title: Cytochrome P450 monooxygenase CYP53 family in fungi: comparative structural and evolutionary analysis and its role as a common alternative anti-fungal drug target.
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 gene-structure 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.
authors.affiliation: Department of Health Sciences, Faculty of Health and Environmental Sciences, Central University of Technology, Bloemfontein, Free State, South Africa.
authors.forename: Poojah
authors.initials: P
authors.lastname: Jawallapersand
authors.affiliation: Department of Health Sciences, Faculty of Health and Environmental Sciences, Central University of Technology, Bloemfontein, Free State, South Africa.
authors.forename: Samson Sitheni
authors.initials: SS
authors.lastname: Mashele
authors.affiliation: Conway Institute, School of Medicine and Medical Sciences, University College Dublin, Belfield, Dublin 4, Ireland; Department of Molecular Biomedical Sciences, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia.
authors.forename: Lidija
authors.initials: L
authors.lastname: Kovačič
authors.affiliation: Faculty of Medicine, Institute of Biochemistry, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia.
authors.forename: Jure
authors.initials: J
authors.lastname: Stojan
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia.
authors.forename: Radovan
authors.initials: R
authors.lastname: Komel
authors.affiliation: Department of Biochemistry, Sri Krishnadevaraya University, Anantapur, Andhra Pradesh, India.
authors.forename: Suresh Babu
authors.initials: SB
authors.lastname: Pakala
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia.
authors.forename: Nada
authors.initials: N
authors.lastname: Kraševec
authors.affiliation: Department of Health Sciences, Faculty of Health and Environmental Sciences, Central University of Technology, Bloemfontein, Free State, South Africa.
authors.forename: Khajamohiddin
authors.initials: K
authors.lastname: Syed
mesh_terms: D001203:Ascomycota / Q000201:enzymology / Q000235:genetics; D001487:Basidiomycota / Q000201:enzymology / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005658:Fungi / Q000201:enzymology* / Q000235:genetics*; D016681:Genome, Fungal / Q000235:genetics*; D010802:Phylogeny
chemical_list: D003577:Cytochrome P-450 Enzyme System