Fungal cytochrome P450 protein Cyp51: What we can learn from its evolution, regulons and Cyp51-based azole resistance

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.