Sterol 14α-demethylase (CYP51) (CYP51)

Sterol 14α-demethylase (CYP51) is a vital cytochrome P450 enzyme required for the biosynthesis of ergosterol in trypanosomatid parasites, such as Trypanosoma cruzi and Trypanosoma brucei (Source: UniProt Q4E001; Lepesheva et al., 2018). Unlike human cells that utilize cholesterol, these parasites depend on ergosterol to maintain the structural integrity and fluidity of their cell membranes (Source: McCall et al., 2015). The enzyme catalyzes the oxidative removal of the 14α-methyl group from precursors like lanosterol or eburicol. Inhibition of CYP51 by azole derivatives leads to the depletion of ergosterol and the accumulation of methylated sterol intermediates, which are toxic and disrupt the function of membrane-bound proteins and cellular lipids (Source: Nature Reviews Microbiology, 2013). This disruption ultimately results in parasite growth arrest and death, making it a primary target for treating Chagas disease and African Sleeping Sickness (Source: Expert Opinion on Therapeutic Targets, 2011). Despite the potency of inhibitors like posaconazole in vitro, clinical trials have faced challenges with parasite recrudescence, highlighting the need for more effective dosing or next-generation inhibitors like VNI (Source: Science Translational Medicine, 2013). The target is also relevant in Leishmania species, where similar sterol biosynthetic pathways are essential for survival. Research into this target often involves structural biology to design inhibitors that are highly selective for the parasite enzyme over human CYP51 to minimize side effects.

Other names

Lanosterol 14-alpha demethylaseCytochrome P450 51CYP51A1Obtusifoliol 14-alpha demethylaseTrypanosomal sterol 14α-demethylase

Inhibition of the heme-dependent sterol 14α-demethylase enzyme, blocking the conversion of lanosterol to ergosterol, which causes membrane instability and accumulation of toxic sterol precursors (Source: PubMed PMID: 21254951).