handle10.1107/S0907444994009194 Occurrence Handle15299332

    Article  PubMed  Google Scholar 

  44. H. Yeom S.G. Sligar H. Li T.L. Poulos A.J. Fulco (1995) Biochemistry 34 14733–14740 Occurrence Handle10.1021/bi00045a014 Occurrence Handle7578081

    Article  PubMed  Google Scholar 

  45. D.R. Dutton A. Parkinson (1989) Arch. Biochem. Biophys. 268 617–629 Occurrence Handle10.1016/0003-9861(89)90329-9 Occurrence Handle2536534

    Article  PubMed  Google Scholar 

  46. G.T. Miwa S.B. West M.T. Huang A.Y. Lu (1979) J. Biol. Chem. 254 5695–5700 Occurrence Handle109441

    PubMed  Google Scholar 

  47. J.A. Peterson R.E. Ebel D.H. Oȁ9Keeffe T. Matsubara R.W. Estabrook (1976) J. Biol. Chem. 251 4010–4016 Occurrence Handle819436

    PubMed  Google Scholar 

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Author notes

  1. Eszter Hazai & Zsolt Bikádi

    Present address: School of Medicine, Department of Molecular Pharmacology and Biochemistry, University of Massachusetts, Room 815, 364 Plantation St, Worcester, MA, 01605, USA

Authors and Affiliations

  1. School of Medicine, Department of Molecular Pharmacology and Biochemistry, University of Massachusetts, Room 815, 364 Plantation St, Worcester, MA, 01605, USA

    David Kupfer

  2. Institute of Biomolecular Chemistry, Chemical Research Center, POB 17, H-1525, Budapest, Hungary

    Eszter Hazai, Zsolt Bikádi & Miklós Simonyi

Authors
  1. Eszter Hazai
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  2. Zsolt Bikádi
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Correspondence to Eszter Hazai.

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Eszter Hazai and Zsolt Bikádi contributed equally to this work

David Kupfer-Deceased

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Hazai, E., Bikádi, Z., Simonyi, M. et al. Association of Cytochrome P450 Enzymes is a Determining Factor in their Catalytic Activity. J Comput Aided Mol Des 19, 271–285 (2005). https://doi.org/10.1007/s10822-005-4995-4

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  • DOI: https://doi.org/10.1007/s10822-005-4995-4

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