Fungal cytochrome P450 lanosterol 14-alpha demethylase (CYP51)

Fungal cytochrome P450 lanosterol 14-alpha demethylase (CYP51) is a heme-containing monooxygenase enzyme located in the endoplasmic reticulum of fungi[3]. It catalyzes the three-step oxidative demethylation of lanosterol (and closely related sterols) at the 14-alpha position, a critical step in the biosynthesis of ergosterol—the major membrane sterol in fungi[2][5]. CYP51 is highly conserved across eukaryotes but displays sufficient sequence and structural variation between fungi and mammals that enables selective inhibition by azole antifungal drugs, which are mainstays in the treatment of systemic and superficial mycoses. Inhibition of fungal CYP51 disrupts ergosterol synthesis and leads to increased membrane permeability, growth inhibition, and fungal cell death. Mutations in fungal CYP51 are a common mechanism of azole resistance, representing an important clinical and research focus[5].

Other names

Sterol 14-alpha demethylaseLanosterol 14-alpha demethylaseCYP51Cytochrome P450 51Cytochrome P450-14DMP45014DMEC 1.14.14.154Obtusifoliol 14-demethylase

Drugs inhibit fungal CYP51 by binding to the heme iron, blocking access of the substrate (lanosterol or similar sterol) and thus preventing demethylation; this leads to defective ergosterol synthesis, altering membrane structure and increasing fungal cell toxicity. These are competitive and non-competitive inhibition mechanisms, mainly through azole ring–heme iron coordination.