Structure and function of oxidative defense systems

提出的研究的主要目标是表征蛋白质和更大的细胞器，保护生物体免受氧化应激经历在我们的富氧环境。20多年来，Loewen实验室的研究一直集中在单功能过氧化氢酶和双功能过氧化氢酶-过氧化物酶上，它们的主要生理作用是将潜在有毒的过氧化氢降解为无害的水和氧气。这个长期的研究项目已经从细菌遗传分析，通过分子遗传表征到蛋白质结构测定，并极大地提高了对酶在不同生物体中如何应对生理挑战的理解。此外，它还使罗文成为该地区国际公认的权威。这项拟议研究的持续目标是描述为生物体提供保护的机制，主要是防止过氧化氢（细胞代谢的常见产物），但也防止其他活性过羟基化合物。一个特定的目标是表征和合理化影响过氧化氢酶-过氧化物酶和单功能过氧化氢酶催化机制的结构特征，包括过氧化氢酶反应和广泛使用的抗结核前药异烟肼在结核分枝杆菌中的激活。第二个具体目标是表征酵母过氧化物酶体蛋白参与蛋白质运输。该研究将扩大我们对基本蛋白质结构和功能的理解，并为分枝杆菌和过氧化物酶体相关疾病的药物活化和耐药性提供更好的理解。

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.