The cytochrome b5 CybE is regulated by iron availability and is crucial for azole resistance in A. fumigatus.

摘要: Cytochrome P450 enzymes (P450) play essential roles in redox metabolism all domains of life including detoxification reactions and sterol biosynthesis. The activity P450s is fuelled by two electron-transferring mechanisms, heme-independent reductase (CPR) the heme-dependent cytochrome b5 (CYB5)/cytochrome (CB5R) system. In this study, we characterised role regulation CybE fungal pathogen Aspergillus fumigatus. Deletion encoding gene (cybE) caused a severe growth defect different A. fumigatus isolates, emphasising importance CB5R system pathogen, while non-essentiality cybE indicates partial redundancy CPR systems. Interestingly, loss function was even more drastic strain AfS77 compared to A1160P+ indicating strain-dependent degree compensation, which supported azole resistance studies. agreement with being important for assistance ergosterol biosynthetic Cyp51, deletion decreased Cyp51-targeting antifungal voriconazole accumulation pathway intermediate eburicol. Northern analysis indicated that deficiency leads compensatory transcriptional upregulation Cyp51-encoding cyp51A CPR-encoding cprA. Overexpression did not affect suggesting rate limiting. Expression found be repressed during iron starvation iron-regulatory transcription factor HapX demonstrating dependence only at level enzyme but also expression.