Directed Evolution of New Enzymes for Sustainable Chemical Manufacture in Microbial Cells

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The creation of new enzymes for the synthesis of drug-like molecules has revolutionised chemical manufacture, especially on the industrial scale.[1] However, despite significant advances in this field in recent years, enzymatic replacements for every organic transformation do not exist. Whilst the sequencing of newly-discovered microorganisms and the analysis of environmental metagenomes will continue to populate the biocatalytic toolbox, it seems unlikely that this approach will ever become a general solution to creating a new biocatalyst for any given organic reaction. The design and re-engineering of existing enzymes to perform novel chemical transformations is therefore an important challenge in organic chemistry.[2]This project will use directed evolution and a mechanistic knowledge of organic chemistry to create a new family of enzymes capable of catalysing reactions that have (to the best of our knowledge) never existed in Nature. These enzymes will then be used as modular components in designer metabolic pathways to produce small molecules of interest to the pharmaceutical industry directly from renewable resources via microbial fermentation.[3]The highly multidisciplinary nature of this project will allow the student to develop a strong proficiency in a variety of chemical and biological techniques (e.g. recombinant DNA techniques, PCR, directed evolution, microbiology, in vitro assay development, genome engineering, multistep chemical synthesis and spectroscopic analysis).