Collaborative Research: Synthetic acetyl-CoA-responsive metabolons for enhanced biosynthesis in yeast

Acetyl-CoA (AcCoA) is a central metabolite in Baker’s yeast. It serves as a precursor in the biosynthesis of many important projects. A balanced supply of AcCoA is essential to achieve high productivity and robust cell growth. Metabolons are multienzyme complexes that are capable of rapidly redirecting biosynthesis. This project will produce synthetic metabolons that respond to AcCoA. The synthetic metabolons will be used to investigate the role of AcCoA in metabolic regulation. The insights gained will be used to modify the metabolons to optimize biosynthesis involving AcCoA. The project will also provide opportunities for training students at all levels. The project will conduct outreach activities for local high school teachers and students to promote interest in biotechnology. The subcellular localization and availability of AcCoA often dictate the production of commercially important products. Dynamic reconfiguration of biosynthesis in response to AcCoA fluctuations could improve the balance between cell growth and product synthesis. The overall goal is to repurpose a native AcCoA-dependent, reversible protein-protein interaction as a framework to drive enhanced pathway efficiency. The proposed work could transform the field of synthetic biology in numerous ways. Efficient substrate channeling can reveal insights into yeast metabolism, optimize flux to desired products, and be implemented in a wide range of eukaryotic and prokaryotic cells. The results could lay the foundation for a transformative approach for implementing metabolite-mediated dynamic metabolons in productive industrial microorganisms. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.