Sterol 14-alpha-demethylase (CYP51) (CYP51; also known as ERG11 in fungi)

Sterol 14-alpha-demethylase (CYP51) is a cytochrome P450 monooxygenase enzyme that catalyzes a critical step in fungal sterol biosynthesis, specifically the demethylation of lanosterol and related sterol precursors.[2][4] This enzymatic reaction is essential for the production of ergosterol, a fungal-specific sterol that is a fundamental structural component of fungal cell membranes, where it regulates membrane fluidity and permeability.[1][3][4] Because ergosterol is indispensable for fungal cell membrane integrity and function, CYP51 has become a major clinical target for antifungal therapy.[1][3][4] Azole-based antifungal drugs such as voriconazole and fluconazole work by inhibiting CYP51 activity, thereby blocking ergosterol synthesis and causing membrane dysfunction and fungal cell death.[1][3][4] The enzyme's narrow substrate specificity and phylum-specific structural features have enabled the development of selective inhibitors that effectively target fungal CYP51 while minimizing inhibition of human sterol 14-alpha-demethylase orthologs.[1] However, the emergence of mutations in fungal CYP51 genes, particularly in Aspergillus fumigatus, represents a growing clinical challenge associated with azole resistance.[3]

Other names

Sterol 14-demethylaseLanosterol 14-alpha-demethylaseCYP51A and CYP51B (fungal isoforms)Erg11

Inhibition of ergosterol biosynthesis through blockade of the 14-alpha-demethylation reaction. Prevention of demethylation of lanosterol and sterol precursors. Accumulation of 14-alpha-methylated sterol precursors. Depletion of ergosterol, leading to disruption of fungal membrane structure and function.