Collaborative Research: SusChEM: A Robust Yeast Platform for the Synthesis and Engineering of Polyketide-Based Pharmaceuticals and Chemicals

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1605357/1605877Da Silva, Nancy A./Tang, YiPolyketide-derived natural products represent an important class of pharmaceuticals with application to nearly all major types of human diseases, including antibiotics, anticancer, and anti-hypercholesterolemia. In recent years, polyketides have also been attractive as renewable chemicals and fuels, due to the flexibility in their synthesis and their structures. This research will engineer the yeast Saccharomyces cerevisiae for the high-level synthesis of polyketides, leading to new methods for the sustainable production of chemicals and pharmaceuticals. The research will also enable the discovery of new enzymes and biochemicals. The research will impact the field by providing new, renewable ways of producing a variety of commercially important compounds. From an educational and outreach perspective, the research will span the core disciplines of engineering, chemistry and biology, and will therefore provide ample opportunities for student training in multiple areas. Polyketides are microbial and plant metabolites that have significantly impacted human health. They are synthesized in bacteria, fungi and plants by polyketide synthases from simple primary metabolite building blocks such as acetyl-CoA and malonyl-CoA. As more genome sequences have become available and understanding of polyketide biosynthesis grows, there are significant opportunities to engineer the production of these compounds in model organisms such as Saccharomyces cerevisiae. This research will combine polyketide chemistry and yeast metabolic engineering to outfit yeast as a high-level production host for different valuable fungal and plant polyketides. State of the art synthetic biology and genetic tools will be used to optimize the capacity of yeast to supply the polyketide precursors, as well as to abundantly express the bottleneck, rate-limiting polyketide synthases. The engineered yeast will be applied towards the production of three sets of polyketide compounds: i) compounds of therapeutic values from the fungal kingdom; ii) biochemical building blocks and biosurfactants; and iii) novel compounds new to science discovered from genome mining of sequenced fungal species. This integrated approach will lead to yeast heterologous hosts that are powerful, general and drop-in for polyketide production, and can reveal insights into yeast metabolism and optimization of foreign (and difficult) protein expression. The work on biochemical production using various polyketide synthases can enable renewable production of value added chemicals, as well as examine the dexterity of corresponding polyketide synthases.This award by the Biotechnology and Biochemical Engineering Program of the CBET Division is co-funded by the Biomaterials Program of the Division of Materials Research.