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Volume 34 Issue 2
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Article Navigation >  Journal of Pharmaceutical Practice and Service  > 2016  >  34(2): 106-109

LI Ran, ZHANG Dazhi. Development in research of CYP51 as the target of triazoles[J]. Journal of Pharmaceutical Practice and Service, 2016, 34(2): 106-109. doi: 10.3969/j.issn.1006-0111.2016.02.003
Citation: LI Ran, ZHANG Dazhi. Development in research of CYP51 as the target of triazoles[J]. Journal of Pharmaceutical Practice and Service, 2016, 34(2): 106-109. doi: 10.3969/j.issn.1006-0111.2016.02.003
shu

Development in research of CYP51 as the target of triazoles

doi: 10.3969/j.issn.1006-0111.2016.02.003

  • Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China

  • Received Date: 2015-12-21
  • Rev Recd Date: 2016-01-26
  • Triazoles are the most widely used antifungal drugs in clinic with broad spectrum and high efficacy, which targets sterol 14α-demethylase(CYP51), an enzyme expressed by the gene EGR 11, which is a key enzyme in the fungi ergosterol biosynthesis. On the one hand, the CYP51 belongs to a transmembrane protein. It is difficult to get the exact functional structure conformation which becomes a big challenge for the development of new drugs. On the other hand, it becomes consensus that EGR11 exon mutation cause CYP51 structural change is one of the major reasons for antifungal drugs resistance. Therefore, study of the structural changes toward the antifungal drug resistance is quite important. The review authors have summarized the research progress on CYP51 over the recent years.
  • [1] Lepesheva GI, Waterman MR. Sterol 14alpha-demethylase(cyp51) as a therapeutic target for human trypanosomiasis and leishmaniasis[J]. Curr Top Med Chem, 2011, 11(16):2060-2071.
    [2] Yoshida Y. Cytochrome P450 of fungi:primary target for azole antifungal agents[J]. Curr Top Med Mycol, 1988, 2:388-418.
    [3] Warrilow AG, Melo N, Martel, CM, et al. Expression, purification, and characterization of Aspergillus fumigatus sterol 14α-demethylase(CYP51) isoenzymes A and B[J]. Antimicrob Agents Chemother, 2010, 54(10):4225-4234.
    [4] Lepesheva GI, Waterman MR. Structural basis for conservation in the CYP51 family[J]. Biochim Biophys Acta,2011, 1814(1):88-93.
    [5] Sheng CQ, Miao ZY, Ji HT, et al. Three-dimensional model of lanosterol 14α-demethylase from cryptococcus neoformans:active-site characterization and insights into azole binding[J]. Antimicrob Agents Chemother, 2009, 53(8):3487-3495.
    [6] Monk BC, Tomasiak TM, Keniya MV, et al. Architecture of a single membrane spanning cytochrome P450 suggests constraints that orient the catalytic domain relative to a bilayer[J]. Proc Natl Acad Sci(USA), 2014, 111(10):3865-3870.
    [7] Ji, HT, Zhang WN, Zhou YJ, et al. A three-dimensional model of lanosterol 14α-demethylase of Candida albicans and its interaction with azole antifungal[J]. J Med Chem, 2000, 43(13):2493-2505.
    [8] Sheng CQ, Zhang WN, Zhang MY, et al. Homology modeling of lanosterol 14α-demethylase of Candida albicans and Aspergillus fumigatus and insights into the enzymesubstrate interactions[J]. J Biomol Struct Dyn, 2004, 22(1):91-99.
    [9] Li X, Vincent M, Andrew SC, et al. Three-dimensional models of wild-type and mutated forms of cytochrome P45014-sterol demethylases from aspergillus fumigatus and Candida albicans provide insights into Posaconazole binding[J]. Antimicrob Agents Chemother, 2004, 48(2):568-574.
    [10] Warrilow AG, Parker JE, Kelly DE, et al. Azole affinity of sterol 14-demethylase(CYP51) enzymes from Candida albicans and Homo sapiens[J]. Antimicrob Agents Chemother, 2013, 57(3):1352-1360.
    [11] Fan J, Urban M, Parker JE, et al. Characterization of the sterol 14α-demethylases of Fusarium graminearum identifies a novel genus-specific CYP51 function[J]. New Phytol, 2013, 198(3):821-835.
    [12] Hawkins NJ, Cools HJ, Sierotzki H, et al. Paralog re-emergence:a novel,historically contingent mechanism in the evolution of antimicrobial resistance[J]. Mol Biol Evol, 2014, 31(7):1793-1802.
    [13] Hargrove TY, Wawrzak Z, Lamb DC,et al.Structure-functional characterization of cytochrome P450 sterol 14α-demethylase(CYP51B) from Aspergillus fumigatus and molecular basis for the development of antifungal drugs[J].J Biol Chem, 2015, 290(39):23916-23934.
    [14] Cools HJ, Mullins JG, Fraaije BA, et al. Impact of recently emerged sterol 14 alpha-demethylase(CYP51) variants of Mycosphaerella graminicola on azole fungicide sensitivity[J]. Appl Environ Microbiol, 2011, 77(11):3830-3837.
    [15] Eddouzi J, Parker JE, Vale-Silva LA, et al. Molecular mechanisms of drug resistance in clinical Candida species isolated from Tunisian hospitals[J].Antimicrob Agents Chemother, 2013, 57(7):3182-3193.
    [16] Morio F, Loge C, Besse B, et al. Screening for amino acid substitutions in the Candida albicans Erg11 protein of azole-susceptible and azole-resistant clinical isolates:new substitutions and a review of the literature[J]. Diagn Microbiol Infect Dis, 2010, 66(4):373-384.
    [17] Marichal P, Koymans L, Willemsens S, et al. Contribution of mutations in the cytochrome P45014alpha-demethylase(Erg11p, Cyp51p) to azole resistance in Candida albicans[J]. Microbiology, 1999, 145:2701-2713.
    [18] Kudo M, Ohi M, Aoyama Y, et al. Effects of Y132H and F145L substitutions on the activity, azole resistance and spectral properties of Candida albicans sterol 14-demethylase P450(CYP51):a live example showing the selection of altered P450 through interaction with environmental compounds[J]. J Biochem, 2005, 137(5):625-632.
    [19] Bellamine A, Lepesheva GI, Waterman MR. Fluconazole binding and sterol demethylation in three CYP51 isoforms indicate differences in active site topology[J]. J Lipid Res, 2004, 45(11):2000-2007.
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    [21] Warrilow AG, Mullins JG, Hull CM, et al. S279 point mutations in Candida albicans sterol 14-alpha demethylase(CYP51) reduce in vitro inhibition by fluconazole[J]. Antimicrob Agents Chemother, 2012, 56(4):2099-2107.
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    [24] Lamb DC, Kelly DE, Schunck WH, et al. The mutation T315A in Candida albicans sterol 14alpha-demethylase causes reduced enzyme activity and fluconazole resistance through reduced affinity[J]. J Biol Chem, 1997, 272(9):5682-5688.
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    [27] Rodriguez-Tudela JL, Alcazar-Fuoli L, Mellado E, et al. Epidemiological cutoffs and cross-resistance to azole drugs in Aspergillus fumigatus[J]. Antimicrob Agents Chemother, 2008, 52(7):2468-2472.
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    [29] Rodero L, Mellado E, Rodriguez AC, et al. G484S amino acid substitution in lanosterol 14-alpha demethylase(ERG11) is related to fluconazole resistance in a recurrent Cryptococcus neoformans clinical isolate[J]. Antimicrob Agents Chemother, 2003, 47(11):3653-3656.
    [30] Sionov E, Chang YC, Garraffo HM, et al. Identification of a Cryptococcus neoformans cytochrome P450 lanosterol 14alpha-demethylase(Erg11) residue critical for differential susceptibility between fluconazole/voriconazole and itraconazole/posaconazole[J]. Antimicrob Agents Chemother, 2012, 56(3):1162-1169.
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Development in research of CYP51 as the target of triazoles

doi: 10.3969/j.issn.1006-0111.2016.02.003
  • Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
  • Received Date: 2015-12-21
  • Rev Recd Date: 2016-01-26

Abstract: Triazoles are the most widely used antifungal drugs in clinic with broad spectrum and high efficacy, which targets sterol 14α-demethylase(CYP51), an enzyme expressed by the gene EGR 11, which is a key enzyme in the fungi ergosterol biosynthesis. On the one hand, the CYP51 belongs to a transmembrane protein. It is difficult to get the exact functional structure conformation which becomes a big challenge for the development of new drugs. On the other hand, it becomes consensus that EGR11 exon mutation cause CYP51 structural change is one of the major reasons for antifungal drugs resistance. Therefore, study of the structural changes toward the antifungal drug resistance is quite important. The review authors have summarized the research progress on CYP51 over the recent years.

LI Ran, ZHANG Dazhi. Development in research of CYP51 as the target of triazoles[J]. Journal of Pharmaceutical Practice and Service, 2016, 34(2): 106-109. doi: 10.3969/j.issn.1006-0111.2016.02.003
Citation: LI Ran, ZHANG Dazhi. Development in research of CYP51 as the target of triazoles[J]. Journal of Pharmaceutical Practice and Service, 2016, 34(2): 106-109. doi: 10.3969/j.issn.1006-0111.2016.02.003
shu

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