Comparative structural analysis of cytochrome P450 family CYP51 in the genus Cryptococcus

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dc.contributor.authorAkapo, Olufunmilayo Olukemi
dc.date.accessioned2023-03-14T10:29:23Z
dc.date.available2023-03-14T10:29:23Z
dc.date.issued2020
dc.descriptionA thesis submitted to the Faculty of Science, Agriculture and Engineering in fulfilment of the requirements for the Degree of Doctor of Philosophy in the Department of Biochemistry and Microbiology at the University of Zululand, South Africa, 2020en_US
dc.description.abstractCytochrome P450 monooxygenase CYP51 (sterol 14α-demethylase) is a well-known target of the azole drug fluconazole for treating cryptococcosis, a life-threatening fungal infection in immune-compromised patients in poor countries. Studies indicate that mutations in CYP51 confer fluconazole resistance on cryptococcal species. Despite the importance of CYP51 in these species, genome data mining, annotation and phylogenetic analysis of CYPs has not been reported. Furthermore, few studies on the structural analysis of CYP51 and its interactions with different azole drugs have been reported. This study is aimed to address these two research gaps. Comprehensive genome-wide CYP analysis revealed the presence of 203 CYPs (excluding 16 pseudo-CYPs) in 23 species of Tremellomycetes that can be grouped into 38 CYP families and 72 CYP subfamilies. Twenty-three CYP families are new and three CYP families (CYP5139, CYP51 and CYP61) were conserved across 23 species of Tremellomycetes. Pathogenic cryptococcal species have 50% fewer CYP genes than non-pathogenic species. After successful identification of CYPs, in silico structural analysis of 12 CYP51s from cryptococcal species and other Tremellomycetes were carried out. Interactions of 12 CYP51s with nine ligands (three substrates and six azoles) performed by Rosetta docking using 10 000 combinations for each of the CYP51-ligand complex (12 CYP51s x 9 ligands =108 complexes) and hierarchical agglomerative clustering were used for selecting the complexes. A web application for visualization of CYP51s’ interactions with ligands was developed (http://bioshell.pl/azoledocking/). The study results indicated that Tremellomycetes CYP51s have a high preference for itraconazole, corroborating the in vitro effectiveness of itraconazole compared to fluconazole. Amino acids interacting with different ligands were found to be conserved across CYP51s, indicating that the procedure employed in this study is accurate and can be automated for studying P450-ligand interactions to cater for the growing number of P450s. The results of this study will serve as reference for future annotation and characterization of CYPs in species of Tremellomycetesen_US
dc.identifier.urihttps://hdl.handle.net/10530/2258
dc.language.isoenen_US
dc.publisherUniversity of Zululanden_US
dc.subjectCytochrome P450 family, Genus cryptococcus, CYP51en_US
dc.titleComparative structural analysis of cytochrome P450 family CYP51 in the genus Cryptococcusen_US
dc.typeThesisen_US
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