Structure and function of oxidative defense systems

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The primary goal of the proposed research is to characterize proteins and larger organelles that protect organisms against oxidative stress experienced in our oxygen rich environment. For over 20 years, research in the Loewen laboratory has been focused on monofunctional catalases and bifunctional catalase-peroxidases which have as their main physiological role the degradation of potentially toxic hydrogen peroxide to harmless water and oxygen. This long term program of research has progressed from bacterial genetic analysis, through molecular genetic characterization to protein structure determination and has provided a greatly improved understanding of how the enzymes respond to physiological challenge in different organisms. In addition, it has made Loewen an internationally recognized authority in the area. The continuing goal of the proposed research is to characterize the mechanisms that provide protection for organisms primarily against hydrogen peroxide, a common product of cellular metabolism, but also against other reactive perhydroxy compounds. One specific objective is to characterize and rationalize structural features that affect the catalytic mechanisms in catalase-peroxidases and monofunctional catalases including both the catalase reaction and the activation of the widely used anti-tubercular pro-drug isoniazid in Mycobacterium tuberculosis . A second specific objective is the characterization of yeast peroxisomal proteins involved in protein transport. The research will expand our understanding of basic protein structure and function and provide a better understanding of drug activation and resistance in mycobacterial species and of peroxisomal-related diseases.