Intellectual merit: Saccharomyces cerevisiae (yeast) is one of the most widely used microorganisms for production of commodity chemicals and fuels, and proteins. This research will develop genetic, computer aided design, and strain engineering tools for yeast and will demonstrate their use in expressing multi-component polyketide synthases for the production of important chemicals. The choice to engineer yeast for polyketide synthesis is derived from the fact that the most useful natural products are polyketides and the biosynthetic enzymes involved can be engineered to produce a broad range of pharmaceuticals, commodity and specialty chemicals, and fuels. The expression of functional polyketide synthases and the production of the necessary precursors to supply the biosynthetic machinery is a challenging problem that requires a better biological host and the appropriate gene expression tools. The specific aims of the project are to 1) develop generalized methods for the rapid modification of the S. cerevisiae genome to create modified versions of yeast strains that are capable of growing and/or surviving extreme conditions; 2) create a suite of gene expression control devices and demonstrate their utility for producing polyketide synthase complexes for the production of specific commodity chemicals; 3) construct pathways for the synthesis of polyketide precursors; 4) create libraries of polyketide synthases for production of diverse chemicals; and 5) develop computer aided design (CAD) software that will enable the rapid construction of yeasts.
Broader impacts: The tools developed for the synthesis of polyketides will be broadly applicable for the engineering of yeast to produce a variety of products as well as exploring fundamental yeast biology. This translational research effort will bring state-of-the-art synthetic biology advances to an industrially-relevant organism. The major potential benefits to society will be replacement of existing, petroleum-based polymer monomers with monomers derived from renewable resources; production of novel monomers for new materials that cannot be made; biological components for engineering yeast for scientific projects and applications; and computer-aided design tools for biology. The investigators will use relationships developed through the Synthetic Biology Engineering Research Center to help small and large companies grow the bioeconomy. The investigators will use the research findings to teach and train a cutting-edge workforce of post-docs, graduate students, and undergraduate students in this new area of research. The project will support underrepresented undergraduate students through established REU programs at UC Berkeley and MIT, and underprivileged high school students through a novel high school program developed by post-doctoral fellows in SynBERC.
