Artificial metalloenzymes as evolvable catalysts for selective chemical synthesis

点击翻译按钮获取中文摘要

Catalysts are molecules that participate in a chemical reaction to speed it up but are not consumed in the process. They are vital to everyday life enabling scientists to make the products we need to survive - drugs, plastics, clothing. A well know catalytic example is the Haber-Borsch process which provides ammonia for fertiliser that ultimately helps feed the half the world. This man-made nitrogen fixation process requires high temperatures and pressures using 1-2% of the world's energy supply. In contrast, plants perform nitrogen fixation at ambient temperatures and pressures using metalloenzymes. Enzymes and metalloenzymes are nature's catalysts: proteins that have evolved over time to be highly selective and efficient catalysts for making a wide range of products from abundant natural resources, such as sugars, water, and air. Chemists have long sought to mimic enzymes in pursuit of the ideal catalyst for a sustainable chemical future providing for society's needs. Artificial metalloenzymes (ArMs), that combine enzymes and organometallic catalysts, present an exciting opportunity to obtain the ideal catalyst by introducing unprecedented chemical reactivity into metalloenzymes, preserving the benefits of enzymes whilst widening their synthetic utility. Metal catalysts allow a wide range of reactions to occur, including the activation of inert C-H bonds (also known as C-H functionalisation). The transformation of two C-H bonds into a C-C bond represents one of the most efficient transformations available to chemists with only two hydrogen atoms generated as waste. These reactions have enormous potential in reducing waste and also in reducing the number of chemical steps required for product formation by avoiding the need to activate the C-H bond before C-C bond creation, thus lowering the energy and time costs of synthesis.C-H functionalisation reactions are difficult to carry out selectively as many C-H bonds are present in the starting molecules and the innate selectivity of the molecule is not always the desired selectivity for product formation. By carefully modelling and designing new metal centres into protein scaffolds, I will create ArMs, which use the protein scaffold to influence the active site environment and lead to high control of selectivity. One advantage of using ArMs is that they are encoded by DNA allowing the selectivity and activity to be rapidly optimised using directed evolution - a method based on natural selection. Using this approach, I will create highly selective and active ArMs for C-H functionalisation reactions. The genetic nature of the ArMs also allows them to be transferred into bacterial cells to carry out unnatural chemical reactions within a cell. I aim to introduce these artificial metalloenzymes into novel biosynthetic pathways to provide access to unnatural 'natural' products and other complex molecules. The ArMs developed in this project will have the potential to introduce unnatural activities into living organisms, and can be applied in areas beyond chemical synthesis including energy, biomaterials and health applications.