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Enzymes are the proteinaceous catalysts developed by billions of years of evolution that accelerate chemical reactions into the realm of biological significance. The efficiency of these catalysts is astounding, with enzymes often requiring milliseconds to catalyze reactions that can otherwise require thousands of years. Given their efficiency and negligible environmental impact, enzymes are attractive alternatives to more traditional synthetic transformations that offer the possibility of a sustainable chemical industry. While protein engineering through directed evolution permits the development of efficient enzymes for industrially important xenobiotic chemical reactions, the precise mechanisms by which this technique converts one biocatalyst into another remain entirely unclear. This presentation will detail our efforts to shine a light on the ‘black box’ of directed evolution through the combined use of kinetic isotope effects and quantum mechanical calculations. These techniques permit the characterization of enzyme-catalyzed transition states and offer extremely detailed information about the mechanisms of catalysis. By elucidating how these transition states and the broader enzyme mechanisms are altered over the course of directed evolution, this work will provide fundamental insights into the source of enzymatic catalysis, as well as the features that are required for the development of new biocatalysts. These insights will allow enzyme engineers to progress from current unguided ‘blind’ applications of directed evolution towards semi-rational engineering efforts that reduce the time and costs associated with the repetitious cycles of mutagenesis and screening required for the development of useful biocatalysts. Ongoing efforts in our lab to engineer truly sustainable biocatalysts for industrial applications will also be detailed.
Graeme received his Hon. B.Sc. in Chemistry from the University of Toronto. After graduation, Graeme remained in Toronto and carried out his doctoral studies with Prof. Ronald Kluger, studying the mechanisms of decarboxylation of vitamin B1-derived intermediates and aromatic acids. After receiving his doctorate in 2016, Graeme traveled south of the border to study enzyme mechanisms under the supervision of Prof. Wilfred van der Donk at the University of Illinois at Urbana-Champaign as an NSERC Postdoctoral Fellow. Graeme began his independent career in the Department of Chemistry at Queen’s University in July of 2019. His research program is focused on understanding how enzymes evolve and the engineering of enzymes into new and improved biocatalysts.