Cytochrome P450 monooxygenase CYP53 family in fungi: comparative structural and evolutionary analysis and its role as a common alternative anti-fungal drug target.

Poojah Jawallapersand,Lidija Kovačič,Samson Sitheni Mashele,Nada Kraševec,Jure Stojan,Suresh Babu Pakala,Khajamohiddin Syed,Radovan Komel,Kap-Hoon Han

doi:10.1371/journal.pone.0107209

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.

Highlights

Among microorganisms, fungi, the largest biological kingdom comprising diverse lower eukaryotic microorganisms, have acquired a special place owing to their ability to be pathogens for humans and other animals and plants (Table 1)
The present study is such an example; we explored fungal genome sequencing results to understand the role of a P450 family (CYP53) in serving as a common drug target against pathogenic ascomycetes and in basidiomycetes, in terms of the wood-degradation process
Our findings suggest that this P450 family can serve as a common anti-fungal drug target in view of its highly conserved protein structure in ascomycetes

Summary

Introduction

Fungi, the largest biological kingdom comprising diverse lower eukaryotic microorganisms, have acquired a special place owing to their ability to be pathogens for humans and other animals and plants (Table 1). These lower eukaryotes develop or are constantly developing new strategies to adapt to diverse ecological niches. Gov/programs/fungi/index.jsf) resulted in genome sequencing of a large number of fungal species. Genome sequencing analysis of fungal species revealed the presence of a large number of cytochrome P450 monooxygenases Species. Total count Basidiomycota Phanerochaete chrysosporium Postia placenta. Ustilago maydis Cryptococcus neoformans Cryptococcus gattii Laccaria bicolor Malassezia globosa Puccinia graminis Sporobolomyces roseus Phanerochaete carnosa

Objectives

Methods

Results

Conclusion