Alkyl Hydroperoxide Reductase and Related Redox Systems

描述(申请人提供)：过氧化氢是一种被人类免疫系统用来杀死感染性生物的毒素，越来越多的证据表明，它也是真核信号中常见的第二信使。在人类中，肿瘤坏死因子、表皮生长因子和胰岛素是被认为通过过氧化氢发出信号的三种激素。过氧化氢酶和谷胱甘肽过氧化物酶一直被认为是细胞中降解过氧化氢的主要酶，然而在过去的几年里，一个独特的、高度丰富的过氧化氢还原酶家族--过氧化还蛋白(Prxs)已经从相对鲜为人知的水平成为氧化还原生物学研究的主要焦点。多年来，真核生物Prxs的过氧化物酶活性一直被忽视，因为那些在真核生物中高表达的Prxs很容易被过氧化氢灭活。十多年来，我们在从病原菌(如鼠伤寒沙门氏菌AhpC)中鉴定Prx的过程中，积累了Prx酶学方面的专业知识。这些Prx是抗生素开发的目标，因为它们在保护细菌免受人类免疫系统的攻击方面起到了作用。2003年，我们对鼠伤寒沙门氏菌AhpC的结构和功能的研究使我们发现了对过氧化的敏感性的结构基础，这种结构基础对于在所有真核生物中高度表达的Prx的子集是保守的。我们进一步提出了“闸门假说”，即这种对失活的敏感性如何在过氧化氢被用作信号分子的生物体中实际上是有益的，以便在适当的条件下可以关闭Prxs的抗氧化特性，以允许过氧化氢水平的可控爆发。鉴于Prxs在病原体防御和人类细胞中对抗氧化应激和细胞调控的重要性，我们建议扩大我们的研究计划，既继续我们成熟的工作，通过各种已知Prxs阐明催化的基本结构和生化方面(特定目标1，2和4)，并通过开发一种新的系统生物学方法来了解Prxs和其他过氧化物酶对真核细胞中过氧化氢稳态的相对贡献(特定目标3)。氧化损伤被认为在衰老、癌症的发展和许多退行性疾病中都是重要的。此外，控制增殖、分化和凋亡的细胞信号过程的损害与许多疾病状态有关。因此，加强对Prxs及其在细胞信号和抗氧化保护中所起作用的了解将对预防人类疾病具有重要意义。此外，Prxs在保护人类病原体免受免疫系统杀害方面的作用使Prxs成为开发新的治疗药物以对抗传染病的靶点。

DESCRIPTION (provided by applicant): Hydrogen peroxide is a toxin used by the human immune system to kill infectious organisms, and increasing evidence is accumulating that it is also a common second messenger in eukaryotic signaling. In humans, tumor necrosis factor, epidermal growth factor and insulin are three examples of hormones thought to signal via hydrogen peroxide. Catalase and glutathione peroxidase have long been viewed as the major enzymes degrading peroxide in cells, however, over the past few years, a distinct, highly abundant family of peroxide-reducing enzymes, peroxiredoxins (Prxs), have moved from relative obscurity to become a major Focus of redox biology research. The peroxidase activity of eukaryotic Prxs was overlooked for many years, because those Prxs that are highly expressed in eukaryotes are easily inactivated by peroxide. We have developed expertise in Prx enzymology over more than a decade of characterizing of Prxs from pathogenic bacteria (e.g. Salmonella typhimurium AhpC). These Prxs are targets for antibiotic development because of the role they play in protecting the bacteria from the human immune system. In 2003, our structural and functional studies on S. typhimurium AhpC led us to discover the structural basis for the sensitivity toward peroxides that is conserved for a subset of Prxs that are highly expressed across all eukarya. We further proposed the "floodgate hypothesis" for how this sensitivity to inactivation would actually be beneficial in organisms where hydrogen peroxide is being used as a signaling molecule, so that the antioxidant properties of the Prxs could be switched off under appropriate conditions to allow for a controlled burst in peroxide levels. Given the importance of Prxs both in pathogen defense and in human cells for combating oxidative stress and for cellular regulation, we propose here to expand our research program by both continuing our well-established work to elucidate the fundamental structural and biochemical aspects of catalysis by the variety of known Prxs (Specific Aims 1, 2, and 4) and by developing a novel systems biology approach to understand the relative contributions of Prxs and other peroxidases to peroxide homeostasis in eukaryotic cells (Specific Aim 3). Oxidative damage is thought to be important in aging, in the development of cancer and in many degenerative diseases. Moreover, impairments in cell signaling processes controlling proliferation, differentiation and apoptosis are associated with many disease states. An enhanced understanding of Prxs and the roles they play in both cell signaling and antioxidant protection will thus have important implications for the prevention of human diseases. In addition, the role of Prxs in protecting human pathogens against killing by the immune system implicates Prxs as targets for the development of new therapeutic agents to combat infectious diseases.