Enabling Native Amine Dehydrogenases (nat-AmDHs) for the Sustainable Synthesis of Chiral Amines

The chemicals industry is looking for more green and sustainable routes to the synthesis of important molecules as it looks towards a carbon net zero future. Many current synthetic methods require toxic reagents and energy-intensive reaction conditions. In some cases, these issues can be addressed through the use of enzymes, which can be used under mild conditions and possess excellent reaction selectivities that suit the synthesis of complex pharmaceutical molecules. Amines, for example, are a class of compound that feature in a large proportion of small molecule drugs, and their synthesis in single ‘optical isomer’ form, which is highly important for the synthesis of bioactive molecules and drugs, can be achieved using a range of enzymes. The current choice of enzyme - ‘transaminases’ - present a number of drawbacks with respect to industrial application, and there is a need for complementary enzymes with better industrial potential and superior properties. In this project, we will look to investigate the potential of one emerging alternative class of enzyme, ‘native Amine Dehydrogenases’ (nat-AmDHs), and to enable these for the scalable synthesis of pharmaceutical compounds and their precursors. Our collaborators in France, Gensocope, have performed exhaustive screens of known biological sequences of proteins for AmDHs. Together with our team at York, we will start to investigate the scope and potential of the new enzymes. Our aims are to use a mixture of synthetic organic chemistry and molecular biology to make enzymes and test them for their synthetic potential. We will determine the structures of the enzymes using X-ray crystallography, so that we can then engineer the enzymes for altered and improved activity, stability and process suitability. We will then look to apply the enzymes at a demonstration scale. The project will yield catalysts and processes that we anticipate will supersede the performance of transaminase enzymes for the industrial synthesis of amines, and advance the uptake of green and sustainable methods for pharmaceutical synthesis in the chemicals industry.