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  • Review Article
  • Published:

Engineered autonomous dynamic regulation of metabolic flux

Nature Reviews Bioengineering volume 2, pages 233–243 (2024)Cite this article

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Abstract

Metabolic engineering is a powerful tool to reprogramme cells to produce value-added chemicals. Such engineering strategies require the fine-tuning of a cell’s metabolism to balance competition for resources and prevent negative impacts on growth. Dynamic regulation enables the shifting of resources or metabolic flux toward different pathways based on a received input to increase titres of value-added chemicals in microbial production strains. In this Review, we discuss autonomous dynamic regulation, that is, responses triggered directly by a stimulus without the need for human intervention, and its application to metabolic engineering. We highlight strategies to control the transcription of genes using metabolite-specific regulation, including by transcription factors and through biosensing, and non-specific regulation, in particular, environmental regulation, growth-phase responses and quorum sensing, examining the application of these regulation strategies to the bioproduction of different chemicals.

Key points

  • Autonomous dynamic regulation can be used to shift metabolic flux in microorganisms without external intervention to control the accumulation of biomass or metabolites.

  • Metabolite-specific transcription factors and biosensors provide fine-tuned control of the expression of target genes requiring specific substrates for induction.

  • Globally regulated promoters can regulate genes using native machinery in response to common metabolites but are often subject to carbon catabolite repression and require complex networks of regulation.

  • Environmentally responsive regulators that respond to external stimuli, such as metals, pH, light and temperature, are useful tools for bioremediation and specialized bioproduction.

  • Quorum sensing, which provides consistent regulation based on the population density of the culture, is a versatile regulation strategy but requires cellular resources to produce and detect signalling molecules.

  • Autonomous dynamic regulation may improve the efficiency of bioproduction and bioremediation.

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Fig. 1: Transcriptional regulation using dynamic stimuli.
Fig. 2: Non-specific regulation of metabolic flux.

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Acknowledgements

This work was supported by an MIT Bose Research Grant (award number 2116642).

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  1. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Michael Ream & Kristala L. J. Prather

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M.R. and K.L.J.P conceptualized the manuscript. M.R. researched and wrote the manuscript. K.L.J.P. edited the manuscript.

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Correspondence to Kristala L. J. Prather.

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Ream, M., Prather, K.L.J. Engineered autonomous dynamic regulation of metabolic flux. Nat Rev Bioeng 2, 233–243 (2024). https://doi.org/10.1038/s44222-023-00140-7

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