Fungal cytochrome P450 protein Cyp51: What we can learn from its evolution,regulons and Cyp51-based azole resistance |
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| Institution: | 1. The Key Laboratory of Biotechnology for Medicinal Plants of Jiangsu Province & School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu 221116, PR China;2. Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Engineering and Technology Research Center for Microbiology, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, PR China;1. Aberdeen Oomycete Laboratory, Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, Scotland, United Kingdom;2. International Centre for Aquaculture Research and Development (ICARD), University of Aberdeen, Scotland, United Kingdom;3. School of Fisheries and Aquaculture Sciences, Universiti Malaysia Terengganu, 21030, Malaysia;1. Bavarian Forest National Park, Danziger Str. 20, 63916 Amorbach, Germany;2. Chair of Ecology and Conservation Biology, Institute of Plant Sciences, University of Regensburg, Germany;1. Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran;2. Student Research Committee, Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran |
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| Abstract: | Cyp51 (Sterol 14α-demethylase) is the single cytochrome P450 (Cyp) required for sterol biosynthesis in different phyla. Among hundreds of P450 proteins, Cyp51 is evolutionarily the oldest P450 protein and is the only cytochrome P450 protein present in most biological kingdoms including fungi, bacteria, plants and animals. A valuable class of antifungals such as azoles, amphotericin B, specifically target the fungal Cyp51 (Erg11), a lanosterol demethylase that is critical for the specific component of the fungal plasma membrane ergosterol biosynthesis. However, pathogenic fungi worldwide have developed resistance to azoles, largely through mutations in the Cyp51/Erg11 protein. Structural studies have elucidated the resistance mechanisms associated with these mutations are mostly caused by decreased the binding affinity of the azoles to the Cyp51 protein and affect the stability of Cyp51 protein. In addition, the overexpression of the cyp51 gene will also increase azole resistance, which addresses the critical role of Cyp51 regulators. In this review, we explore the fungal Cyp51 from the evolution, regulation and the contribution of Cyp51 mutations to azole resistance aspects. Knowledge gained from Cyp51 research will benefit to develop novel Cyp51-based antifungals. |
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| Keywords: | Azole resistance Cyp51 regulators Fungal Cyp51 |
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