Chemistry Defense: Utsuki Yano: "Engineering Metabolic and Enzymatic Biosynthesis Platforms for the Production of Valuable Chemicals"

Engineering Metabolic and Enzymatic Biosynthesis Platforms for the Production of Valuable Chemicals

The development of sustainable microbial production platforms is critical for reducing reliance on petrochemical-based synthesis and enabling the use of renewable feedstocks. Although microbialfermentation has advanced through synthetic biology and metabolic engineering, its industrial performance is often limited by native regulatory networks that prioritize survival over production,thereby restricting efficient and robust production. In this thesis, I address these limitations by redesigning central metabolism in Escherichia coli through a novel architecture termed the gluconate bypass (GBP), which decouples glucose uptake from glycolytic regulation. This enables sustained glucose uptake, reduces pyruvate-mediated inhibition, and supports robust production in stationary phase. Using L-alanine as a model commodity chemical, the GBP improved titer, yield, and productivity by prolonging the production phase. The GBP also enabled simultaneous co-utilization of lignocellulosic sugars, including glucose, xylose, arabinose, and galactose, improving the efficiency and economic
viability of microbial production from low-cost feedstocks. The GBP platform was further applied to myo-inositol production, where coupling central metabolic rewiring with dynamic control allowed elimination of glycerol co-feed while enhancing intracellular precursor availability and improving
production yield. Finally, this thesis expands beyond microbial fermentation to a combinatorial exponential biosynthesis (CEBS) platform for generating structurally diverse, drug-like molecules and expanding accessible chemical space through enzyme engineering. Together, this thesis establishes strategies to improve microbial production of commodity and specialty chemicals and extends
biosynthesis beyond native metabolites to generate structurally diverse derivatives and access new chemical space.

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