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Functional characterization and analysis of Trichophyton rubrum sub4 serine proteases domains.

Charles W. Lynde, MD, Toronto Western Hospital Research Foundation, Toronto, ON.

The fungal pathogen Trichophyton rubrum is responsible for skin and nail diseases including onychomycosis and tinea pedis. Onychomycosis, affecting as much as 13% of the North American population, is a chronic and difficult to treat infection. In certain disease states such as diabetes, it can predispose to soft tissue infection and ulceration, which can sometimes result in more serious morbidity. Currently available treatments for onychomycosis are associated with limited cure rates (terbinafine: 40%, itraconazole: 14%, ciclopirox nail lacquer 8%), and high relapse rates even when cure is achieved. T. rubrum invades the nail by secreting enzymes that degrade keratin to form channels; therefore, studies of this mechanism at the molecular level are essential to understanding T. rubrum virulence. Several serine proteases encoded by SUB genes have a catalytic triad consisting of Asp/His/Ser for binding of other protein, including SUB4 which exhibits high keratin degradation. Comparison of serine protease sequences identified a conserved domain SGT at C-terminal with the serine of this domain being a component of the catalytic triad. The functional characterization and determination of other protein interaction with the catalytic triad and SGT would help elucidate the mechanism and role of serine proteases in T. rubrum. It follows that serine proteases catalytic triad or SGTS domain may be possible targets for antifungal drugs and further research in this area could aid in the development of antimycotic agents that would be effective in the treatment of tinea infections including onychomycosis.

(C2006)