Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Engineered autonomous dynamic regulation of metabolic flux

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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

Similar content being viewed by others

References

  1. Ni, C., Dinh, C. V. & Prather, K. L. J. Dynamic control of metabolism. Annu. Rev. Chem. Biomol. Eng. 12, 519–541 (2021).

    Article  CAS  PubMed  Google Scholar 

  2. Tan, S. Z. & Prather, K. L. Dynamic pathway regulation: recent advances and methods of construction. Curr. Opin. Chem. Biol. 41, 28–35 (2017).

    Article  CAS  PubMed  Google Scholar 

  3. Cui, S. et al. Multilayer genetic circuits for dynamic regulation of metabolic pathways. ACS Synth. Biol. 10, 1587–1597 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Xu, P. Production of chemicals using dynamic control of metabolic fluxes. Curr. Opin. Biotechnol. 53, 12–19 (2018).

    Article  CAS  PubMed  Google Scholar 

  5. Shen, X., Wang, J., Li, C., Yuan, Q. & Yan, Y. Dynamic gene expression engineering as a tool in pathway engineering. Curr. Opin. Biotechnol. 59, 122–129 (2019).

    Article  CAS  PubMed  Google Scholar 

  6. Lv, Y. et al. Coupling feedback genetic circuits with growth phenotype for dynamic population control and intelligent bioproduction. Metab. Eng. 54, 109–116 (2019).

    Article  CAS  PubMed  Google Scholar 

  7. Zhang, Q. et al. Production of proteins and commodity chemicals using engineered Bacillus subtilis platform strain. Essays Biochem. 65, 173–185 (2021).

    Article  CAS  PubMed  Google Scholar 

  8. Venayak, N., Anesiadis, N., Cluett, W. R. & Mahadevan, R. Engineering metabolism through dynamic control. Curr. Opin. Biotechnol. 34, 142–152 (2015).

    Article  CAS  PubMed  Google Scholar 

  9. Zhang, X., Lin, Y., Wu, Q., Wang, Y. & Chen, G. Q. Synthetic biology and genome-editing tools for improving PHA metabolic engineering. Trends Biotechnol. 38, 689–700 (2020).

    Article  CAS  PubMed  Google Scholar 

  10. Li, C., Zhang, R., Wang, J., Wilson, L. M. & Yan, Y. Protein engineering for improving and diversifying natural product biosynthesis. Trends Biotechnol. 38, 729–744 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zubi, Y. S. et al. Metal-responsive regulation of enzyme catalysis using genetically encoded chemical switches. Nat. Commun. 13, 1864 (2022).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  12. Grohmann, C. et al. Development of NanoLuc-targeting protein degraders and a universal reporter system to benchmark tag-targeted degradation platforms. Nat. Commun. 13, 2073 (2022).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  13. Zaslaver, A. et al. Just-in-time transcription program in metabolic pathways. Nat. Genet. 36, 486–491 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Gao, C., Xu, P., Ye, C., Chen, X. & Liu, L. Genetic circuit-assisted smart microbial engineering. Trends Microbiol. 27, 1011–1024 (2019).

    Article  CAS  PubMed  Google Scholar 

  15. Moser, F. et al. Dynamic control of endogenous metabolism with combinatorial logic circuits. Mol. Syst. Biol. 14, e8605 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Liang, C. et al. Dynamic control of toxic natural product biosynthesis by an artificial regulatory circuit. Metab. Eng. 57, 239–246 (2020).

    Article  CAS  PubMed  Google Scholar 

  17. Zhang, D. et al. Global and gene-specific translational regulation in Escherichia coli across different conditions. PLoS Comput. Biol. 18, e1010641 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Balleza, E. et al. Regulation by transcription factors in bacteria: beyond description. FEMS Microbiol. Rev. 33, 133–151 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Engstrom, M. D. & Pfleger, B. F. Transcription control engineering and applications in synthetic biology. Synth. Syst. Biotechnol. 2, 176–191 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Mitchler, M. M., Garcia, J. M., Montero, N. E. & Williams, G. J. Transcription factor-based biosensors: a molecular-guided approach for natural product engineering. Curr. Opin. Biotechnol. 69, 172–181 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhou, S., Alper, H. S., Zhou, J. & Deng, Y. Intracellular biosensor-based dynamic regulation to manipulate gene expression at the spatiotemporal level. Crit. Rev. Biotechnol. 43, 646–663 (2023).

    Article  CAS  PubMed  Google Scholar 

  22. Lyu, M. et al. AccR, a TetR family transcriptional repressor, coordinates short-chain acyl coenzyme A homeostasis in Streptomyces avermitilis. Appl Environ Microbiol. 86, e00508–e00520 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chen, Y. et al. Tuning the dynamic range of bacterial promoters regulated by ligand-inducible transcription factors. Nat. Commun. 9, 64 (2018).

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  24. d’Oelsnitz, S. et al. Using fungible biosensors to evolve improved alkaloid biosyntheses. Nat. Chem. Biol. 18, 981–989 (2022).

    Article  PubMed  Google Scholar 

  25. Xiong, D. et al. Improving key enzyme activity in phenylpropanoid pathway with a designed biosensor. Metab. Eng. 40, 115–123 (2017).

    Article  CAS  PubMed  Google Scholar 

  26. Zhou, S. et al. Development of a growth coupled and multi-layered dynamic regulation network balancing malonyl-CoA node to enhance (2S)-naringenin biosynthesis in Escherichia coli. Metab. Eng. 67, 41–52 (2021).

    Article  CAS  PubMed  Google Scholar 

  27. Wu, Y. et al. CRISPR–dCas12a-mediated genetic circuit cascades for multiplexed pathway optimization. Nat. Chem. Biol. 19, 367–377 (2023).

    Article  CAS  PubMed  Google Scholar 

  28. Brückner, R. & Titgemeyer, F. Carbon catabolite repression in bacteria: choice of the carbon source and autoregulatory limitation of sugar utilization. FEMS Microbiol. Lett. 209, 141–148 (2002).

    Article  PubMed  Google Scholar 

  29. Kunitake, E. et al. cAMP signaling factors regulate carbon catabolite repression of hemicellulase genes in Aspergillus nidulans. AMB Express 12, 126 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Galinier, A. et al. New protein kinase and protein phosphatase families mediate signal transduction in bacterial catabolite repression. Proc. Natl Acad. Sci. USA 95, 1823–1828 (1998).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  31. Weinhandl, K., Winkler, M., Glieder, A. & Camattari, A. Carbon source dependent promoters in yeasts. Microb. Cell Fact. 13, 5 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ferreira, R. et al. Metabolic engineering of Saccharomyces cerevisiae for overproduction of triacylglycerols. Metab. Eng. Commun. 6, 22–27 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Görke, B. & Stülke, J. Carbon catabolite repression in bacteria: many ways to make the most out of nutrients. Nat. Rev. Microbiol. 6, 613–624 (2008).

    Article  PubMed  Google Scholar 

  34. Yu, T. et al. Metabolic reconfiguration enables synthetic reductive metabolism in yeast. Nat. Metab. 4, 1551–1559 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kong, W., Qian, Y., Stewart, P. S. & Lu, T. De novo engineering of a bacterial lifestyle program. Nat. Chem. Biol. 19, 488–497 (2022).

    Article  PubMed  Google Scholar 

  36. Deng, J. et al. A synthetic promoter system for well-controlled protein expression with different carbon sources in Saccharomyces cerevisiae. Microb. Cell Fact. 20, 202 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Blazeck, J., Garg, R., Reed, B. & Alper, H. S. Controlling promoter strength and regulation in Saccharomyces cerevisiae using synthetic hybrid promoters. Biotechnol. Bioeng. 109, 2884–2895 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Callaghan, J. D. et al. Xylose-inducible promoter tools for Pseudomonas species and their use in implicating a role for the type II secretion system protein XcpQ in the inhibition of corneal epithelial wound closure. Appl. Environ. Microbiol. 86, e00250-20 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Wei, W. et al. Engineering prokaryotic transcriptional activator xylr as a xylose-inducible biosensor for transcription activation in yeast. ACS Synth. Biol. 9, 1022–1029 (2020).

    Article  CAS  PubMed  Google Scholar 

  40. Kim, S., Lee, K., Bae, S. J. & Hahn, J. S. Promoters inducible by aromatic amino acids and γ-aminobutyrate (GABA) for metabolic engineering applications in Saccharomyces cerevisiae. Appl. Microbiol. Biotechnol. 99, 2705–2714 (2015).

    Article  CAS  PubMed  Google Scholar 

  41. den Haan, R. et al. Heterologous production of cellulose- and starch-degrading hydrolases to expand Saccharomyces cerevisiae substrate utilization: lessons learnt. Biotechnol. Adv. 53, 107859 (2021).

    Article  Google Scholar 

  42. Zhang, M. et al. MULTiPly: a novel multi-layer predictor for discovering general and specific types of promoters. Bioinformatics 35, 2957–2965 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Li, F. et al. Computational prediction and interpretation of both general and specific types of promoters in Escherichia coli by exploiting a stacked ensemble-learning framework. Brief. Bioinform. 22, 2126–2140 (2021).

    Article  CAS  PubMed  Google Scholar 

  44. Tang, H. et al. Promoter architecture and promoter engineering in Saccharomyces cerevisiae. Metabolites 10, 320 (2020).

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yang, Y. et al. Structural visualization of transcription activated by a multidrug-sensing MerR family regulator. Nat. Commun. 12, 2702 (2021).

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  46. Su, Y., Liu, C., Jiang, X. & Wei, W. Different bacterial host-based lux reporter array for fast identification and toxicity indication of multiple metal ions. Anal. Bioanal. Chem. 412, 8127–8134 (2020).

    Article  CAS  PubMed  Google Scholar 

  47. Travis, B. A. et al. Molecular dissection of the glutamine synthetase-GlnR nitrogen regulatory circuitry in Gram-positive bacteria. Nat. Commun. 13, 3793 (2022).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  48. Stirling, F. et al. Synthetic cassettes for pH-mediated sensing, counting, and containment. Cell Rep. 30, 3139–3148.e4 (2020).

    Article  CAS  PubMed  Google Scholar 

  49. Chin, M. Y. et al. Genetically encoded, pH-sensitive mTFP1 biosensor for probing lysosomal pH. ACS Sens. 6, 2168–2180 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chien, T. et al. Enhancing the tropism of bacteria via genetically programmed biosensors. Nat. Biomed. Eng. 6, 94–104 (2022).

    Article  CAS  PubMed  Google Scholar 

  51. Ji, H., Lu, X., Zong, H. & Zhuge, B. A synthetic hybrid promoter for D-xylonate production at low pH in the tolerant yeast Candida glycerinogenes. Bioengineered 8, 700–706 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Yin, X. et al. P gas, a low-pH-induced promoter, as a tool for dynamic control of gene expression for metabolic engineering of Aspergillus niger. Appl. Environ. Microbiol. 83, e03222-16 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Healey, E. M. et al. Effects of nitrate and ammonium on assimilation of nitric oxide by Heterosigma akashiwo. Sci. Rep. 13, 621 (2023).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  54. Rohac, R. et al. Structural determinants of DNA recognition by the NO sensor NsrR and related Rrf2-type [FeS]-transcription factors. Commun. Biol. 5, 769 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Huang, M. et al. Efficient production of succinic acid in engineered Escherichia coli strains controlled by anaerobically-induced nirB promoter using sweet potato waste hydrolysate. J. Environ. Manag. 237, 147–154 (2019).

    Article  CAS  Google Scholar 

  56. Magerand, R., Rey, P., Blanchard, L. & de Groot, A. Redox signaling through zinc activates the radiation response in Deinococcus bacteria. Sci. Rep. 11, 4528 (2021).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  57. Xia, P. et al. Zinc is an important inter-kingdom signal between the host and microbe. Vet. Res. 52, 39 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Harms, A., Brodersen, D. E., Mitarai, N. & Gerdes, K. Toxins, targets, and triggers: an overview of toxin-antitoxin biology. Mol. Cell 70, 768–784 (2018).

    Article  CAS  PubMed  Google Scholar 

  59. Zhen, X. et al. Molecular mechanism of toxin neutralization in the HipBST toxin-antitoxin system of Legionella pneumophila. Nat. Commun. 13, 4333 (2022).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  60. Mobed, A. & Hasanzadeh, M. Sensitive recognition of Shiga toxin using biosensor technology: an efficient platform towards bioanalysis of pathogenic bacterial. Microchem. J. 172, 106900 (2022).

    Article  CAS  Google Scholar 

  61. Bertani, P. & Lu, W. Cyanobacterial toxin biosensors for environmental monitoring and protection. Med. Nov. Technol. Devices 10, 100059 (2021).

    Article  Google Scholar 

  62. Selim, A. S., Perry, J. M., Nasr, M. A., Pimprikar, J. M. & Shih, S. C. C. A synthetic biosensor for detecting putrescine in beef samples. ACS Appl. Bio Mater. 5, 5487–5496 (2022).

    Article  CAS  PubMed  Google Scholar 

  63. Schmauder, L., Sima, S., Hadj, A. B., Cesar, R. & Richter, K. Binding of the HSF-1 DNA-binding domain to multimeric C. elegans consensus HSEs is guided by cooperative interactions. Sci Rep 12, 8984 (2022).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  64. Almblad, H. et al. Bacterial cyclic diguanylate signaling networks sense temperature. Nat. Commun. 12, 1986 (2021).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  65. Wang, X. et al. Reversible thermal regulation for bifunctional dynamic control of gene expression in Escherichia coli. Nat. Commun. 12, 1411 (2021).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  66. Lovelett, R. J. et al. Dynamical modeling of optogenetic circuits in yeast for metabolic engineering applications. ACS Synth. Biol. 10, 219–227 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhao, E. M. et al. Optogenetic amplification circuits for light-induced metabolic control. ACS Synth. Biol. 10, 1143–1154 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Zhao, E. M. et al. Design and characterization of rapid optogenetic circuits for dynamic control in yeast metabolic engineering. ACS Synth. Biol. 9, 3254–3266 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lalwani, M. A. et al. Optogenetic control of the lac operon for bacterial chemical and protein production. Nat. Chem. Biol. 17, 71–79 (2021).

    Article  CAS  PubMed  Google Scholar 

  70. An-adirekkun, J. et al. A yeast optogenetic toolkit (yOTK) for gene expression control in Saccharomyces cerevisiae. Biotechnol. Bioeng. 117, 886–893 (2020).

    Article  CAS  PubMed  Google Scholar 

  71. Zhang, J. et al. Near-infrared light-activatable spherical nucleic acids for conditional control of protein activity. Angew. Chem. Int. Ed. 61, e202117562 (2022).

    Article  CAS  ADS  Google Scholar 

  72. Dahl, R. H. et al. Engineering dynamic pathway regulation using stress-response promoters. Nat. Biotechnol. 31, 1039–1046 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Yang, S., Du, G., Chen, J. & Kang, Z. Characterization and application of endogenous phase-dependent promoters in Bacillus subtilis. Appl. Microbiol. Biotechnol. 101, 4151–4161 (2017).

    Article  CAS  PubMed  Google Scholar 

  74. Boo, A., Amaro, R. L. & Stan, G.-B. Quorum sensing in synthetic biology: a review. Curr. Opin. Syst. Biol. 28, 100378 (2021).

    Article  CAS  Google Scholar 

  75. Mukherjee, S. & Bassler, B. L. Bacterial quorum sensing in complex and dynamically changing environments. Nat. Rev. Microbiol. 17, 371–382 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gu, P. et al. Application of quorum sensing system in microbial synthesis of valuable chemicals: a mini-review. World J. Microbiol. Biotechnol. 38, 192 (2022).

    Article  PubMed  Google Scholar 

  77. Garg, N., Manchanda, G. & Kumar, A. Bacterial quorum sensing: circuits and applications. Antonie van Leeuwenhoek 105, 289–305 (2014).

    Article  PubMed  Google Scholar 

  78. Choudhary, S. & Schmidt-Dannert, C. Applications of quorum sensing in biotechnology. Appl. Microbiol. Biotechnol. 86, 1267–1279 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Wu, S., Liu, J., Liu, C., Yang, A. & Qiao, J. Quorum sensing for population-level control of bacteria and potential therapeutic applications. Cell. Mol. Life Sci. 77, 1319–1343 (2020).

    Article  CAS  PubMed  Google Scholar 

  80. Kylilis, N., Tuza, Z. A., Stan, G. B. & Polizzi, K. M. Tools for engineering coordinated system behaviour in synthetic microbial consortia. Nat. Commun. 9, 2677 (2018).

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  81. Papenfort, K. & Bassler, B. L. Quorum sensing signal–response systems in Gram-negative bacteria. Nat. Rev. Microbiol. 14, 576–588 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Tekel, S. J. et al. Engineered orthogonal quorum sensing systems for synthetic gene regulation in Escherichia coli. Front. Bioeng. Biotechnol. 7, 80 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Jiang, W. et al. Two completely orthogonal quorum sensing systems with self-produced autoinducers enable automatic delayed cascade control. ACS Synth. Biol. 9, 2588–2599 (2020).

    Article  CAS  PubMed  Google Scholar 

  84. Grant, P. K. et al. Orthogonal intercellular signaling for programmed spatial behavior. Mol. Syst. Biol. 12, 849 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Scott, S. R. et al. A stabilized microbial ecosystem of self-limiting bacteria using synthetic quorum-regulated lysis. Nat. Microbiol. 2, 17083 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Soma, Y. & Hanai, T. Self-induced metabolic state switching by a tunable cell density sensor for microbial isopropanol production. Metab. Eng. 30, 7–15 (2015).

    Article  CAS  PubMed  Google Scholar 

  87. Gupta, A., Reizman, I. M. B., Reisch, C. R. & Prather, K. L. J. Dynamic regulation of metabolic flux in engineered bacteria using a pathway-independent quorum-sensing circuit. Nat. Biotechnol. 35, 273–279 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Soma, Y. et al. Design of synthetic quorum sensing achieving induction timing-independent signal stabilization for dynamic metabolic engineering of E. coli. ACS Synth. Biol. 10, 1384–1393 (2021).

    Article  CAS  PubMed  Google Scholar 

  89. Qin, H.-B., Zhou, J.-P., Zhang, B., Liu, Z.-Q. & Zheng, Y.-G. Combing with redox regulation via quorum-sensing system and fermentation strategies for improving D-pantothenic acid production. Process Biochem. 121, 681–688 (2022).

    Article  CAS  Google Scholar 

  90. Ge, C. et al. Redesigning regulatory components of quorum-sensing system for diverse metabolic control. Nat. Commun. 13, 2182 (2022).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  91. Styles, M. J. et al. Autoinducer-fluorophore conjugates enable FRET in LuxR proteins in vitro and in cells. Nat. Chem. Biol. 18, 1115–1124 (2022).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  92. Gao, C. et al. Dynamic consolidated bioprocessing for direct production of xylonate and shikimate from xylan by Escherichia coli. Metab. Eng. 60, 128–137 (2020).

    Article  CAS  PubMed  Google Scholar 

  93. Liu, H. & Lu, T. Autonomous production of 1,4-butanediol via a de novo biosynthesis pathway in engineered Escherichia coli. Metab. Eng. 29, 135–141 (2015).

    Article  CAS  PubMed  Google Scholar 

  94. Hawver, L. A., Jung, S. A. & Ng, W. L. Specificity and complexity in bacterial quorum-sensing systems. FEMS Microbiol. Rev. 40, 738–752 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Tian, J. et al. Developing an endogenous quorum-sensing based CRISPRi circuit for autonomous and tunable dynamic regulation of multiple targets in Streptomyces. Nucleic Acids Res. 48, 8188–8202 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Gamby, S. et al. Altering the communication networks of multispecies microbial systems using a diverse toolbox of AI-2 analogues. ACS Chem. Biol. 7, 1023–1030 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Hu, F., Liu, Y. & Li, S. Rational strain improvement for surfactin production: enhancing the yield and generating novel structures. Microb. Cell Fact. 18, 42 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  98. van Gestel, J. et al. Short-range quorum sensing controls horizontal gene transfer at micron scale in bacterial communities. Nat. Commun. 12, 2324 (2021).

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  99. Rutherford, S. T. & Bassler, B. L. Bacterial quorum sensing: its role in virulence and possibilities for its control. Cold Spring Harb. Perspect. Med. 2, a012427 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Lin, J., Cheng, J., Wang, Y. & Shen, X. The Pseudomonas quinolone signal (PQS): not just for quorum sensing anymore. Front. Cell. Infect. Microbiol. 8, 230 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Hauk, P. et al. Homologous quorum sensing regulatory circuit: a dual-input genetic controller for modulating quorum sensing-mediated protein expression in E. coli. ACS Synth. Biol. 9, 2692–2702 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Dinh, C. V. & Prather, K. L. Layered and multi-input autonomous dynamic control strategies for metabolic engineering. Curr. Opin. Biotechnol. 65, 156–162 (2020).

    Article  CAS  PubMed  Google Scholar 

  103. Doong, S. J., Gupta, A. & Prather, K. L. J. Layered dynamic regulation for improving metabolic pathway productivity in Escherichia coli. Proc. Natl Acad. Sci. USA 115, 2964–2969 (2018).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  104. Biarnes-Carrera, M., Lee, C. K., Nihira, T., Breitling, R. & Takano, E. Orthogonal regulatory circuits for Escherichia coli based on the γ-butyrolactone system of Streptomyces coelicolor. ACS Synth. Biol. 7, 1043–1055 (2018).

    Article  CAS  PubMed  Google Scholar 

  105. Wu, J. et al. Developing a pathway-independent and full-autonomous global resource allocation strategy to dynamically switching phenotypic states. Nat. Commun. 11, 5521 (2020).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  106. Malešević, M. et al. Pseudomonas aeruginosa quorum sensing inhibition by clinical isolate Delftia tsuruhatensis 11304: involvement of N-octadecanoylhomoserine lactones. Sci. Rep. 9, 16465 (2019).

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  107. Meschwitz, S. M. et al. Antagonism of quorum sensing phenotypes by analogs of the marine bacterial secondary metabolite 3-methyl-N-(20-phenylethyl)-butyramide. Mar. Drugs 17, 389 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Swem, L. R. et al. A quorum-sensing antagonist targets both membrane-bound and cytoplasmic receptors and controls bacterial pathogenicity. Mol. Cell 35, 143–153 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kato, L. M., Kawamoto, S., Maruya, M. & Fagarasan, S. The role of the adaptive immune system in regulation of gut microbiota. Immunol. Rev. 260, 67–75 (2014).

    Article  CAS  PubMed  Google Scholar 

  110. Yue, B. et al. Regulation of the intestinal microbiota: an emerging therapeutic strategy for inflammatory bowel disease. World J. Gastroenterol. 26, 4378–4393 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Wen, J., Tian, L., Liu, Q., Zhang, Y. & Cai, M. Engineered dynamic distribution of malonyl-CoA flux for improving polyketide biosynthesis in Komagataella phaffii. J. Biotechnol. 320, 80–85 (2020).

    Article  CAS  PubMed  Google Scholar 

  112. Kunjapur, A. M. & Prather, K. L. J. Development of a vanillate biosensor for the vanillin biosynthesis pathway in E. coli. ACS Synth. Biol. 8, 1958–1967 (2019).

    Article  CAS  PubMed  Google Scholar 

  113. Li, C. et al. Intelligent microbial cell factory with genetic pH shooting (GPS) for cell self-responsive base/acid regulation. Microb. Cell Fact. 19, 202 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Bandi, C. K. et al. Engineered regulon to enable autonomous azide ion biosensing, recombinant protein production, and in vivo glycoengineering. ACS Synth. Biol. 10, 682–689 (2021).

    Article  CAS  PubMed  Google Scholar 

  115. Li, B. et al. Structural and mechanistic basis for redox sensing by the cyanobacterial transcription regulator RexT. Commun. Biol. 5, 275 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Brandenberg, O. F., Schubert, O. T. & Kruglyak, L. Towards synthetic PETtrophy: engineering Pseudomonas putida for concurrent polyethylene terephthalate (PET) monomer metabolism and PET hydrolase expression. Microb. Cell Fact. 21, 119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Dinh, C. V., Chen, X. & Prather, K. L. J. Development of a quorum-sensing based circuit for control of coculture population composition in a naringenin production system. ACS Synth. Biol. 9, 590–597 (2020).

    Article  CAS  PubMed  Google Scholar 

  118. Kim, E. M. et al. Autonomous control of metabolic state by a quorum sensing (QS)-mediated regulator for bisabolene production in engineered E. coli. Metab. Eng. 44, 325–336 (2017).

    Article  CAS  PubMed  Google Scholar 

  119. Taylor, N. D. et al. Engineering an allosteric transcription factor to respond to new ligands. Nat. Methods 13, 177–183 (2016).

    Article  CAS  PubMed  Google Scholar 

  120. Charlier, D., Nguyen Le Minh, P. & Roovers, M. Regulation of carbamoylphosphate synthesis in Escherichia coli: an amazing metabolite at the crossroad of arginine and pyrimidine biosynthesis. Amino Acids 50, 1647–1661 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kotoky, R., Ogawa, N. & Pandey, P. The structure-function relationship of bacterial transcriptional regulators as a target for enhanced biodegradation of aromatic hydrocarbons. Microbiol. Res. 262, 127087 (2022).

    Article  CAS  PubMed  Google Scholar 

  122. Huang, X., Song, Q., Guo, S. & Fei, Q. Transcription regulation strategies in methylotrophs: progress and challenges. Bioresour. Bioprocess. 9, 126 (2022).

    Article  Google Scholar 

  123. Dong, X. et al. Genetic manipulation of the human gut bacterium Eggerthella lenta reveals a widespread family of transcriptional regulators. Nat. Commun. 13, 7624 (2022).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  124. Karr, J. P., Ferrie, J. J., Tjian, R. & Darzacq, X. The transcription factor activity gradient (TAG) model: contemplating a contact-independent mechanism for enhancer–promoter communication. Genes Dev. 36, 7–16, https://doi.org/10.1101/GAD.349160.121 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Shahein, A. et al. Systematic analysis of low-affinity transcription factor binding site clusters in vitro and in vivo establishes their functional relevance. Nat. Commun. 13, 5273 (2022).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  126. Ali, F. & Seshasayee, A. S. N. Dynamics of genetic variation in transcription factors and its implications for the evolution of regulatory networks in Bacteria. Nucleic Acids Res. 48, 4100–4114 (2021).

    Article  Google Scholar 

  127. Li, H. et al. Inferring transcription factor regulatory networks from single-cell ATAC-seq data based on graph neural networks. Nat. Mach. Intell. 4, 389–400 (2022).

    Article  Google Scholar 

  128. Jayaram, N., Usvyat, D. & Martin, A. C. R. Evaluating tools for transcription factor binding site prediction. BMC Bioinformatics 17, 547 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Park, P. J. ChIP–seq: advantages and challenges of a maturing technology. Nat. Rev. Genet. 10, 669–680 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Gomes, A. L. C. & Wang, H. H. The role of genome accessibility in transcription factor binding in bacteria. PLoS Comput. Biol. 12, e1004891 (2016).

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  131. Furey, T. S. ChIP–seq and beyond: new and improved methodologies to detect and characterize protein-DNA interactions. Nat. Rev. Genet. 13, 840–852 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Hua, C. et al. Bacterial transcription factors bind to coding regions and regulate internal cryptic promoters. mBio 13, e0164322 (2022).

    Article  PubMed  Google Scholar 

  133. Tu, X. et al. Reconstructing the maize leaf regulatory network using ChIP-seq data of 104 transcription factors. Nat. Commun. 11, 5089 (2020).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  134. Park, J. Y., Rimal, H., Bang, I., Nong, L. K. & Kim, D. Genome-wide identification of DNA-protein interaction to reconstruct bacterial transcription regulatory network. Biotechnol. Bioprocess Eng. 25, 944–954 (2020).

    Article  CAS  Google Scholar 

  135. Dos Santos, A. L. S. et al. What are the advantages of living in a community? A microbial biofilm perspective! Mem. Inst. Oswaldo Cruz. 113, e180212 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

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

    Michael Ream & Kristala L. J. Prather

Authors
  1. Michael Ream
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kristala L. J. Prather
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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

Corresponding author

Correspondence to Kristala L. J. Prather.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Bioengineering thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s44222-023-00140-7

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research