Polyketide synthases as enzymatic platforms for high-value bioproducts
Polyketide synthases (PKSs) are molecular factories that produce an array of antibiotics, cancer therapeutics, and other medicinal compounds. While explored for over five decades, genomic sequencing has shown that the vast majority of polyketides have yet to be successfully reproduced in the laboratory setting. As a natural product applied towards therapeutics, the value of polyketide discovery is clear with a track record of success. However, the underlying biosynthetic logic of PKSs also provides an attractive engineering tool for the production of high value compounds.
Currently, I am a postdoctoral fellow in Dr. Jay Keasling’s laboratory at UC Berkeley, investigating polyketide synthases (PKS), large multi-modular proteins that produce anti-cancer and antimicrobial drugs. A central challenge in PKS design is replacing a partially reductive module with a fully reductive module through a reductive loop exchange, thereby generating a saturated β-carbon. In my work, I established a new engineering strategy for reductive loop exchanges based on chemoinformatics, a field traditionally used in drug discovery. I demonstrated that chemical similarity between the substrate of the original and donor PKS correlated with product titers (JACS, 2020). I have since leveraged this knowledge to produce potential biofuels and specialty chemicals such as branched fatty acids, ketones, lactams and lactones (Met. Eng, 2020). Collectively, my work formalizes a new chemoinformatic paradigm for de novo PKS biosynthesis which will accelerate the production of valuable bioproducts.