Formation of Tyrosine Radicals in haem proteins: their role in electron transfer

许多酶使用高活性自由基来执行其催化功能。自由基是含有未成对电子的化合物，在许多生物过程中发挥重要作用，其中许多是维持生命所必需的。然而，由于它们的高反应性，自由基也可以参与不必要的副反应，导致细胞损伤，可能导致许多疾病，包括关节炎，阿尔茨海默病和癌症。有些酶要求自由基移动很长的距离，而有些酶要求自由基不从它们的产生点移动。酶控制自由基运动的方式具有重要的科学意义。我们打算通过使用模型蛋白质系统（即肌红蛋白和血红蛋白）来研究自由基在酶和蛋白质中移动的方式，在模型蛋白质系统中，我们可以随意控制自由基的形成。已知这些蛋白质在与过氧化物反应时形成并移位自由基。我们打算使用各种直接和间接的自由基检测方法来跟踪这些自由基的迁移，以发现自由基运动主要是在蛋白质内还是传递到其他蛋白质。此外，我们打算通过重新设计蛋白质的部分来操纵这些自由基迁移的途径。由于这些蛋白质的结构是已知的，我们可以使用这些信息与遗传方法一起删除现有的途径，并创建潜在的新途径。所获得的信息对于理解蛋白质控制自由基的机制将是有价值的，并且对于理解为什么这些过程在某些蛋白质中出错也将是重要的，例如人工设计的基于血红蛋白的血液替代品。

Many enzymes use highly reactive free radicals to perform their catalytic functions. Free radicals are compounds containing unpaired electrons and play an important role in a number of biological processes, many of which are necessary to sustain life. However, because of their high reactivity free radicals can also participate in unwanted side reactions, causing cell damage that may lead to many diseases including arthritis, Alzheimer's disease and cancer. Some enzymes require that free radicals are moved over large distances, whereas some require that free radicals do not move from their point of creation. The way in which enzymes control free radical movement is of important scientific interest. We intend to examine the ways in which radicals move through enzymes and proteins by using model proteins systems, namely myoglobin and haemoglobin, in which we can control the formation of free radicals at will. These proteins are known to form and translocate free radicals when they react with peroxides. We intend to follow the migration of these free radicals, using various direct and indirect free radical detection methods, to discover whether radical movement is mainly within the protein or is transmitted to other proteins. Also, we intend to manipulate the pathways through which these radicals migrate by re-designing parts of the protein. As the structures of these proteins are known we can use this information together with genetic methods to remove existing pathways and to create potential new ones. The information gained will be valuable in understanding the mechanisms by which proteins control radicals and will also be of importance in understanding why these processes go wrong in some proteins such as artificially designed haemoglobin-based blood substitutes.