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Metabolic engineering has enabled the production of a wealth of chemicals with microorganisms. Classic strategies for pathway engineering rely on the expression of heterologous enzymes in a host that convert native intermediates into target products. Although traditional implementations are based on open-loop control, recent advances in gene circuit engineering offer opportunities for building feedback systems that dynamically control pathway activity. Here we present a framework for the design of metabolic control circuits based on multi objective optimization. We show that positive and negative feedback loops produce a range of optimal dynamics along a Pareto front. Such regulatory loops define connectivities between pathway intermediates and enzymatic genes that trade-off metabolic production against the burden to the host. Our results lay the groundwork for the automated design of gene circuitry in applications at the interface of synthetic biology and metabolic engineering.

Multiobjective optimization of gene circuits for metabolic engineering