A three-dimensional protein model for human cytochrome P450 2D6 based on the crystal structures of P450 101, P450 102, and P450 108

Chemical Research in Toxicology

Volumn 9, Issue 7, 1996, Pages 1079-1091

  De Groot, Marcel J ^a,b   Vermeulen, Nico P E ^a   Kramer, Jeroen D ^a,b   Van Acker, Frédérique A A ^a,b   Donné Op Den Kelder, Gabriëlle M ^a,b  

^a LEIDEN UNIVERSITY   (Netherlands)

^b VU UNIVERSITY AMSTERDAM   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOCHROME P450;

ARTICLE; CATALYSIS; CRYSTAL STRUCTURE; ENZYME ACTIVE SITE; ENZYME SUBSTRATE; MOLECULAR MODEL; PROTEIN SECONDARY STRUCTURE;

AMINO ACID SEQUENCE; BACTERIAL PROTEINS; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; CYTOCHROME P-450 CYP2D6; CYTOCHROME P-450 ENZYME SYSTEM; DEBRISOQUIN; HUMANS; MIXED FUNCTION OXYGENASES; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; PIPERAZINES; PROTEIN STRUCTURE, SECONDARY; SECOLOGANIN TRYPTAMINE ALKALOIDS; SEQUENCE ALIGNMENT; SUBSTRATE SPECIFICITY; YOHIMBINE;

BACTERIA (MICROORGANISMS);

EID: 0029995711     PISSN: 0893228X     EISSN: None     Source Type: Journal    
DOI: 10.1021/tx960003i     Document Type: Article

References (94)

1. Nelson, D. R., Kamataki, T., Waxman, D. J., Guengerich, F. P., Estabrook, R. W., Feyereisen, R., Gonzalez, F. J., Coon, M. J., Gunsalus, I. C., Gotoh, O., Okuda, K., and Nebert, D. W. (1993) The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol. 12, 1-51.
2. Mahgoub, A., Idle, J. R., Dring, L. G., Lancaster, R., and Smith, R. L. (1977) Polymorphic oxidation of debrisoquine in man. Lancet 11, 584-586.
3. Eichelbaum, M., Spannbrucker, N., Steineke, B., and Dengler, H. J. (1979) Defective N-oxidation of sparteine in man: a new pharmacogenetic effect. Eur. J. Clin. Pharmacol. 16, 183-187.
4. Armstrong, M., Fairbrother, K., Idle, J. R., and Daly, A. K. (1994) The cytochrome-P450 CYP2D6 allelic variant CYP2D6J and related polymorphisms in a European population. Pharmacogenetics 4, 73-81.
5. Eichelbaum, M., and Gross, A. S. (1990) The genetic polymorphism of debrisoquine/sparteine metabolism-clinical aspects. Pharmacol. Ther. 46, 377-394.
6. Korzekwa, K. R., and Jones, J. P. (1993) Predictingthe cytochrome P450 mediated metabolism of xenobiotics. Pharmacogenetics 3, 1-18.
7. Koymans, L. M. H., Donné-Op den Kelder, G. M., te Koppele, J. M., and Vermeulen, N. P. E. (1993) Cytochromes P450: their active site structure and mechanism of oxidation. Drug Metab. Rev. 25, 325-387.
8. Koymans, L. M. H., Vermeulen, N. P. E., van Acker, S. A. B. E., te Koppele, J. M., Heykants, J. J. P., Lavrijsen, K., Meuldermans, W., and Donné-Op den Kelder, G. M. (1992) A predictive model for substrates of cytochrome P-450-debrisoquine (2D6). Chem. Res. Toxicol. 5, 211-219.
9. Strobl, G. R., von Kreudener, S., Stöckigt, J., Guengerich, F. P., and Wolff, T. (1993) Development of a pharmacophore for inhibition of human liver cytochrome P-450 2D6: molecular modelling and inhibition studies. J. Med. Chem. 36, 1136-1145.
10. Wolff, T., Distlerath, L. M., Worthington, M. T., Groopman, J. D., Hammons, G. J., Kadlubar, F. F., Prough, R. A., Martin, M. M., and Guengerich, F. P. (1985) Substrate specificity of human liver cytochrome P-450 debrisoquine hydroxylase probed using immunochemical inhibition and chemical modeling. Cancer Res. 45, 2116-2122.
11. Meyer, U. A., Gut, J., Kronbach, T., Skoda, C., Meier, U. T., Catin, T., and Dayer, P. (1986) The molecular mechanism of two common polymorphisms of drug oxidation. Evidence for functional changes in cytochrome P-450 isozymes catalysing bufuralol and mephenytoin oxidation. Xenobiotica 16, 449-464.
12. Islam, S. A., Wolf, C. R., Lennard, M. S., and Sternberg, M. J. E. (1991) A three-dimensional molecular template for substrates of human cytochrome P450 involved in debrisoquine 4-hydroxylation. Carcinogenesis 12, 2211-2219.
13. de Groot, M. J., Bijloo, G. J., Hansen, K. T., and Vermeulen, N. P. E. (1995) Computer prediction and experimental validation of cytochrome P450-2D6 dependent oxidation of GBR 12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine). Drug Metab. Dispos. 23, 667-669.
14. Poulos, T. L., Finzel, B. C., Gunsalus, I. C., Wagner, G. C., and Kraut, J. (1985) The 2.6-Å crystal structure of Pseudomonas putida cytochrome P-450. J. Biol. Chem. 260, 16122-16130.
15. Ravichandran, K. G., Boddupalli, S. S., Hasemann, C. A., Peterson, J. A., and Deisenhofer, J. (1993) Crystal structure of hemoprotein domain of P450BM-3, a prototype for microsomal P450s. Science 261, 731-736.
16. BM-3. Acta Crystallogr., Sect. D: Biol. Crystallogr. 51, 21-32.
17. Cupp-Vickery, J. R., Li, H. Y., and Poulos, T. L. (1994) Preliminary crystallographic analysis of an enzyme involved in erythromycin biosynthesis: Cytochrome P450eryF. Proteins: Struct., Funct., Genet. 20, 197-201.
18. Cupp-Vickery, J. R., and Poulos, T. L. (1995) Structure of cytochrome P450eryF involved in erythromycin biosynthesis. Nature, Struct. Biol. 2, 144-153.
19. terp at 2.3 Å resolution. J. Mol. Biol. 236, 1169-185.
20. Nakahara, K., Shoun, H., Adachi, S., Iizuka, T., and Shiro, Y. (1994) Crystallization and preliminary X-ray diffraction studies of nitric oxide reductase cytochrome P450nor from Fusarium oxysporum. J. Mol. Biol. 239, 158-159.
21. Poulos, T. L. (1995) Cytochrome P450. Curr. Opin. Struct. Biol. 5, 767-774.
22. Zvelebil, M. J. J. M., Wolf, C. R., and Sternberg, M. J. E. (1991) A predicted three-dimensional structure of human cytochrome P450: implications for substrate specificity. Protein Eng. 4, 271-282.
23. Lewis, D. F. V., Ioannides, C., and Parke, D. V. (1994) Molecular modelling of cytochrome cyp1A1: A putative access channel explains differences in induction potency between the isomers benzo(a)pyrene and benzo(e)pyrene, and 2- and 4-acetylaminofluorene. Toxicol. Lett. 71, 235-243.
24. Szklarz, G. D., Ornstein, R. L., and Halpert, J. P. (1994) Application of 3-dimensional homology modeling of cytochrome P450 2B1 for interpretation of site-directed mutagenesis results. J. Biomol. Struct. Dyn. 12, 61-78.
25. Koymans, L. M. H., Vermeulen, N. P. E., Baarslag, A., and Donné-Op den Kelder, G. M. (1993) A preliminary 3D model for cytochrome P450 2D6 constructed by homology model building. J. Comput.-Aided Mol. Des. 7, 281-289.
26. Ferenczy, G. G., and Morris, G. M. (1989) The active site of cytochrome P-450 nifedipine oxidase: a model-building study. J. Mol. Graphics 7, 206-211.
27. scc. Biochim. Biophys. Acta 1160, 281-286.
28. 17α, a major target for the chemotherapy of prostatic cancer. Biochem. Biophys. Res. Commun. 171, 1160-1167.
29. Lin, D., Zhang, L. H., Chiao, E., and Miller, W. L. (1994) Modeling and mutagenesis of the active site of human P450c17. Mol. Endocrinol. 8, 392-402.
30. Graham-Lorence, S., Khalil, M. W., Florence, M. C., Mendelson, C. R., and Simpson, E. R. (1991) Structure-function relationships of human aromatase cytochrome P-450 using molecular modeling and site-directed mutagenesis. J. Biol. Chem. 266, 11939-11946.
31. Laughton, C. A., Zvelebil, M. J. J. M., and Neidle, S. (1993) A detailed molecular model for human aromatase. J. Steroid Biochem. Mol. Biol. 44, 399-407.
32. SG1: complete primary structures deduced from cloned DNAs. Biochem. Biophys. Res. Commun. 155, 317-323.
33. Boscott, P. E., and Grant, G. H. (1994) Modeling cytochrome P450 14a demethylase (Candida albicans) from P450cam. J. Mol. Graphics 12, 185-192.
34. Braatz, J. A., Bass, M. B., and Ornstein, R. L. (1994) An evolution of molecular models of the cytochrome P450 Streptomyces griseolus enzymes P450SU1 and P450SU2. J. Comput.-Aided Mol. Des. 8, 607-622.
35. Lewis, D. F. V., and Moereels, H. (1992) The sequence homologies of cytochrome P-450 and active-site geometries. J. Comput.-Aided Mol. Des. 6, 235-252.
36. bm3). Xenobiotica 25, 333-366.
37. Lewis, D. F. V., and Lake, B. G. (1995) Molecular modelling of members of the P4502A subfamily: application to studies of enzyme specificity. Xenobiotica 25, 585-598.
38. Ruan, K. H., Milfeld, K., Kulmacz, R. J., and Wu, K. K. (1994) Comparison of the construction of a 3-D model for human thromboxane synthase using P450cam and BM-3 as templates: implications for the substrate binding pocket. Protein Eng. 7, 1345-1351.
39. Szklarz, G. D., He, Y. A., and Halpert, J. R. (1995) Site-directed mutagenesis as a tool for molecular modeling of cytochrome P450 2B1. Biochemistry 34, 14312-14322.
40. Graham-Lorence, S., Amarneh, B., White, R. E., Peterson, J. A., and Simpson, E. R. (1995) A three-dimensional model of aromatase cytochrome P450. Protein Sci. 4, 1065-1080.
41. Koymans, L. M. H., Moereels, H., and Bossche, H. V. (1995) A molecular model for the interaction between vorozole and other non-steroidal inhibitors and human cytochrome P450 19 (P450 aromatase). J. Steroid Biochem. Mol. Biol. 53, 191-197.
42. Bernstein, F. C., Koetzle, T. F., Williams, G. J. B., Meyer, E. F., Jr., Brice, M. D., Rodgers, J. R., Kennard, O., Shimanouchi, T., and Tatsumi, M. (1977) The Protein Data Bank: a computer-based archival file for macromolecular structures. J. Mol. Biol. 112, 535-542.
43. Abola, E. E., Bernstein, F. C., Bryant, S. H., Koetzle, T. F., and Weng, J. (1987) Protein Data Bank. In Crystallographic data-bases-information contents, software systems, scientific applications (Allen, F. H., Bergerhoff, G., and Sievers, R., Eds.) pp 107-132, Data Commision of the International Union of Crystallography, Bonn/Cambridge/Chester.
44. George, D. G., and Barker, W. C. (1989) PSQ User's Guide, Protein Identification Resource, National Biomedical Research Foundation, Washington.
45. Leunissen, J. A. M., ter Vergert, J. M., and van Gelder, C. W. G. (1990) CAMMSA User Manual, version 1.0, CAOS/CAMM Center, University of Nijmegen, Nijmegen.
46. The University of York (1992) Quanta, version 4.0.
47. Harvard College (1992) CHARMm (Chemistry at HARvard Macromolecular mechanics), version 22.0.
48. Brooks, B. R., Bruccoleri, R. E., Olafson, B. D., States, D. J., Swaminathan, S., and Karplus, M. J. (1983) CHARMm: A program for macromolecular energy, minimization and dynamics calculations. J. Comput. Chem. 4, 187-217.
49. Evans, S.V. (1993) SETOR: Hardware-lighted three-dimensional solid model representations of macromolecules. J. Mol. Graphics 11, 134-138.
50. Evans, S. V., and University of British Columbia (1995) SETOR, version 4.13.4.
51. Hasemann, C. A., Kurumbail, R. G., Boddupalli, S. S., Peterson, J. A., and Deisenhofer, J. (1995) Structure and function of cytochromes P450: a comparative analysis of three crystal structures. Structure 2, 41-62.
52. Nelson, D. R., and Strobel, H. W. (1988) On the membrane topology of vertebrate cytochrome P-450 proteins. J. Biol. Chem. 263, 6038-6050.
53. cam. Biochemistry 28, 656-660.
54. Gotoh, O. (1992) Substrate recognition sites in cytochrome P450 family 2 (CYP2) proteins inferred from comparative analyses of amino acid and coding nucleotide sequences. J. Biol. Chem. 267, 83-90.
55. cam electron-transfer complex. Biochemistry 28, 8201-8205.
56. Williams, R. W., Chang, A., Juretic, D., and Loughran, S. (1987) Secondary structure predictions and medium range interactions. Biochim. Biophys. Acta 916, 200-204.
57. Wilmot, C. M., and Thornton, J. M. (1988) Analysis and prediction of the different types of β-turn in proteins. J. Mol. Biol. 203, 221-232.
58. Branden, C., and Tooze, J. (1991) Introduction to protein structure, Garland Publishing, New York.
59. Stryer, L. (1981) Biochemistry, 2nd ed., W. H. Freeman, New York.
60. Biosym Technologies (1994) Minimization. In Discover 2.9.5/94.0 User Guide, pp 4-1-4-28, Biosym Technologies, San Diego.
61. Schlegel, H. B. (1987) Optimization of equilibrium geometries and transition structures. In Ab Initio Methods in Quantum Chemistry (Lawley, K. P., Ed.) pp 249-286, Wiley, London.
62. Ellis, S. W., Hayhurst, G. P., Smith, G., Lightfoot, T., Wong, M. M. S., Simula, A. P., Ackland, M. J., Sternberg, M. J. E., Lennard, M. S., Tucker, G. T., and Wolf, C. R. (1995) Evidence that aspartic acid 301 is a critical substrate-contact residue in the active site of cytochrome P450 2D6. J. Biol. Chem. 270, 29055-29058.
63. Paulsen, M. D., and Ornstein, R. L. (1995) Dramatic differences in the motions of the mouth of open and closed cytochrome P450BM-3 by molecular dynamics simulations. Proteins: Struct., Funct., Genet. 21, 237-243.
64. Poulos, T. L., Finzel, B. C., and Howard, A. J. (1986) Crystal structure of substrate-free Pseudomonas putida cytochrome P-450. Biochemistry 25, 5314-5322.
65. cam binding surface as defined by site-directed mutagenesis and electrostatic modeling. Biochemistry 29, 7381-7386.
66. Straub, P., Lloyd, M., Johnson, E. F., and Kemper, B. (1993) Cassette mutagenesis of a potential substrate recognition region of cytochrome P450 2C2. J. Biol. Chem. 268, 21997-22003.
67. Straub, P., Lloyd, M., Johnson, E. F., and Kemper, B. (1994) Differential effects of mutations in substrate recognition site 1 of cytochrome P450 2C2 on lauric acid and progesterone hydroxylation. Biochemistry 33, 8029-8034.
68. cam. Biochemistry 26, 8165-8174.
69. Luo, Z., He, Y. A., and Halpert, J. R. (1994) Role of residues 363 and 206 in conversion of cytochrome P450 2B1 from steroid 16-hydroxylase to a 15α-hydroxylase. Arch. Biochem. Biophys. 309, 52-57.
70. He, Y., Luo, Z., Klekotka, P. A., Burnett, V. L., and Halpert, J. R. (1994) Structural determinants of cytochrome P450 2B1 specificity: evidence for five substrate recognition sites. Biochemistry 33, 4419-4424.
71. He, Y. Q., He, Y. A., and Halpert, J. R. (1995) Escherichia coli expression of site-directed mutants of cytochrome P450 2B1 from six substrate recognition sites: substrate specificity and inhibitor selectivity studies. Chem. Res. Toxicol. 8, 574-579.
72. coh substrate specificity by mutation of a single amino-acid residue. Nature 399, 632-634.
73. Juvonen, R. O., Iwasaki, M., and Negishi, M. (1991) Structural function of residue-209 in coumarin 7-hydroxylase (P450coh). Enzyme-kinetic studies and site-directed mutagenesis. J. Biol. Chem. 266, 16431-16435.
74. Iwasaki, M., Darden, T. A., Pedersen, L. G., Davis, D. G., Juvonen, R. O., Sueyoshi, T., and Negishi, M. (1993) Engineering mouse P450coh to a novel corticosterone 15α-hydroxylase and modeling steroid-binding orientation in the substrate pocket. J. Biol. Chem. 268, 759-762.
75. 7a): role of residue-209 in determining steroid-cytochrome P-450 interaction. Biochem. J. 291, 569-573.
76. Christou, M., Mitchell, M. J., Aoyama, T., Gelboin, H. V., Gonzalez, F. J., and Jefcoate, C. R. (1992) Selective suppresion of the catalytic activity of cDNA-expressed cytochrome P4502B1 toward polycyclic hydrocarbons in the microsomal membrane: modification of this effect by specific amino acid substitutions. Biochemistry 31, 2835-2841.
77. Hasler, J. A., Harlow, G. R., Szklarz, G. D., John, G. H., Kedzie, K. M., Burnett, V. L., He, Y. A., Kaminsky, L. S., and Halpert, J. R. (1994) Site-directed mutagenesis of putative substrate recognition sites in cytochrome P450 2B11: importance of amino acid residues 114, 290, and 363 for substrate specificity. Mol. Pharmacol. 46, 338-345.
78. Imai, Y., and Nakamura, M. (1989) Point mutations at threonine-301 modify substrate specificity of rabbit liver microsomal cytochromes P-450 (laurate (ω-1)-hydroxylase and testosterone 16α-hydroxylase). Biochem. Biophys. Res. Commun. 158, 717-722.
79. Fukuda, T., Imai, Y., Lomori, M., Nakamura, M., Kusunose, E., Satouchi, K., and Kusunose, M. (1993) Replacement of Thr-303 of P450 2E1 with serine modifies the regioselectivity of its fatty acid hydroxylase activity. J. Biochem. 113, 7-12.
80. Kaminsky, L. S., de Morais, S. M. F., Faletto, M. B., Dunbar, D. A., and Goldstein, J. A. (1993) Correlation of human cytochrome P4502C substrate specificities with primary structure: warfarin as a probe. Mol. Pharmacol. 43, 234-239.
81. Gonzalez, F. J., Skoda, R. C., Kimura, S., Umeno, M., Zanger, U. M., Nebert, D. W., Gelboin, H. V., Hardwick, J. P., and Meyer, U. A. (1988) Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 331, 442-446.
82. Ellis, S. W., Rowland, K., Harlow, J. R., Simula, A. P., Leonard, M. S., Woods, H. F., Tucker, G. T., and Wolf, C. R. (1994) Regio- and enantioselective metabolism of metoprolol by two human cDNA-derived CYP2D6 proteins. Br. J. Pharmacol. 112, 244P.
83. Mautz, D. S., Nelson, W. L., and Shen, D. D. (1995) Regioselective and stereoselective oxidation of metoprolol and bufuralol catalyzed by microsomes containing cDNA-expressed human P4502D6. Drug Metab. Dispos. 23, 513-517.
84. Grimm, S. W., Dyroff, M. C., Philpot, R. M., and Halpert, J. R. (1994) Catalytic selectivity and mechanism-based inactivation of stably expressed and hepatic cytochromes P450 2B4 and 2B5: implications of the cytochrome P450 2B5 polymorphism. Mol. Pharmacol. 46, 1090-1099.
85. Hsu, M. H., Griffin, K. J., Wang, Y., Kemper, B., and Johnson, E. F. (1993) A single amino acid substitution confers progesteron 60-hydroxylase activity to rabbit cytochrome P450 2C3. J. Biol. Chem. 268, 6939-6944.
86. Matsunaga, E., Zanger, U. M., Hardwick, J. P., Gelboin, H. V., Meyer, U. A., and Gonzalez, F. J. (1989) The CYP2D gene subfamily: analysis of the molecular basis of the debrisoquine 4-hydroxylase deficiency in DA rats. Biochemistry 28, 7349-7355.
87. max, of the enzyme for bufuralol but not debrisoquine hydroxylation. J. Biol. Chem. 265, 17197-17201.
88. Kedzie, K. M., Balfour, C. A., Escobar, G. Y., Grimm, S. W., He, Y. A., Pepperl, D. J., Regan, J. W., Stevens, J. C., and Halpert, J. R. (1991) Molecular basis for a functionally unique cytochrome P450IIB1 variant. J. Biol. Chem. 266, 22515-22521.
89. He, Y. A., Balfour, C. A., Kedzie, K. M., and Halpert, J. R. (1992) Role of residue 478 as a determinant of the substrate specificity of cytochrome P450 2B1. Biochemistry 31, 9220-9226.
90. Halpert, J. R., and He, Y. A. (1993) Engineering of cytochrome P450 2B1 specificity. Conversion of an androgen 16β-hydroxylase to a 15α-hydroxylase. J. Biol. Chem. 268, 4453-4457.
91. Li, H., and Poulos, T. L. (1994) Structural variation in heme enzymes: a comparative analysis of peroxidase and P450 crystal structures. Structure 2, 461-464.
92. Groves, J. T., Haushalter, R. C., Nakamura, M., Nemo, T. E., and Evans, B. J. (1981) High-valent iron-porphyrin complexes related to peroxydase and cytochrome P-450. J. Am. Chem. Soc. 103, 2884-2886.
93. Groves, J. T., and Watanabe, Y. (1988) Reactive iron porphyrin derivatives related to the catalytic cycles of cytochrome P-450 and peroxydase. Studies of the mechanism of oxygen activation. J. Am. Chem. Soc. 110, 8443-8452.
94. Mizutani, Y., Watanabe, Y., and Kitagawa, T. (1994) Resonance Raman characterization of iron(III)porphyrin N-oxide, Evidence for an Fe-O-N bridged structure. J. Am. Chem. Soc. 116, 3439-3441.