Y132H substitution in Candida albicans sterol 14α-demethylase confers fluconazole resistance by preventing binding to haem

FEMS Microbiology Letters

Volumn 180, Issue 2, 1999, Pages 171-175

  Kelly, Steven L ^a   Lamb, David C ^a   Kelly, Diane E ^a  

^a ABERYSTWYTH UNIVERSITY   (United Kingdom)

Author keywords

Azole antifungal; Candida albicans; P450; Resistance; Sterol

Indexed keywords

CYTOCHROME P450 ISOENZYME; ERGOSTEROL; FLUCONAZOLE; HEME; MUTANT PROTEIN;

ARTICLE; CANDIDA ALBICANS; DEMETHYLATION; DRUG RESISTANCE; MUTATION; NONHUMAN; NUCLEOTIDE SEQUENCE; PRIORITY JOURNAL; SITE DIRECTED MUTAGENESIS; SPECTROPHOTOMETRY; STEROL SYNTHESIS;

AMINO ACID SUBSTITUTION; ANTIFUNGAL AGENTS; CANDIDA ALBICANS; CYTOCHROME P-450 ENZYME SYSTEM; DRUG RESISTANCE, MICROBIAL; FLUCONAZOLE; HEME; HUMANS; MUTAGENESIS, SITE-DIRECTED; OXIDOREDUCTASES; RECOMBINANT PROTEINS; SACCHAROMYCES CEREVISIAE; SPECTROPHOTOMETRY;

CANDIDA ALBICANS;

EID: 0032733078     PISSN: 03781097     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0378-1097(99)00478-4     Document Type: Article

References (20)

1. Lamb, D.C., Kelly, D.E. and Kelly, S.L. (1998) Molecular diversity of sterol 14α-demethylase substrates in plants, fungi and humans. FEBS Lett. 425, 263-265.
2. Lamb, D.C., Kelly, D.E., Manning, N.J. and Kelly, S.L. (1998) A sterol biosynthetic pathway in Mycobacterium. FEBS Lett. 437, 142-144.
3. Aoyama, Y., Horiuchi, T., Gotoh, O., Noshiro, M. and Yoshida, Y. (1998) CYP51-like gene of Mycobacterium tuberculosis actually encodes a P450 similar to eukaryotic CYP51. J. Biochem. 124, 694-696.
4. Stromstedt, M., Rozman, D. and Waterman, M.R. (1996) The ubiquitously expressed human CYP51 encodes lanosterol 14 alpha- demethylase, a cytochrome P450 whose expression is regulated by oxysterols. Arch. Biochem. Biophys. 329, 73-81.
5. Kelly, S.L., Lamb, D.C., Kelly, D.E., Loeffler, J. and Einsele, H. (1996) Resistance to fluconazole and amphotericin in Candida albicans from AIDS patients. Lancet 348, 1523-1524.
6. Law, D., Moore, C.B., Wardle, H.M., Ganguli, L.A., Keaney, M.G. and Denning, D.W. (1994) High prevalence of antifungal resistance in Candida spp. from patients with AIDS. J. Antimicrob. Chemother. 34, 659-668.
7. Lamb, D.C., Kelly, D.E., Schunck, W.H., Shyadehi, A.Z., Akhtar, M., Lowe, D.J., Baldwin, B.C. and Kelly, S.L. (1997) The mutation T315A in Candida albicans sterol 14alpha-demethylase causes reduced enzyme activity and fluconazole resistance through reduced affinity. J. Biol. Chem. 272, 5682-5688.
8. Loffler, J., Kelly, S.L., Hebart, H., Schumacher, U., Lass-Florl, C. and Einsele, H. (1997) Molecular analysis of CYP51 from fluconazole-resistant Candida albicans strains. FEMS Microbiol. Lett. 151, 263-268.
9. Sanglard, D., Ischer, F., Koymans, L. and Bille, J. (1998) Amino acid substitutions in the cytochrome P-450 lanosterol 14alpha- demethylase (CYP51A1) from azole-resistant Candida albicans clinical isolates contribute to resistance to azole antifungal agents. Antimicrob. Agents Chemother. 42, 241-253.
10. White, T.C. (1997) The presence of an R467K amino acid substitution and loss of allelic variation correlate with an azole-resistant lanosterol 14alpha demethylase in Candida albicans. Antimicrob. Agents Chemother. 41, 1488-1494.
11. Asai, K., Tsuchimori, N., Okonogi, K., Perfect, J.R., Gotoh, O. and Yoshida, Y. (1999) Formation of azole-resistant Candida albicans by mutation of sterol 14-demethylase P450. Antimicrob. Agents Chemother. 43, 1163-1169.
12. Delye, C., Laigret, F. and Corio-Costet, M.F. (1997) A mutation in the 14 alpha-demethylase gene of Uncinula necator that correlates with resistance to a sterol biosynthesis inhibitor. Appl. Environ. Microbiol. 63, 2966-2970.
13. Shyadehi, A.Z., Lamb, D.C., Kelly, S.L., Kelly, D.E., Schunck, W.H., Wright, J.N., Corina, D. and Akhtar, M. (1996) The mechanism of the acyl-carbon bond cleavage reaction catalyzed by recombinant sterol 14 alpha-demethylase of Candida albicans (other names are: lanosterol 14 alpha-demethylase, P-45014DM, and CYP51). J. Biol. Chem. 271, 12445-12450.
14. Omura, T. and Sato, R. (1964) The carbon monoxide binding pigment of liver microsomes. I. Evidence for its haemoprotein nature. J. Biol. Chem. 239, 2370-2378.
15. Lowry, O.H., Rosenbrough, N.J., Farr, A.O. and Randall, R.J. (1951) Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193, 928-929.
16. Wiggins, T. and Baldwin, B.C. (1984) Binding of azole fungicides related to diclobutrazol to cytochrome P450. Pesticide Sci. 15, 206-209.
17. Santos, A.S., Keith, G. and Tuite, M.F. (1993) Non-standard translational events in Candida albicans mediated by an unusual seryl-tRNA with a 5′ -CAG-3′ (leucine) anticodon. EMBO J. 12, 607-616.
18. Yoshida, Y. and Aoyama, Y. (1987) Interaction of azole antifungal agents with cytochrome P45014DM purified from Saccharomyces cerevisiae microsomes. Biochem. Pharmacol. 36, 229-235.
19. Boscott, P.E. and Grant, G.H. (1994) Modeling cytochrome P450 14 alpha demethylase (Candida albicans) from P450cam. J. Mol. Graph. 12, 185-192, 195.
20. Lamb, D.C., Kelly, D.E., Venkateswarlu, K., Schunck, W.-H. and Kelly, S.L. (1999) Generation of a complete, soluble and catalytically active sterol 14α-demethylase-reductase complex. Biochemistry 38, 8733-8738.