UC Berkeley

Natural products use exquisite structural complexity to tailor a limited repertoire of functional groups for different molecular functions. These molecules have been adopted or adapted by humans to create a large fraction of current therapeutics. However, those adaptations have not always been able to combine the chemical diversity possible for totally synthetic compounds with the many advantages of biosynthesis. Extremely rare in nature but ubiquitous in synthetic pharmaceuticals, fluorine is a unique tool for molecular design, and an excellent candidate for expanding biosynthetic diversity. This dissertation describes our work to enable efficient fluorine incorporation into complex biosynthetic pathways, both in vitro and in the context of a whole organism, and our progress in enabling fluorinated polyketide biosynthesis. We hope to set the stage for a dramatic expansion in polyketide structural diversity via engineered biosynthesis, using a design element that could improve bioactive properties and furnish new therapeutics.