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.

Cyp51（固醇14α-脱甲基酶）是不同门中固醇生物合成所需的单一细胞色素P450（Cyp）。在数百种P450蛋白中，Cyp51在进化上是最古老的P450蛋白，并且是大多数生物界（包括真菌，细菌，植物和动物）中唯一存在的细胞色素P450蛋白。有价值的一类抗真菌剂，例如唑类，两性霉素B，专门针对真菌Cyp51（Erg11），这是一种对动物质膜麦角固醇生物合成的特定成分至关重要的羊毛甾醇脱甲基酶。但是，世界范围内的致病性真菌对唑类的耐药性主要是通过Cyp51 / Erg11蛋白的突变引起的。结构研究已经阐明了与这些突变相关的抗性机制主要是由于唑类与Cyp51蛋白的结合亲和力降低，并影响了Cyp51蛋白的稳定性。此外，cyp51基因也将增加对唑的抗性，这解决了Cyp51调节剂的关键作用。在这篇综述中，我们从Cyp51突变的演变，调控和对吡咯抗性的贡献中探索真菌Cyp51。从Cyp51研究中获得的知识将有益于开发新型的基于Cyp51的抗真菌剂。