High-throughput approaches in enzyme discovery and engineering

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Enzymes are extraordinary biocatalysts - they are the machinery of cell factories, crafted by Nature over aeons of evolution. In Nature, enzymes catalyze the chemical reactions within living organisms, whereas in biotechnological applications, they are taken out of their natural context and used for chemical processes that are important in many industries. Since enzymes in industrial biocatalysis are often used in conditions and for purposes quite different from the natural context and function for which they have evolved, there is much room to improve their performance in these processes. The potential of enzymes in bioindustrial applications is greatly expanded through enzyme engineering efforts, such as directed evolution. I propose a research program focused on the discovery and engineering of enzyme biocatalysts for the production of high-value bioactive compounds and of biorenewable chemicals as alternatives to petroleum products. This will be achieved by initially targeting two classes of enzymes: glycosyltransferases that attach sugar units onto natural product scaffolds to produce bioactive glycosylated small molecules; and decarboxylases involved in the conversion of fatty acids into hydrocarbons that can potentially be used to replace petrochemicals as fuels and chemical building blocks. We will develop methods that will enable us not only to discover, but to engineer the enzymes that produce these valuable compounds. Using directed evolution we will improve the efficiency of these enzyme biocatalysts in producing such compounds, and alter their specificity to expand the kinds of molecules that they can produce. The engineering of biocatalyst tools for producing renewable resources and high-value bioactive chemicals will be of significant social and economic benefit.