Structural rationalization of novel drug metabolizing mutants of cytochrome P450 BM3

Proteins: Structure, Function and Genetics

Volumn 71, Issue 1, 2008, Pages 336-352

  Stjernschantz, Eva ^a   Van Vugt Lussenburg, Barbara M A ^a   Bonifacio, Alois ^a   De Beer, Stephanie B A ^a   Van Der Zwan, Gert ^a   Gooijer, Cees ^a   Commandeur, Jan N M ^a   Vermeulen, Nico P E ^a   Oostenbrink, Chris ^a  

^a VU UNIVERSITY AMSTERDAM   (Netherlands)

Author keywords

Cytochrome P450 BM3; Molecular dynamics simulations; Mutagenesis; R47 F81 L86 L188 E267; Resonance Raman

Indexed keywords

CARBOXYLIC ACID; CYTOCHROME P450 2D6; CYTOCHROME P450 BM3; DRUG METABOLIZING ENZYME; HEME; MUTANT PROTEIN; NITROGEN; PROPIONIC ACID;

ARTICLE; CONFORMATIONAL TRANSITION; CRYSTAL STRUCTURE; ENZYME BINDING; ENZYME MECHANISM; ENZYME METABOLISM; ENZYME STRUCTURE; ENZYME SUBSTRATE; METABOLITE; MOLECULAR DYNAMICS; MOLECULAR INTERACTION; MOLECULAR MODEL; MUTAGENESIS; PRIORITY JOURNAL; RAMAN SPECTROMETRY; RANDOMIZATION; SIMULATION; ULTRAVIOLET SPECTROSCOPY;

COMPUTER SIMULATION; CYTOCHROME P-450 CYP2D6; CYTOCHROME P-450 ENZYME SYSTEM; HUMANS; LIGANDS; MODELS, MOLECULAR; MUTATION; PHARMACEUTICAL PREPARATIONS; PROTEIN CONFORMATION;

EID: 40549094980     PISSN: 08873585     EISSN: 10970134     Source Type: Journal    
DOI: 10.1002/prot.21697     Document Type: Article

References (60)

1. Guengerich FP. Cytochrome P450 enzymes in the generation of commercial products. Nat Rev Drug Discov 2002;1:359-366.
2. Urlacher VB, Lutz-Wahl S, Schmid RD. Microbial P450 enzymes in biotechnology. Appl Microbiol Biotechnol 2004;64:317-325.
3. Narhi LO, Fulco AJ. Characterization of a catalytically self-sufficient 119,000-dalton cytochrome P-450 monooxygenase induced by bar biturates in Bacillus megaterium. J Biol Chem 1986;261:7160-7169.
4. Munro AW, Leys DG, McLean KJ, Marshall KR, Ost TW, Daff S, Miles CS, Chapman SK, Lysek DA, Moser CC, Page CC, Dutton PL. P450 BM3: the very model of a modern flavocytochrome. Trends Biochem Sci 2002;27:250-257.
5. Glieder A, Farinas ET, Arnold FH. Laboratory evolution of a soluble, self-sufficient, highly active alkane hydroxylase. Nat Biotechnol 2002;20:1135-1139.
6. Li QS, Schwaneberg U, Fischer P, Schmid RD. Directed evolution of the fatty-acid hydroxylase P450 BM-3 into an indole-hydroxylating catalyst. Chemistry 2000;6:1531-1536.
7. Otey CR, Bandara G, Lalonde J, Takahashi K, Arnold FH. Preparation of human metabolites of propranolol using laboratory-evolved bacterial cytochromes P450. Biotechnol Bioeng 2006;93:494-499.
8. Ravichandran KG, Boddupalli SS, Hasermann CA, Peterson JA, Deisenhofer J. Crystal structure of hemoprotein domain of P450BM-3, a prototype for microsomal P450's. Science 1993;261:731-736.
9. Li H, Poulos TL. Modeling protein-substrate interactions in the heme domain of cytochrome P450(BM-3). Acta Crystallogr D Biol Crystallogr 1995;51(Pt 1):21-32.
10. Sevrioukova IF, Li H, Zhang H, Peterson JA, Poulos TL. Structure of a cytochrome P450-redox partner electron-transfer complex. Proc Natl Acad Sci USA 1999;96:1863-1868.
11. Haines DC, TomchickDR, Machius M, Peterson JA. Pivotal role of water in the mechanism of P450BM-3. Biochemistry 2001;40:13456-13465.
12. Li H, Poulos TL. The structure of the cytochrome p450BM-3 haem domain complexed with the fatty acid substrate, palmitoleic acid. Nat Struct Biol 1997;4:140-146.
13. Clark JP, Miles CS, Mowat CG, Walkinshaw MD, Reid GA, Daff SN, Chapman SK. The role of Thr268 and Phe393 in cytochrome P450 BM3. J Inorg Biochem 2006;100(5/6):1075-1090.
14. Li QS, Ogawa J, Schmid RD, Shimizu S. Residue size at position 87 of cytochrome P450 BM-3 determines its stereoselectivity in propylbenzene and 3-chlorostyrene oxidation. FEBS Lett 2001;508:249-252.
15. Munro AW, Malarkey K, McKnight J, Thomson AJ, Kelly SM, Price NC, Lindsay JG, Coggins JR, Miles JS. The role of tryptophan 97 of cytochrome P450 BM3 from Bacillus megaterium in catalytic function. Evidence against the 'covalent switching' hypothesis of P-450 electron transfer. Biochem J 1994;303 (Pt 2):423-428.
16. Noble MA, Miles CS, Chapman SK, Lysek DA, MacKay AC, Reid GA, Hanzlik RP, Munro AW. Roles of key active-site residues in flavocytochrome P450 BM3. Biochem J 1999;339 (Pt 2):371-379.
17. Ost TW, Miles CS, Munro AW, Murdoch J, Reid GA, Chapman SK. Phenylalanine 393 exerts thermodynamic control over the heme of flavocytochrome P450 BM3. Biochemistry 2001;40:13421-13429.
18. Yeom H, Sligar SG, Li H, Poulos TL, Fulco AJ. The role of Thr268 in oxygen activation of cytochrome P450BM-3. Biochemistry 1995;34:14733-14740.
19. Carmichael AB, Wong LL. Protein engineering of Bacillus megaterium CYP102. The oxidation of polycyclic aromatic hydrocarbons. Eur J Biochem 2001;268:3117-3125.
20. Li QS, Schwaneberg U, Fischer M, Schmitt J, Pleiss J, Lutz-Wahl S, Schmid RD. Rational evolution of a medium chain-specific cytochrome P-450 BM-3 variant. Biochim Biophys Acta 2001;1545(1/2):114-121.
21. van Vugt-Lussenburg BMA, Damsten MC, Maasdijk DM, Vermeulen NPE, Commandeur JNM. Heterotropic and homotropic cooper-ativity by a drug-metabolising mutant of cytochrome P450 BM3. Biochem Biophys Res Commun 2006;346:810-818.
22. Oliver CF, Modi S, Sutcliffe MJ, Primrose WU, Lian LY, Roberts GC. A single mutation in cytochrome P450 BM3 changes substrate orientation in a catalytic intermediate and the regiospecificity of hydroxylation. Biochemistry 1997;36:1567-1572.
23. van Vugt-Lussenburg BMA, Stjernschantz E, Lastdrager J, Oostenbrink C, Vermeulen NPE, Commandeur JNM. Identification of critical residues in novel drug metabolising mutants of Cytochrome P450 BM3 using random mutagenesis. J Med Chem 2007;50:455-461.
24. Ludemann SK, Lounnas V, Wade RC. How do substrates enter and products exit the buried active site of cytochrome P450cam? 1. Random expulsion molecular dynamics investigation of ligand access channels and mechanisms. J Mol Biol 2000;303:797-811.
25. Hildebrandt P. Resonance Raman spectroscopy of cytochrome P450. Berlin: Akademie Verlag Berlin; 1992.
26. Spiro TG, Li X. Resonance Raman spectroscopy of metalloporphyrins. New York: Wiley; 1987.
27. Chen Z, Ost TW, Schelvis JP. Phe393 mutants of cytochrome P450 BM3 with modified heme redox potentials have altered heme vinyl and propionate conformations. Biochemistry 2004;43:1798-1808.
28. Molecular Operating Environment (MOE), Montreal, Quebec, Canada: Chemical Computing Group Inc.
29. Christen M, Hunenberger PH, Bakowies D, Baron R, Burgi R, Geerke DP, Heinz TN, Kastenholz MA, Krautler V, Oostenbrink C, Peter C, Trzesniak D, van Gunsteren WF. The GROMOS software for biomolecular simulation: GROMOS05. J Comput Chem 2005; 26:1719-1751.
30. Schuler LD, Daura X, van Gunsteren WF. An improved GRO-MOS96 force field for aliphatic hydrocarbons in the condensed phase. J Comput Chem 2001;22:1205-1218.
31. van Gunsteren WF, Billeter SR, Eising AA, Hunenberger PH, Kruger P, Mark AE, Scott WRP, Tironi IG. Biomolecular simulation: the GROMOS96 manual and user guide. Zurich: Vdf Hochschulverlag AG an der ETH Zurich; 1996.
32. Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and validation of a genetic algorithm for flexible docking. J Mol Biol 1997;267:727-748.
33. Eldridge MD, Murray CW, Auton TR, Paolini GV, Mee RP. Empirical scoring functions. I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. J Comput Aided Mol Des 1997;11:425-445.
34. Murray CW, Auton TR, Eldridge MD. Empirical scoring functions. II. The testing of an empirical scoring function for the prediction of ligand-receptor binding affinities and the use of Bayesian regression to improve the quality of the model. J Comput Aided Mol Des 1998;12:503-519.
35. Karki SB, Dinnocenzo JP, Jones JP, Korzekwa KR. Mechanism of oxidative amine dealkylation of substituted N,N-dimethylanilines by cytochrome P-450: application of isotope effect profiles. J Am Chem Soc 1995;117:3657-3664.
36. Berendsen HJC, van der Spoel D, van Drunen R. GROMACS: a message-passing parallel molecular dynamics implementation. Comput Phys Commun 1995;91:43-56.
37. Lindahl E, Hess B, van der Spoel D. GROMACS 3.0: a package for molecular simulation and trajectory analysis. J Mol Mod 2001;7:306-317.
38. Berendsen HJC, Postma JPM, van Gunsteren WF, Hermans J. Interaction models for water in relation to protein hydration. Intermolecular forces. Dordrecht, The Netherlands: Reidel; 1981. pp 331-342.
39. Ryckaert J-P, Ciccotti G, Berendsen HJC. Numerical integration of Cartesian equations of motion of a system with constraints', molecular dynamics of n-alkanes. J Comput Phys 1977;23:327-341.
40. Berendsen HJC, Postma JPM, van Gunsteren WF, di Nola A, Haak JR. Molecular dynamics with coupling to an external bath. J Chem Phys 1984;81:3684-3690.
41. Tironi IG, Sperb R, Smith PE, van Gunsteren WF. A generalized reaction field method for molecular-dynamics simulations. J Chem Phys 1995;102:5451-5459.
42. Maurer SC, Schulze H, Schmid RD, Urlacher V. Immobilisation of P450 BM-3 and an NADP+ cofactor recycling system: towards a technical application of heme-containing monooxygenases in fine chemical synthesis. Adv Synth Catal 2003;345:802-810.
43. de Graaf C, Oostenbrink C, Keizers PH, van der Wijst T, Jongejan A, Vermeulen NP. Catalytic site prediction and virtual screening of cytochrome P450 2D6 substrates by consideration of water and rescoring in automated docking. J Med Chem 2006;49:2417-2430.
44. Keizers PH, de Graaf C, de Kanter FJ, Oostenbrink C, Feenstra KA, Commandeur JN, Vermeulen NP. Metabolic regio- and stereo-selectivity of cytochrome P450 2D6 towards 3,4-methylenedioxy-N-alkylamphetamines: in silico predictions and experimental validation. J Med Chem 2005;48:6117-6127.
45. Wade RC, Winn PJ, Schlichting I, Sudarko . A survey of active site access channels in cytochromes P450. J Inorg Biochem 2004;98:1175-1182.
46. Cojocaru V, Winn PJ, Wade RC. The ins and outs of cytochrome P450s. Biochim Biophys Acta 2006;1770:390-401.
47. Boddupalli SS, Pramanik BC, Slaughter CA, Estabrook RW, Peterson JA. Fatty acid monooxygenation by P450BM-3: product identification and proposed mechanisms for the sequential hydroxylation reactions. Arch Biochem Biophys 1992;292:20-28.
48. Miles JS, Munro AW, Rospendowski BN, Smith WE, McKnight J, Thomson AJ. Domains of the catalytically self-sufficient cytochrome P-450 BM-3. Genetic construction, overexpression, purification and spectroscopic characterization. Biochem J 1992;288 (Pt 2):503-509.
49. Joyce MG, Girvan HM, Munro AW, Leys D. A single mutation in cytochrome P450 BM3 induces the conformational rearrangement seen upon substrate binding in the wild-type enzyme. J Biol Chem 2004;279:23287-23293.
50. Modi S, Sutcliffe MJ, Primrose WU, Lian LY, Roberts GC. The catalytic mechanism of cytochrome P450 BM3 involves a 6 Å movement of the bound substrate on reduction. Nat Struct Biol 1996;3:414-417.
51. Reed JR, Hollenberg PF. Comparison of substrate metabolism by cytochromes P450 2B1, 2B4, and 2B6: relationship of heme spin state, catalysis, and the effects of cytochrome b5. J Inorg Biochem 2003;93(3/4):152-160.
52. Dias JM, Alves T, Bonifacio C, Pereira AS, Trincao J, Bourgeois D, Moura I, Romao MJ. Structural basis for the mechanism of Ca(2+) activation of the di-heme cytochrome c peroxidase from Pseudomonas nautica 617. Structure 2004;12:961-973.
53. Guallar V, Olsen B. The role of the heme propionates in heme biochemistry. J Inorg Biochem 2006;100:755-760.
54. Sharp KH, Mewies M, Moody PC, Raven EL. Crystal structure of the ascorbate peroxidase-ascorbate complex. Nat Struct Biol 2003;10:303-307.
55. Takayama SJ, Mikami S, Terui N, Mita H, Hasegawa J, Sambongi Y, Yamamoto Y. Control of the redox potential of Pseudomonas aeruginosa cytochrome c551 through the Fe-Met coordination bond strength and pKa of a buried heme propionic acid side chain. Biochemistry 2005;44:5488-5494.
56. Gruenke LD, Konopka K, Cadieu M, Waskell L. The stoichiometry of the cytochrome P-450-catalyzed metabolism of methoxyflurane and benzphetamine in the presence and absence of cytochrome b5. J Biol Chem 1995;270:24707-24718.
57. Imai M, Shimada H, Watanabe Y, Matsushima-Hibiya Y, Makino R, Koga H, Horiuchi T, Ishimura Y. Uncoupling of the cytochrome P-450cam monooxygenase reaction by a single mutation, threonine-252 to alanine or valine: possible role of the hydroxy amino acid in oxygen activation. Proc Natl Acad Sci USA 1989;86:7823-7827.
58. Raag R, Martinis SA, Sligar SG, Poulos TL. Crystal structure of the cytochrome P-450CAM active site mutant Thr252Ala. Biochemistry 1991;30:11420-11429.
59. Wen Z, Baudry J, Berenbaum MR, Schuler MA. Ile115Leu mutation in the SRS1 region of an insect cytochrome P450 (CYP6B1) compromises substrate turnover via changes in a predicted product release channel. Protein Eng Des Sel 2005;18:191-199.
60. Pan L, Wen Z, Baudry J, Berenbaum MR, Schuler MA. Identification of variable amino acids in the SRS1 region of CYP6B1 modulating furanocoumarin metabolism. Arch Biochem Biophys 2004;422:31-41.