Biological redox chemistry underlying nitric oxide and hydrogen peroxide signaling

我们正在研究过氧化氢(H2O2)和一氧化氮(NO)等氧化还原活性小分子如何与金属蛋白和其他生物分子相互作用，以控制细胞的功能。过量的过氧化氢会损害细胞，并导致细胞程序性死亡(凋亡)，涉及到血红素蛋白，细胞色素c。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必要的。在正常情况下，细胞内的过氧化氢水平受到严格控制。由于其易于遗传操作，我们正在使用面包酵母来寻找新的过氧化氢传感和信号传递的分子机制。我们的重点是血红素酶，细胞色素c过氧化物酶(CCP)，它可以通过催化过氧化氢还原为水来解毒。我们正在研究产生CCP突变或根本不产生CCP的转基因酵母菌株。我们还对纯化的CCP及其突变体进行了体外研究，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关于有机体如何对富氧环境中发生的氧化还原挑战做出快速反应的化学见解。氧化应激是导致衰老和与年龄相关的疾病的主要因素。

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.