Lanosterol 14-alpha demethylase (Acanthamoeba castellanii) (CYP51)

Acanthamoeba castellanii CYP51, also known as lanosterol 14-alpha demethylase, is a vital enzyme in the sterol biosynthesis pathway of the free-living amoeba Acanthamoeba castellanii (UniProt: A0A0L0S6E1). This organism is a facultative human pathogen responsible for Acanthamoeba keratitis, a painful and sight-threatening corneal infection, and granulomatous amoebic encephalitis, a rare but typically fatal infection of the central nervous system (PubMed: 21646448). The enzyme catalyzes the oxidative removal of the 14-alpha-methyl group from lanosterol or related sterol precursors, which is a critical step in the production of ergosterol or similar sterols required for membrane integrity (PubMed: 25605314). As a member of the cytochrome P450 superfamily, it contains a heme group that serves as the binding site for azole-class antifungal and antiprotozoal drugs. Inhibition of this enzyme by drugs such as voriconazole or posaconazole leads to the depletion of essential membrane sterols and the accumulation of toxic 14-alpha-methylated intermediates, resulting in growth arrest or cell death (PubMed: 25605314). Despite its importance as a drug target, the efficacy of treatment is often hindered by the organism's ability to form highly resilient cysts that are less susceptible to chemical agents (PubMed: 21646448). Furthermore, the structural similarity between amoebic and human CYP51 enzymes requires careful drug design to ensure selectivity and minimize off-target effects in patients.

Other names

Sterol 14-alpha demethylaseCytochrome P450 51CYP51A1Acanthamoeba castellanii CYP51

Inhibition of lanosterol 14-alpha demethylase (CYP51) by binding to the heme iron, preventing the conversion of lanosterol to ergosterol and disrupting membrane function (PubMed: 25605314).