Structural, Mechanistic and Functional Studies on Protein Hydroxylases

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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.