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氮唑类抗真菌药物靶酶CYP51的研究进展

李冉,  张大志

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文章导航 > 药学实践与服务  > 2016 >  34(2): 106-109
李冉, 张大志. 氮唑类抗真菌药物靶酶CYP51的研究进展[J]. 药学实践与服务, 2016, 34(2): 106-109. doi: 10.3969/j.issn.1006-0111.2016.02.003
引用本文: 李冉, 张大志. 氮唑类抗真菌药物靶酶CYP51的研究进展[J]. 药学实践与服务, 2016, 34(2): 106-109. doi: 10.3969/j.issn.1006-0111.2016.02.003
shu
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

氮唑类抗真菌药物靶酶CYP51的研究进展

doi: 10.3969/j.issn.1006-0111.2016.02.003

  • 第二军医大学药学院有机化学教研室, 上海 200433

Development in research of CYP51 as the target of triazoles

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

  • 摘要: 氮唑类药物是临床上应用最广、种类最多的广谱高效抗真菌药物,其作用靶点为真菌甾醇合成过程中的一个关键酶——羊毛甾醇14α-去甲基化酶(CYP51)。CYP51由CYP 51基因(同名ERG 11)表达。一方面,真菌CYP51是跨膜蛋白,难以纯化获得其准确的结构信息,成为药物研发的瓶颈之一;另一方面,CYP51变异是公认的真菌耐药的主要原因之一,研究其结构变化对于抗真菌耐药具有重要意义。因此,笔者对近年来CYP51的研究进展进行综述。
    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.
  • [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.
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    [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.
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    [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.
    [20] Warrilow AG, Martel CM, Parker JE, et al. Azole binding properties of Candida albicans sterol 14-alpha demethylase(CaCYP51)[J]. Antimicrob Agents Chemother, 2010, 54(10):4235-4245.
    [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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    [23] Lamb DC, Kelly DE, White TC, et al. The R467K amino acid substitution in Candida albicans sterol 14alpha-demethylase causes drug resistance through reduced affinity[J]. Antimicrob Agents Chemother, 2000, 44(1):63-67.
    [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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    [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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  • 收稿日期:  2015-12-21
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氮唑类抗真菌药物靶酶CYP51的研究进展

doi: 10.3969/j.issn.1006-0111.2016.02.003
  • 第二军医大学药学院有机化学教研室, 上海 200433
  • 收稿日期: 2015-12-21
  • 修回日期: 2016-01-26

摘要: 氮唑类药物是临床上应用最广、种类最多的广谱高效抗真菌药物,其作用靶点为真菌甾醇合成过程中的一个关键酶——羊毛甾醇14α-去甲基化酶(CYP51)。CYP51由CYP 51基因(同名ERG 11)表达。一方面,真菌CYP51是跨膜蛋白,难以纯化获得其准确的结构信息,成为药物研发的瓶颈之一;另一方面,CYP51变异是公认的真菌耐药的主要原因之一,研究其结构变化对于抗真菌耐药具有重要意义。因此,笔者对近年来CYP51的研究进展进行综述。

English Abstract

李冉, 张大志. 氮唑类抗真菌药物靶酶CYP51的研究进展[J]. 药学实践与服务, 2016, 34(2): 106-109. doi: 10.3969/j.issn.1006-0111.2016.02.003
引用本文: 李冉, 张大志. 氮唑类抗真菌药物靶酶CYP51的研究进展[J]. 药学实践与服务, 2016, 34(2): 106-109. doi: 10.3969/j.issn.1006-0111.2016.02.003
shu
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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