Unlocking the potential of engineered C-C bond forming enzymes for biocatalysis

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The future success of the global pharmaceutical and chemical industries is dependent on the successful development of efficient, selective and sustainable ways of making new organic molecules with useful properties. Historically, such methods have centered on the use of synthetic organic chemistry to fuse and tailor simple chemical building blocks into a vast array of complex molecular architectures, which may in-turn be used as the basis for amongst other things new drugs, crop protection agents, or materials. Despite the undoubted success of synthetic chemistry, problems exist, including the over-reliance on certain types of reactions that have led to an excessive representation of molecules with predominantly flat, 2D architectures, which are of limited value as drugs. In contrast to chemical catalysts, biological catalysts, termed enzymes, are able to perform challenging chemical reactions that can rapidly build complex 3D chemical structures with multiple bonds under precise stereochemical control. In addition, enzymes can perform such reactions under ambient conditions and without any requirement for environmentally damaging reagents. For these reasons there is significant interest in developing biocatalytic routes to current and future pharmaceuticals and similarly important molecules. A carbon-carbon bond forming reaction known as the Diels-Alder reaction is an effective means of building complex 3D molecules in a single step. However, a limitation of this reaction is that to achieve high yields, stereoselectivity and regioselectivity, the electronic properties of the reactants need to be complementary and often harsh reaction conditions are required. This research project builds on our exciting recent discovery of a naturally evolved co-factor independent enzyme that catalyzes the Diels-Alder reaction at room temperature and on substrates which cannot be transformed using conventional synthetic organic chemistry. This discovery opens up the possibility of using this enzyme to generate a whole new series of complex molecules that could form the basis of new drugs or similarly important chemical compounds. During this project we will establish the practical and theoretical limits of the reactions that this and other related Diels-Alderases can catalyze, we will also rationally re-engineer these enzyme to purposefully change their function to allow access to an even greater variety of products. We will partner these engineered biocatalysts with auxiliary enzymes which catalyze further ring forming reactions to develop routes to industrially useful molecules. This project is a strategically important partnership between the University of Bristol and the pharmaceutical company AstraZeneca, and we will work together to develop natural and engineered enzymes and deploy them to generate a vast array of new 3D molecules that can be used as the basis for new drugs to treat a diverse array of human diseases.