Abstract:
Cytochrome P450 monooxygenases (CYPs/P450s) are heme-thiolate proteins whose role as a drug target against
pathogenic microbes has been explored because of their stereo- and regio-specific oxidation activity. We aimed to assess
the CYP53 family’s role as a common alternative drug target against animal (including human) and plant pathogenic fungi
and its role in fungal-mediated wood degradation. Genome-wide analysis of fungal species revealed the presence of CYP53
members in ascomycetes and basidiomycetes. Basidiomycetes had a higher number of CYP53 members in their genomes
than ascomycetes. Only two CYP53 subfamilies were found in ascomycetes and six subfamilies in basidiomycetes,
suggesting that during the divergence of phyla ascomycetes lost CYP53 P450s. According to phylogenetic and genestructure
analysis, enrichment of CYP53 P450s in basidiomycetes occurred due to the extensive duplication of CYP53 P450s
in their genomes. Numerous amino acids (103) were found to be conserved in the ascomycetes CYP53 P450s, against only
seven in basidiomycetes CYP53 P450s. 3D-modelling and active-site cavity mapping data revealed that the ascomycetes
CYP53 P450s have a highly conserved protein structure whereby 78% amino acids in the active-site cavity were found to be
conserved. Because of this rigid nature of ascomycetes CYP53 P450s’ active site cavity, any inhibitor directed against this
P450 family can serve as a common anti-fungal drug target, particularly toward pathogenic ascomycetes. The dynamic
nature of basidiomycetes CYP53 P450s at a gene and protein level indicates that these P450s are destined to acquire novel
functions. Functional analysis of CYP53 P450s strongly supported our hypothesis that the ascomycetes CYP53 P450s ability
is limited for detoxification of toxic molecules, whereas basidiomycetes CYP53 P450s play an additional role, i.e. involvement
in degradation of wood and its derived components. This study is the first report on genome-wide comparative structural
(gene and protein structure-level) and evolutionary analysis of a fungal P450 family.
