EAGER: Synthetic Control of Metabolism by Dynamic Metabolons

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This project addresses a challenging problem in metabolic engineering, namely the channelling of chemical reactions in the cell into metabolic pathways in an efficient and dynamically controlled manner, but without affecting cellular growth. The two collaborators offer complementary expertise in the analysis of metabolic flux and protein engineering in order to pursue a highly innovative design concept to achieve this goal. The students trained on this project will be exposed to multi-disciplinary training in the context of research that is anticipated to significantly advance biomanufacturing capabilities. The goal is to develop synthetic dynamic metabolons that will allow carbon flux to be redirected as desired. The end result will be the ability to provide dynamic optimization of microbial metabolism for optimal product formation. This will be achieved by dynamic shifts between the assembly and disassembly of synthetic metabolons in order to modulate the overall output function. Specifically, successive metabolic enzymes will be coupled onto Pumilio (PUF) modules, which are also capable of binding specific riboswitches. These riboswitches are designed to respond to specific metabolic or synthetic signals. Feasibility will be demonstrated by designing two multi-enzyme dynamic metabolons, one that converts methanol into hexulose-6-phosphate, which is a valuable precursor for chemical and fuel production. The second metabolon includes enzymes that convert acetyl-CoA into mevalonate. The ultimate goal is to combine the knowledge gained toward the design of dynamic metabolons for enhanced fatty acid synthesis.