The Control of Non-Chemical Steps in Enzyme Catalysis

酶控制着几乎所有生命化学物质发生的速度。它们也是治疗干预、工业生物技术和合成生物学的核心，在这些领域，生物学正以全新的方式得到利用。在这些研究领域中，酶活性的调控都是一个关键因素。因此，了解是什么决定了酶的活性是一个高度优先的问题。酶的活性已经被研究了几十年，但对它们如何发挥作用的重要方面仍然没有当时可用的科学方法。最近，已经开发出一些工具，可以在几乎每个原子的分辨率下检查酶，告诉我们它们的性质、它们如何相互作用以及它们是如何运动的。这为更详细地研究酶在其反应周期的不同阶段的行为提供了机会。对所有这些元素及其相互作用的正确理解对于操纵酶活性至关重要。在这项研究中，我们将解决三个问题。首先，我们将研究为什么酶中特定位置的某些氨基酸在各种不同的生物体中是相同的，但根据目前的模型，这些氨基酸在酶的工作方式中没有作用。其次，我们将检查酶是否使用有时在两种蛋白质相互作用时发生的技巧，以确保相互作用是特定的，但既不强烈也不持久。第三，我们将检查某些酶在休眠阶段的行为是否特定存在，以确保除非条件合适，否则酶的整个种群不会太活跃。当一种酶完成多项工作时，这种情况就会发生，而太快地完成其中一项工作是有害的。这项研究的总体背景是开发更好的预测模型，以改善治疗、工业生物技术和合成生物学环境中酶的利用。

Enzymes control the rate at which almost all chemistry of life occurs. They are also at the core of therapeutic intervention, industrial biotechnology, and synthetic biology, where biology is being utilised in entirely new ways. The manipulation of enzyme activity is a key element in each of these areas of research. Hence, understanding what determines the activity of enzymes is a high priority. Enzyme activity has been studied for many decades but important aspects of how they work have eluded the scientific approaches available at the time. Very recently, tools have been developed that allow the examination of enzymes at the resolution of almost every individual atom, telling us about their properties, how they interact and how they move. This opens up the opportunity to examine in far greater detail than has been possible to-date how enzymes behave at different stages of their reaction cycles. A proper understanding of all of these elements and their interplay is crucial to manipulating enzyme activity. In this study we will address three questions. Firstly we will examine why certain amino acids at specific positions in enzymes are the same in a wide variety of different organisms and yet, according to current models, have no role in how the enzymes work. Secondly, we will examine whether enzymes use tricks that sometimes occur when two proteins interact that make sure that the interaction is specific but neither strong nor long lasting. Thirdly, we will examine whether a behaviour found in some enzymes when they are in a resting phase are specifically present to ensure that the whole population of an enzyme is not too active unless the conditions are right. This scenario occurs when an enzyme does more than one job, and it is detrimental to be too fast doing one of the jobs. The overall context of the study is to develop better predictive models that improve the utilization of enzymes in therapeutic, industrial biotechnology and synthetic biology settings.