Structural, Mechanistic and Functional Studies on Protein Hydroxylases

蛋白质是一种聚合物，对生命的方方面面都至关重要。蛋白质是生物产生的聚合物，由单体氨基酸聚合而成。聚合过程的模板是信使核糖核酸(信使核糖核酸)，信使核糖核酸由DNA编码，用于在所有活着的有机体细胞中相对长期地存储信息。然而，一旦它们被合成，蛋白质就可以在通常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气反应，氧气是一种小而高扩散的分子。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反应。在开创性的工作中，人们发现大气中的氧气与胶原蛋白发生反应，在加氧酶的催化下，胶原蛋白是一种帮助动物细胞粘合在一起的材料。加氧酶是一种酶(或生物催化剂)，可将大气中的氧气结合到其反应产物中。许多加氧酶使用一种金属，如铁，来帮助捕获氧气。在发现加氧酶在胶原生物合成中的作用后，人们发现加氧酶在抗生素的生产中起着关键作用，如青霉素。最近，我们发现加氧酶也催化蛋白质的羟化。从生物学和医学角度来看，加氧酶的一些蛋白质靶标是重要的。一项突破性的发现是，动物细胞对有限氧气做出反应的生理机制实际上是由加氧酶催化的蛋白质羟化来调节的，参与调节DNA到mRNA的转换。在这一发现之后，我们和其他人发现了其他作用于一系列蛋白质残基的蛋白质羟基酶。我们现在处于一个非常好的位置来研究这些酶是如何工作的，包括发展对它们如何结合蛋白质底物的理解。我们将使用结晶学和其他技术，提供有关酶如何作为机器工作的详细信息。结构和机理研究将奠定基础，以便利用基础科学来人为改变加氧酶的活性，利用它们生产高价值的修饰蛋白质，并提供有助于制药行业针对疾病进行靶向的知识。总体而言，这项工作将使联合王国在有关加氧酶的基础科学研究和开发用于高价值化学品生产的新药和催化剂方面继续走在前列。

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.