Sterol 14alpha-demethylase (CYP51) (CYP51)

Trypanosomal CYP51, or sterol 14alpha-demethylase, is a cytochrome P450 enzyme essential for the biosynthesis of ergosterol in kinetoplastid parasites, including Trypanosoma cruzi and Trypanosoma brucei (UniProt: Q4D958, Q388K4). It catalyzes the 14alpha-demethylation of sterol precursors, a rate-limiting step necessary for maintaining the structural integrity and fluidity of the parasite's cell membrane (PubMed: 21810938). In T. cruzi, the causative agent of Chagas disease, inhibition of this enzyme leads to the accumulation of toxic methylated sterols and parasite death (PubMed: 23449548). While human cells also possess a CYP51 enzyme for cholesterol synthesis, structural differences in the parasite's active site allow for the development of selective inhibitors (PubMed: 22334609). Azole-based drugs like posaconazole and ravuconazole have been evaluated in clinical trials for Chagas disease, though they showed high rates of treatment failure compared to benznidazole in chronic cases (PubMed: 24848918). Novel non-azole inhibitors, such as the VNI series, have demonstrated high selectivity and efficacy in preclinical models, representing a promising avenue for future therapy (PubMed: 22334609).

Other names

Lanosterol 14-alpha-demethylaseObtusifoliol 14-alpha-demethylaseCytochrome P450 51Trypanosoma cruzi CYP51Trypanosoma brucei CYP51P450L1

Inhibition of the enzyme's heme-dependent oxidative activity prevents the conversion of lanosterol or obtusifoliol to ergosterol, resulting in membrane dysfunction and parasite growth arrest (PubMed: 21810938).