Structural, Mechanistic and Functional Studies on Protein Hydroxylases

蛋白质是聚合物，对生命的各个方面都至关重要。蛋白质是由单体氨基酸聚合合成的生物产生的聚合物。聚合过程的模板是信使核糖核酸（mRNA），它反过来由DNA编码，DNA用于所有生物体细胞中相对长期的信息存储。然而，一旦它们被合成，蛋白质可以在对其生理功能至关重要的过程中进一步修饰。其中一个过程是与大气中的氧（一种小而高扩散的分子）发生反应。我们感兴趣的是确定蛋白质如何以及为什么与大气中的氧气发生反应。在开创性的工作中，人们发现大气中的氧气在加氧酶的催化下与胶原蛋白发生反应，胶原蛋白是一种帮助动物细胞粘合在一起的物质。加氧酶是一种酶（或生物催化剂），它将大气中的氧气融入其反应产物中。许多加氧酶使用金属，如铁，来帮助捕获氧气。在发现它在胶原蛋白生物合成中的作用之后，人们发现加氧酶在抗生素的生产中起着关键作用，例如青霉素。最近，我们发现加氧酶也催化蛋白质的羟基化。从生物学和医学的角度来看，加氧酶的一些蛋白质靶点是重要的。一个突破性的发现是，动物细胞对限制氧气的生理机制实际上是由加氧酶催化的蛋白质羟基化调节的，参与调节DNA向mRNA的转化。在这一发现之后，我们和其他人又发现了其他作用于一系列蛋白质残基的蛋白质羟化酶。我们现在处于一个非常有利的位置来研究这些酶是如何工作的，包括了解它们是如何结合蛋白质底物的。我们将使用晶体学和其他技术，这将提供关于酶如何作为机器工作的详细信息。结构和机制研究将奠定基础，以便利用基础科学人为地改变加氧酶的活性，利用它们生产高价值的修饰蛋白质，并为制药工业提供针对疾病的有用知识。总的来说，这项工作将使联合王国继续处于加氧酶基础科学研究的前沿，并利用这项研究开发用于高价值化学品生产的新药和催化剂。

Proteins are polymers that are crucial to all aspects of life. Proteins are biologically produced polymers that are synthesised by polymerisation of monomeric amino acids. The template for the polymerisation process is messenger ribonucleic acid (mRNA), which in turn is encoded for by DNA, which is used for relatively long-term storage of information in the cells of all living organisms. However, once they have been synthesised, proteins can be further modified in processes that are often crucial for their physiological function. One such process is reaction with atmospheric oxygen, a small and high diffusible molecule. We are interested in defining how and why proteins react with oxygen from the atmosphere. In pioneering work it was found that atmospheric oxygen reacts with collagen, a material which helps cells to stick together in animals, in a reaction catalysed by oxygenases. Oxygenases are types of enzymes (or biological catalysts), that incorporate atmospheric oxygen into their reaction products. Many oxygenases use a metal, such as iron, to help capture oxygen. Subsequent to the discovery of its role in collagen biosynthesis, it was found that oxygenases play key roles in the production of antibiotics, such as the penicillins. More recently, we have found that oxygenases also catalyse the hydroxylation of proteins. Some of the protein targets of oxygenases are important from biological and medicinal perspectives. A breakthrough was the discovery that the physiological mechanism by which cells in animals respond to limiting oxygen is actually regulated by oxygenase catalysed hydroxylation of proteins, involved in regulating the conversion of DNA to mRNA. Following this discovery we, and others, have found other protein-hydroxylases, acting on a range of protein-residues. We are now in an exceptionally good position to work out how these enzymes work, including developing an understanding of how they bind their protein substrates. We will use crystallographic and other techniques, that will provide detailed information on how the enzymes work as machines. The structural and mechanistic studies will lay the groundwork in order to exploit the basic science to artificially alter the activity of the oxygenases, using them for the production of high-value modified proteins, and to provide knowledge that will be useful for the pharmaceutical industry in targeting them for diseases. Overall the work will enable the United Kingdom to remain at the forefront of basic science research on oxygenases and the exploitation of this research for the development of new medicines and catalysts for high value chemical production.