A three-dimensional model of lanosterol 14α-demethylase of Candida albicans and its interaction with azole antifungals

Journal of Medicinal Chemistry

Volumn 43, Issue 13, 2000, Pages 2493-2505

  Ji, Haitao ^a   Zhang, Wannian ^a   Zhou, Youjun ^a   Zhang, Min ^a   Zhu, Jie ^a   Song, Yunlong ^a   Lü, Jiaguo ^a   Zhu, Jü ^a  

^a SECOND MILITARY MEDICAL UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

2 (2,4 DIFLUOROPHENYL) 1 [3 [2 [4 (2,2,3,3 TETRAFLUOROPROPOXY)PHENYL]VINYL] 1,2,4 TRIAZOL 1 YL] 3 (1,2,4 TRIAZOL 1 YL) 2 PROPANOL; 2 [2 (2,4 DIFLUOROPHENYL) 2 HYDROXY 1 METHYL 3 (1H 1,2,4 TRIAZOL 1 YL)PROPYL] 4 [4 (2,2,3,3 TETRAFLUOROPROPOXY)PHENYL] 1,2,4 TRIAZOL 3(2H) ONE; ALPHA (4 CHLOROPHENYL) ALPHA (1 CYCLOPROPYL 1 METHYLETHYL) 1H 1,2,4 TRIAZOLE 1 ETHANOL; ANTIFUNGAL AGENT; FLUCONAZOLE; FUNGAL ENZYME; GENACONAZOLE; ITRACONAZOLE; KETOCONAZOLE; MICONAZOLE; OXICONAZOLE; PYRROLE DERIVATIVE; RAVUCONAZOLE; VORICONAZOLE;

AMINO ACID SEQUENCE; ARTICLE; CANDIDA ALBICANS; DRUG PROTEIN BINDING; ENZYME ACTIVE SITE; ENZYME BINDING; NONHUMAN;

AMINO ACID SEQUENCE; ANTIFUNGAL AGENTS; AZOLES; CANDIDA ALBICANS; CATALYTIC DOMAIN; CRYSTALLOGRAPHY, X-RAY; CYTOCHROME P-450 ENZYME SYSTEM; ENZYME INHIBITORS; HEME; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MOLECULAR SEQUENCE DATA; OXIDATION-REDUCTION; OXIDOREDUCTASES; PROTEIN BINDING;

EID: 0034729667     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm990589g     Document Type: Article

References (65)

1. Trzaskos, J. M.; Fischer, R. T.; Favata, M. F. Mechanistic studies of lanosterol C-32 demethylation conditions which promote oxysterol intermediate accumulation during the demethylation process. J. Biol. Chem. 1986, 267, 16937-16942.
2. Aoyama, Y.; Yoshida, Y.; Sonoda, Y.; Sato, Y. Metabolism of 32-hydroxy-24,25-dihydrolanosterol by purified cytochrome P-45014DM from yeast. J. Biol. Chem. 1987, 262, 1239-1243.
3. 14DM (Lanosterol 14α-demethylase) from yeast evidence confirming the intermediate step of lanosterol 14α-demethylation. J. Biol. Chem. 1989, 264, 18502-18505.
4. Fischer, R. T.; Trzaskos, J. M.; Magolda, R. L.; Ko, S. S.; Brosz, C. S.; Larsen, B. Lanosterol 14α-methyl demethylase isolation and characterization of the third metabolically generated oxidative demethylation intermediate. J. Biol. Chem. 1991, 266, 6124-6132.
5. Shyadehi, A. Z.; Lamb, D. C.; Kelly, S. L.; Kelly, D. E.; Schunck, W.-H.; Wright, J. N.; Corina, D.; Akhtar, M. The mechanism of the acyl-carbon bond cleavage reaction catalyzed by recombinant sterol 14α-demethylase of Candida albicans. J. Biol. Chem. 1996, 271, 12445-12450.
6. Lamb, D. C.; Kelly, D. E.; Kelly, S. L. Molecular diversity of sterol 14α-demethylase substrates in plants, fungi and humans. FEBS Lett. 1998, 425, 263-265.
7. Aoyama, Y.; Noshiro, M.; Gotoh, O.; Imaoka, S.; Funae, Y.; Kurosawa, N.; Horiuchi, T.; Yoshida, Y. Sterol 14α-demethylase P450 (P45014DM) is one of the most ancient and conserved P450 species. J. Biochem. 1996, 119, 926-933.
8. Yoshida, Y.; Noshiro, M.; Aoyama, Y.; Kawamoto, T.; Horiuchi, T.; Gotoh, O. Structural and evolutionary studies on sterol 14-demethylase P450 (CYP51), the most conserved P450 monooxygenase: II. Evolutionary analysis of protein and gene structures. J. Biochem. 1997, 122, 1122-1128.
9. Lamb, D. C.; Kelly, D. E.; Venkateswarlu, K.; Manning, N. J.; Bligh, H. F.; Schunck, W. H.; Kelly, S. L. Generation of a complete, soluble, and catalytically active sterol 14α-demethylase-reductase complex. Biochemistry 1999, 38, 8733-8738.
10. Cabello-Hurtado, F.; Taton, M.; Forthoffer, N.; Kahn, R.; Bak, S.; Rahier, A.; Werck-Reichhart, D. Optimized expression and catalytic properties of a wheat obtusifoliol 14α-demethylase (CYP51) expressed in yeast. Complementation of erg11Delta yeast mutants by plant CYP51. Eur. J. Biochem. 1999, 262, 435-446.
11. Bellamine, A.; Mangla, A. T.; Nes, W. D.; Waterman, M. R. Characterization and catalytic properties of the sterol 14α-demethylase from Mycobacterium tuberculosis. Proc. Natl. Acad. Sci U.S.A. 1999, 96, 8937-8942.
12. Lai, M. H.; Kirsh, D. R. Nucleotide sequence of cytochrome P450LIA1 (lanosterol 14α-demethylase) from Candida albicans. Nucleic Acid Res. 1989, 17, 804.
13. Van Nistelrooy, J. G. M.; van der Brink, J. M.; van Kan, J. A. L.; van Gorcom, R. F. M.; de Waard, M. A. Isolation and molecular characterisation of the gene encoding eburicol 14α-demethylase (CYP51) from Penicillium italicum. Mol. Gen. Genet. 1996, 250, 725-733.
14. Nitahara, Y.; Aoyama, Y.; Horiuchi, T.; Noshiro, M.; Yoshida, Y. Purification and characterization of rat sterol 14-demethylase P450(CYP51) expressed in Escherichia coli. J. Biochem. 1999, 126, 927-933.
15. Stromstedt, M.; Rozman, D.; Waterman, M. R. The ubiquitously expressed human CYP51 encodes lanosterol 14α-demethylase, a cytochrome P450 whose expression is regulated by oxysterols. Arch. Biochem. Biophys. 1996, 329, 73-81.
16. Poulos, T. L.; Finzel, B. C.; Howard, A. J. High-resolution crystal structure of cytochrome P450cam. J. Mol. Biol. 1987, 195, 687-700.
17. Hasemann, C. A.; Ravichandran, K. G.; Peterson, J. A.; Deisenhofer J. Crystal structure and refinement of cytochrome P450terp at 2.3A resolution. J. Mol. Biol. 1994, 236, 1169-1185.
18. Cupp-Vickery, J. R.; Poulos, T. L. Structure of cytochrome P450eryF involved in erythromycin biosynthesis. Natl. Struct. Biol. 1995, 2, 144-153.
19. Ravichandran, K. G.; Boddupalli, S. S.; Hasemann, C. A.; Peterson, J. A.; Deisenhofer J. Crystal structure of hemoprotein domain of P450BM3, a prototype for microsomal P450's. Science 1993, 261, 731-736.
20. Hasemann, C. A.; Kurumbail, R. G.; Boddupalli, S. S.; Peterson J. A.; Deisenhofer J. Structure and function of cytochromes P450: A comparative analysis of three crystal structures. Structure 1995, 2, 41-62.
21. Ji, H.-T.; Zhang W.-N.; Zhou Y.-J.; Lü, J.-G.; Zhu J. Zhu J. Comparative studies on crystal structures of four members of cytochrome P450 superfamily. Acta Biochim. Biophys. Sin. 1998, 30, 419-426.
22. Zvelebil, M. J. J. M.; Wolf, C. R.; Sternberg, M. J. E. A predicted three-dimensional structure of human cytochrome P450: Implications for substrate specificity. Protein Eng. 1991, 4, 271-282.
23. Szklarz, G. D.; Ornstein, R. L.; Halpert, J. R. Application of 3-dimensional homology modeling of cytochrome P450 2B1 for interpretation of site-directed mutagenesis results. J. Biomol. Struct. Dyn. 1994, 12, 61-78.
24. Lin, D.; Zhang L. H.; Chiao, E.; Miller, W. L. Modeling and mutagenesis of the active site of human P450c17. Mol. Endocrinol. 1994, 8, 392-402.
25. Laughton, C. A.; Zvelebil, M. J. J. M.; Neidle S. A detailed molecular model for human aromatase. J. Steroid Biochem. Mol. Biol. 1993, 44, 4-6.
26. Lewis, D. F. Homology modelling of human cytochromes P450 involved in xenobiotic metabolism and rationalization of substrate selectivity. Exp. Toxicol. Pathol. 1999, 51, 369-374.
27. Lozano, J. J.; Lopez-de-Brinas E.; Centeno N. B.; Guigo R.; Sanz F. Three-dimensional modelling of human cytochrome P450 1A2 and its interaction with caffeine and MeIQ. J. Comput.-Aid. Mol. Des. 1997, 11, 395-408.
28. Lewis, D. F.; Dickins, M.; Lake, B. G.; Eddershaw, P. J.; Tarbit, M. H.; Goldfarb, P. S. Molecular modelling of the human cytochrome P450 isoform CYP2A6 and investigations of CYP2A substrate selectivity. Toxicology 1999, 133, 1-33.
29. Dai, R.; Pincus, M. R.; Friedman, F. K. Molecular modeling of cytochrome P450 2B1: Mode of membrane insertion and substrate specificity. J. Protein Chem. 1998, 17, 121-129.
30. Lewis, D. F.; Lee-Robichaud, P. Molecular modelling of steroidogenic cytochromes P450 from families CYP11, CYP17, CYP19 and CYP21 based on the CYP102 crystal structure. J. Steroid Biochem. Mol. Biol. 1998, 66, 217-233.
31. Ruan, K.-H.; Milfeld, K.; Kulmacz, R. J.; Wu, K. K. Comparison of the concstruction of a 3-D model for human thromboxane synthase using P450camand BM-3 as templates: implications for the substrate binding pocket. Protein Eng. 1994, 7, 1345-1351.
32. Graham-Lorence, S.; Amarneh, B.; White, R. E.; Peterson J. A.; Simpson E. R. A three-dimensional model of aromatase cytochrome P450. Protein Sci. 1995, 4, 1065-1080.
33. Wang, L. H.; Matijevic-Aleksic, N.; Hsu, P. Y.; Ruan, K. H.; Wu, K. K.; Kulmacz, R. J. Identification of thromboxane A2 synthase active site residues by molecular modeling-guided site-directed mutagenesis. J. Biol. Chem. 1996, 271, 19970-19975.
34. Boscott, P. E., Grant, G. H. Modeling cytochrome P450 14α-demethylase (Candida albicans) from P450cam. J. Mol. Graph. 1994, 12, 185-92, 195.
35. Tsukuda, T.; Shiratori, Y.; Watanabe, M.; Ontsuka, H.; Hattori, K.; Shirai, M.; Shimma, N. Modeling, synthesis and biological activity of novel antifungal agents (1). Bioorg. Med. Chem. Lett. 1998, 8, 1819-1824.
36. Holtje, H.-D.; Fattorusso, C. Construction of a model of the Candida albicans lanosterol 14α-demethylase active site using the homology modelling technique. Pharm. Acta Helv. 1998, 72, 271-277.
37. TRIPOS Associates, Inc., 1699S. Hanley Road, Suite 303, St. Louis, MO 63144.
38. Molecular Simulation Inc. 9685 Scranton Road, San Diego, CA 92121-3752.
39. Needlman, S. B.; Wunsch, C. D. A general method applicable to the search for similarities in the amino acid sequences of two proteins. J. Mol. Biol. 1970, 48, 443-453.
40. Maxifield, F. R.; Scheraga, H. A. Status of empirical methods for the prediction of protein backbone topography. Biochemistry 1976, 15, 5138-5153.
41. Kyte, J.; Doolittle, R. F. A simple method for displaying the hydropathic character of a protein. J. Mol. Biol. 1982, 157, 105-132.
42. Claessens, M.; van Cutsem, E.; Lasters, I.; Wodak S. Modelling the polypeptide backbone with 'spare parts' from known protein structures. Protein Eng. 1989, 2, 335-345.
43. Luthy, R.; Bowie, J. U.; Eisenberg, D. Assessment of protein models with three-dimensional profiles. Nature 1992, 356, 83-85.
44. cam. Proteins: Struct. Funct. Genet. 1991, 11, 184-204.
45. Plempel, M. Experience, recognitions and questions in azole antimycotics. Shinkin to Shinkinsho 1982, 23, 17-27.
46. Yoshida, Y.; Aoyama, Y. Interaction of azole antifungal agents with cytochrome P-45014DM purified from Saccharomyces cerevisiae microsomes. Biochem. Pharmacol. 1987, 36, 229-235.
47. Chuman, H.; Ito, A.; Saishoji, T.; Kumazawa S. QSARs and three-dimensional shape studies of fungicidal azolylmethylcyclopentanols. ACS Symp. Ser. 1995, 606, 171-185.
48. Walker, K. A. M.; Hirschfeld, D. R.; Marx M. Antimycotic imidazoles. 2. Synthesis and antifungal properties of esters of 1-[2-hydroxy(mercapto)-2-phenylethyl]-1H-imidazoles. J. Med. Chem. 1978, 21, 1335-1338.
49. Tasaka, A.; Kitazaki, T.; Tsuchimori, N.; Matsushita, Y.; Hayashi, R.; Okonogi, K.; Itoh, K. Optically active antifungal azoles. VII. Synthesis and antifungal activity of stereoisomers of 2-[(1R, 2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]- 4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (TAK-187). Chem. Pharm. Bull. 1997, 45, 321-326.
50. Rotstein, D. M.; Kertesz, D. J.; Walker, K. A. M.; Swinney, D. C. Stereoisomers of Ketoconazole: Preparation and biological activity. J. Med. Chem. 1992, 35, 2818-2825.
51. Tasaka, A.; Tamura, N.; Matsushita, Y.; Teranishi, K.; Hayashi, R.; Okonogi, K.; Itoh, K. Optically active antifungal azoles. I. synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol and its stereoisomers. Chem. Pharm. Bull. 1993, 41, 1035-1042.
52. CAM. Biochemistry 1993, 32, 4571-4578.
53. Kelly, S. L.; Lamb, D. C.; Loeffler, J.; Einsele, H.; Kelly, D. E. The G464S amino acid substitution in Candida albicans sterol 14α-demethylase causes fluconazole resistance in the clinic through reduced affinity. Biochem. Biophys. Res. Commun. 1999, 262, 174-179.
54. White, T. C. The presence of an R467K amino acid substitution and loss of allelic variation correlate with an azole-resistant lanosterol 14α-demethylase in Candida albicans. Antimicrob. Agents Chemother. 1997, 41, 1488-1494.
55. SG1: complete primary structures deduced from clone DNAs. Biochem. Biophy. Res. Commun. 1988, 155, 317-323.
56. Lamb, D. C.; Kelly, D. E.; Schunck, W.-H.; Shyadehi, A. Z.; Akhtar, M.; Lowe, D. J.; Baldwin, B. C.; Kelly, S. L. The Mutation T315A in candida albicans sterol 14α-demethylase causes reduced enzyme activity and fluconazole resistance through reduced affinity. J. Biol. Chem. 1997, 272, 5682-5688.
57. 14DM. Biochim. Biophys. Acta 1989, 1006, 209-213.
58. 14DM. Biochim. Biophys. Acta 1989, 1001, 196-200.
59. Aoyama, Y.; Yoshida, Y.; Sonoda, Y.; Sato Y. Role of the side chain of lanosterol in substrate recognition and catalytic activity of lanosterol 14α-demethylase of yeast. Biochim. Biophys. Acta 1991, 1081, 262-266.
60. Aoyama, Y.; Yoshida, Y.; Sonoda, Y.; Sato, Y. Structure analysis of the interaction between the side-chain of substrates and the active site of lanosterol 14α-demethylase of yeast. Biochim. Biophys. Acta 1992, 1122, 251-255.
61. Klopman, G.; Ptchelintsev, D. Antifungal triazole alcohols: a comparative analysis of structure-activity, structure-teratogenicity and structure-therapeutic index relationships using the multiple computer-automated structure evaluation (Multi-CASE) methodology. J. Comput.-Aided Mol. Des. 1993, 7, 349-362.
62. Asai, K.; Tsuchimori, N.; Okonogi, K.; Perfect, J. R.; Gotoh, O.; Yoshida, Y. Formation of azole-resistant Candida albicans by mutation of sterol 14-demethylase P450. Antimicrob. Agents Chemother. 1999, 43, 1163-1169.
63. 14αDM inhibiting azole antifungal agents. J. Chem. Inf. Comput. Sci. 1999, 39, 204-210.
64. Bartroli, J.; Turmo, E.; Alguero, M.; Boncompte, E.; Vericat, M. L.; Conte, L.; Ramis, J.; Merlos, M.; Garcia-Rafanell, J.; Forn, J. New azole antifungals. 2. Synthesis and antifungal activity of heterocyclecarboxamide derivatives of 3-amino-2-aryl-1-azolyl-2-butanol. J. Med. Chem. 1998, 41, 1855-1868.
65. Lewis, D. F. V.; Wiseman, A.; Tarbit, M. H. Molecular modelling of lanosterol 14α-demethylase (CYP51) from Saccharomyces cerevisiae via homology with CYP102, a unique bacterial cytochrome P450 isoform: quantitative structure-activity relationships (QSARs) within two related series of antifungal azole derivatives. J. Enzyme Inhibit. 1999, 14, 175-192.