Non-Enzymatic Catalysis in the Microbial Cell Interior

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Reducing our society's reliance on non-renewable fossil fuels is arguably one of the most important challenges facing the modern chemical industry.Traditionally, the fields of synthetic organic chemistry and metabolic engineering have represented two independent solutions to this challenge. Whereas synthetic organic chemists use largely non-biological reagents to manipulate small molecules in multi-step processes, metabolic engineers encode synthetic pathways within a sequence of DNA and overproduce target compounds via fermentation. However, despite the respective (and potentially complementary) benefits of these two approaches, metabolic engineering and synthetic organic chemistry have existed as largely separate disciplines for over a century. This Fellowship will merge these two fields by developing non-biological reactions for use within metabolically engineered microbial cells. It will, uniquely, focus on exploring these reactions in the cell interior and within designer metabolic pathways. Reactions will be targeted to various compartments of the cell using a "click" reaction between the catalyst scaffold and a genetically-encoded unnatural amino acid. Ultimately, this will enable microbial cells to synthesise molecules that are not found in Nature and therefore cannot be genetically encoded. In doing so, this will also answer fundamental questions in the field, namely:(i) Can non-enzymatic catalysis be truly integrated within an engineered metabolic pathway?(ii) Can interactions between chemical catalysts and biomolecules within the cell enhance catalysis in vivo? (iii) If so, can the chemical environment of the cell interior support modes of catalysis that are currently not possible in organic solvent? Overall, this approach represents a unique solution to the problem of renewable chemical manufacture and will dramatically increase the range of small molecules that can be produced from biological feedstocks using engineered microbial cells.