Evolutionary genetic analysis of unassigned peptidase clan-associated microbial virulence and pathogenesis

Peptidase clan is the largest group of proteases with common ancestry as identified by structural homology. A peptidase with unknown catalytic type is referred to as an unassigned peptidase clan, which can be classified into 8 peptidase families (U32, U40, U49, U56, U57, U62, U69, and U72). The members of this clan are widely dispersed in diverse microbial pathogens and their apparent involvement in the microbial virulence is not yet known for antibiotic drug discovery. In the present study, we have analyzed their common structural and functional characteristics using evolutionary genetic analysis. As shown by our analysis, the molecular and functional characteristics of this clan diverged across the microbial pathogens. It also indicates that the members of each family might have evolved independently and a peptidase core converged to interconnect the unassigned peptidase clan. Several evolutionary constraints have been identified as selective measures from this clan that inferred on their functional evolution and divergence. Genetic diversity analysis described that many members of this clan have evolved as new molecular functions across the microbial pathogens by imposing the Darwinian positive selection. Structural analysis of this study indicates that members of this clan have a conserved fold, convergence in functional parts, and divergence in spatial structural arrangements. As the results of our study, the neofunctionalization of several unassigned peptidases provides a full virulence for microbial pathogens occupying at the different pathophysiological niche.