(197e) Engineered Biosynthesis of Complex Aromatic Polyketides Using Fungal Polyketide Synthase In Escherichia Coli

Bacterial aromatic polyketides are a family of structurally diverse natural products with important pharmaceutical and agricultural applications, including antibiotics tetracyclines and anticancer agents doxorubicin, etc. Since most natural polyketide-producing organisms are slow-growing and/or genetically intractable, it is desirable to transfer polyketide biosynthetic pathways to a more robust host such as Escherichia coli (E. coli) for pathway engineering and product isolation. While E. coli has been recently metabolically engineered to produce simple monocyclic or bicyclic compounds, complex aromatic polyketides have not been synthesized by E. coli largely due to the fact that the responsible type II minimal polyketide synthase (PKS) cannot be functionally expressed in E. coli. In this work, the biosynthetic potential of fungal PKS4 from Gibberella fujikuroi will be explored for combinatorial biosynthesis of bacterial aromatic polyketides in E. coli. Using a catalytic platform that employs a reengineered PKS4 and tailoring enzymes, we demonstrate the biosynthesis of complex aromatic polyketides in E. coli for the first time.