Structure and function of oxidative defense systems

氧化防御系统的结构和功能

• 批准号: 9600-2012
• 负责人: Loewen, Peter
• 金额: $ 3.5万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=592977
• 关键词: Structure; function; oxidative; defense; systems

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.

这项拟议研究的主要目标是确定蛋白质和较大的细胞器的特征，这些蛋白质和较大的细胞器保护生物体免受在富氧环境中经历的氧化应激。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-过氧化氢酶，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。这一长期的研究计划已经从细菌遗传分析，到分子遗传表征，再到蛋白质结构确定，并极大地提高了对不同生物体中的酶如何响应生理挑战的理解。此外，它还使洛文成为该地区国际公认的权威机构。这项拟议研究的持续目标是确定主要为生物体提供保护的机制，这些机制主要针对细胞代谢的常见产物过氧化氢，但也针对其他活性过氧化化合物。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在结核分枝杆菌中广泛使用的抗结核前体药物异烟肼的激活。第二个特定的目标是鉴定参与蛋白质运输的酵母过氧化物体蛋白。这项研究将扩大我们对基本蛋白质结构和功能的理解，并更好地理解分枝杆菌物种中的药物激活和耐药性以及与过氧化体相关的疾病。