Biological redox chemistry underlying nitric oxide and hydrogen peroxide signaling

一氧化氮和过氧化氢信号传导的生物氧化还原化学

• 批准号: 1530-2007
• 负责人: English, Ann
• 金额: $ 5.9万
• 依托单位: Concordia University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2007
• 资助国家: 加拿大
• 起止时间: 2007-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=366440
• 关键词: Biological; redox; chemistry; underlying; nitric

We are investigating how small, redox-active molecules such as hydrogen peroxide (H2O2) and nitric oxide (NO) interact with metalloproteins and other biomolecules to control the functioning of cells. Excess H2O2 can harm cells and cause programmed cell death (apoptosis) involving the heme protein, cytochrome c. We are interested in the detailed chemical processes that trigger this event since an ability to control apoptosis is highly desirable in the treatment of stroke and cancer. Under normal conditions, cellular H2O2 levels are tightly controlled. Because of its ease of genetic manipulation, we are using baker's yeast in our search for new molecular mechanisms of H2O2 sensing and signaling. Our focus is the heme enzyme, cytochrome c peroxidase (CCP), which can detoxifiy H2O2 by catalyzing its reduction to H2O. We are investigating genetically modified yeast strains that produce CCP mutants or no CCP at all. We also study purified CCP and its mutants in vitro to better understand its mode of action in vivo. The goal of this work is to obtain chemical insight into how organisms respond rapidly to redox challenges that occur in an oxygen rich environment. Oxidative stress is a major contributing factor in aging and in age-related diseases.Nitric oxide (NO) influences key biological functions such as blood flow, neuronal signaling and the immune response. We would like to understand how NO chemically modifies proteins and hormones, which can have profound effects on their mode of action. For example, reversible S-nitrosation of protein thiols is a major form of cell signaling, and research in our laboratory focuses on metal-catalyzed processes that promote NO-transfer between thiols. We are also probing the chemical reactions of the one-electron reduction product of NO, nitroxyl (HNO). The proposed studies will increase our knowledge of the bioinorganic chemistry of NO, which is critical in understanding the molecular underpinnings of cardiovascular disease and neurodegeneration.

我们正在研究如何小，氧化还原活性分子，如过氧化氢（H2 O2）和一氧化氮（NO）与金属蛋白和其他生物分子相互作用，以控制细胞的功能。过量的H2 O2会损害细胞，并导致涉及血红素蛋白、细胞色素c的程序性细胞死亡（凋亡）。我们对触发这一事件的详细化学过程感兴趣，因为控制细胞凋亡的能力在中风和癌症的治疗中是非常可取的。在正常情况下，细胞H2 O2水平受到严格控制。由于其易于遗传操作，我们正在使用面包酵母在我们的H2 O2传感和信号的新的分子机制的搜索。我们的重点是血红素酶，细胞色素c过氧化物酶（CCP），它可以解毒H2 O2催化其还原为H2O。我们正在研究转基因酵母菌株产生CCP突变体或根本没有CCP。我们还在体外研究了纯化的CCP及其突变体，以更好地了解其在体内的作用方式。这项工作的目标是获得化学洞察生物体如何快速响应氧化还原的挑战，发生在富氧环境。氧化应激是衰老和与年龄相关疾病的一个主要因素。一氧化氮（NO）影响关键的生物学功能，如血流、神经元信号和免疫反应。我们想了解NO如何化学修饰蛋白质和激素，这可能对它们的作用模式产生深远的影响。例如，蛋白质硫醇的可逆S-亚硝化是细胞信号传导的主要形式，我们实验室的研究重点是促进硫醇之间NO转移的金属催化过程。我们还在探索NO的单电子还原产物硝酰基（HNO）的化学反应。拟议的研究将增加我们对NO的生物无机化学的了解，这对于理解心血管疾病和神经退行性变的分子基础至关重要。