Metabolic Feedback Circuits Provide Rapid Control of Metabolite Dynamics.

Metabolism constitutes the basis of life, and the dynamics of metabolism dictate various cellular processes. However, exactly how metabolite dynamics are controlled remains poorly understood. By studying an engineered fatty acid-producing pathway as a model, we found that upon transcription activation a metabolic product from an unregulated pathway required seven cell cycles to reach to its steady state level, with the speed mostly limited by enzyme expression dynamics. To overcome this limit, we designed metabolic feedback circuits (MeFCs) with three different architectures, and experimentally measured and modeled their metabolite dynamics. Our engineered MeFCs could dramatically shorten the rise-time of metabolites, decreasing it by as much as 12-fold. The findings of this study provide a systematic understanding of metabolite dynamics in different architectures of MeFCs and have potentially immense applications in designing synthetic circuits to improve the productivities of engineered metabolic pathways.