Rapid Evolution of Enzymes and Synthetic Micro-organisms for the Development of Industrial Biocatalysts

During the next 10-20 years the chemical industry around the world will undergo a major transformation. As both oil and natural gas begin to run out society will need to look for alternative sources of the chemicals that have traditionally been derived from these fossil fuels. Driven by the need to develop processes that are both economically and environmentally sustainable, the chemical industry will increasingly turn to renewable feedstocks for the manufacture of a growing range of products. Such products are diverse and produced in large volume and include cosmetics, pharmaceutical drugs, components of automobiles and also fuels. This switchover from oil-based starting materials to those derived from biomass will necessitate the development of Industrial (White) Biotechnology-based processes that are able to convert inexpensive raw materials efficiently to high-value products. Industrial Biotechnology involves the use of Nature's catalysts, known as enzymes, for the production of chemicals and related products. The new opportunity that emerges is to be smart with the rational design and construction of engineered biocatalysts and multi-enzyme pathways that are capable of the efficient and robust conversion of simple, low-cost renewable feedstocks (e.g. cellulose, lipids, waste biomass) to each high value end product. In some cases these biocatalytic transformations will be carried out by isolated enzymes, supported on an inert carrier. In other applications, especially for multi-enzyme conversions, the processes will need to be carried out within the environment of a microbial cell - the so-called 'engineered cell factory' - thereby minimizing production costs and rendering conventional manufacturing technologies uncompetitive. The design and engineering of such cells, which are capable of pre-programmed synthetic conversions, represents a significant challenge for IB and will require the interaction of the disciplines of synthetic chemistry, synthetic-systems biology and process engineering. In collaboration with GlaxoSmithKline (GSK), one of the world's largest pharmaceutical companies, the team of scientists at the University of Manchester will develop a new approach to engineering robust biocatalysts by essentially mimicking the process of Darwinian evolution in the laboratory. This new platform technology will enable us to optimise enzyme for industrial applications in a matter of weeks rather than the months which it currently takes. We will demonstrate the power of this new technology by specially targeting six different synthetic transformations which are on interest to chemists who wish to use biocatalysis in the manufacture of active pharmaceutical ingredients (APIs). These biocatalytic reactions have been specifically chosen because they offer very competitive alternatives to conventional synthetic chemistry methods. These robust biocatalysts will produce the molecules of interest at sufficiently high concentrations, fluxes and yields to ensure economic viability even when crude oil prices are low. At various stages during the project we shall transfer these biocatalysts to GSK who will then apply them to their in-house molecules of interest. We shall also publish the results of the research in the open literature and make the new methods available by web-based tools.