摘要：SummaryTranscription factor-based biosensors naturally occur in metabolic pathways to maintain cell growth and to provide a robust response to environmental fluctuations. Extended metabolic biosensors, i.e., the cascading of a bio-conversion pathway and a transcription factor (TF) responsive to the downstream effector metabolite, provide sensing capabilities beyond natural effectors for implementing context-aware synthetic genetic circuits and bio-observers. However, the engineering of such multi-step circuits is challenged by stability and robustness issues. In order to streamline the design of TF-based biosensors in metabolic pathways, here we investigate the response of a genetic circuit combining a TF-based extended metabolic biosensor with an antithetic integral circuit, a feedback controller that achieves robustness against environmental fluctuations. The dynamic response of an extended biosensor-based regulated flavonoid pathway is analyzed in order to address the issues of biosensor tuning of the regulated pathway under industrial biomanufacturing operating constraints.Graphical AbstractDisplay OmittedHighlights•Fluctuations and perturbations affect dynamics and titers in cell factories•Extended metabolic biosensors expand product sensing and enable pathway regulation•Closed-loop pathway regulation provides robustness to cell factory production•A closed-loop regulated flavonoid production pathway shows robust dynamic responseBioengineering; Metabolic Engineering; Biotechnology
