Lanosterol 14-alpha demethylase (CYP51A1) (CYP51A1)

Lanosterol 14-alpha demethylase (CYP51A1) is a critical cytochrome P450 enzyme in the sterol biosynthetic pathway, responsible for the oxidative removal of the 14-alpha-methyl group from lanosterol [1, 3, 8]. This enzymatic step is essential for the production of cholesterol in animals and ergosterol in fungi, both of which are fundamental components of cellular membranes that regulate fluidity and integrity [6, 8, 11]. Due to its vital role in maintaining fungal cell membrane structure, it serves as the primary therapeutic target for azole antifungal medications such as fluconazole and voriconazole [5, 14, 15]. Beyond its role in infections, human CYP51A1 is increasingly recognized for its involvement in metabolic diseases, cancer progression, and the regulation of cell death pathways like ferroptosis [2, 10, 12]. Dysregulation of this enzyme is linked to conditions such as atherosclerosis, metabolic syndrome, and certain oncological pathologies [2, 10, 13]. Inhibition of the enzyme leads to the depletion of essential sterols and the accumulation of toxic methylated intermediates, which ultimately compromises membrane function and results in pathogen death or inhibited tumor growth [5, 6, 12].

Other names

CYP51CYP51A1Cytochrome P450 14-alpha-demethylaseP450-14DMErg11Erg11pLDMLanosterol 14-alpha-demethylaseSterol 14-demethylase

Azole drugs and other inhibitors bind to the heme iron at the enzyme's active site, blocking the three-step oxidative demethylation of lanosterol; this causes the depletion of vital sterols (ergosterol or cholesterol) and the toxic accumulation of 14-alpha-methyl sterol intermediates, leading to membrane dysfunction and cell death [5, 6, 11, 14].