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Ye Z, Li S, Hennigan JN, et al. Two-stage dynamic deregulation of metabolism improves process robustness & scalability in engineered E. coli. Metab Eng. 2021;68:106-118doi: 10.1016/j.ymben.2021.09.009.
Ye, Z., Li, S., Hennigan, J. N., Lebeau, J., Moreb, E. A., Wolf, J., & Lynch, M. D. (2021). Two-stage dynamic deregulation of metabolism improves process robustness & scalability in engineered E. coli. Metabolic engineering, 68106-118. https://doi.org/10.1016/j.ymben.2021.09.009
Ye, Zhixia, et al. "Two-stage dynamic deregulation of metabolism improves process robustness & scalability in engineered E. coli." Metabolic engineering vol. 68 (2021): 106-118. doi: https://doi.org/10.1016/j.ymben.2021.09.009
Ye Z, Li S, Hennigan JN, Lebeau J, Moreb EA, Wolf J, Lynch MD. Two-stage dynamic deregulation of metabolism improves process robustness & scalability in engineered E. coli. Metab Eng. 2021 Nov;68:106-118. doi: 10.1016/j.ymben.2021.09.009. Epub 2021 Sep 30. PMID: 34600151.
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Metab Eng. 2021 Nov;68:106-118. doi: 10.1016/j.ymben.2021.09.009. Epub 2021 Sep 30.

Two-stage dynamic deregulation of metabolism improves process robustness & scalability in engineered E. coli.

Metabolic engineering

Zhixia Ye, Shuai Li, Jennifer N Hennigan, Juliana Lebeau, Eirik A Moreb, Jacob Wolf, Michael D Lynch

Affiliations

  1. Department of Biomedical Engineering, Duke University, Durham, NC, USA; DMC Biotechnologies, Inc., Durham, NC, USA.
  2. Department of Chemistry, Duke University, Durham, NC, USA.
  3. Department of Biomedical Engineering, Duke University, Durham, NC, USA.
  4. DMC Biotechnologies, Inc., Boulder, CO, USA.
  5. Department of Biomedical Engineering, Duke University, Durham, NC, USA. Electronic address: [email protected].

PMID: 34600151 DOI: 10.1016/j.ymben.2021.09.009

Abstract

We report that two-stage dynamic control improves bioprocess robustness as a result of the dynamic deregulation of central metabolism. Dynamic control is implemented during stationary phase using combinations of CRISPR interference and controlled proteolysis to reduce levels of central metabolic enzymes. Reducing the levels of key enzymes alters metabolite pools resulting in deregulation of the metabolic network. Deregulated networks are less sensitive to environmental conditions improving process robustness. Process robustness in turn leads to predictable scalability, minimizing the need for traditional process optimization. We validate process robustness and scalability of strains and bioprocesses synthesizing the important industrial chemicals alanine, citramalate and xylitol. Predictive high throughput approaches that translate to larger scales are critical for metabolic engineering programs to truly take advantage of the rapidly increasing throughput and decreasing costs of synthetic biology.

Copyright © 2021 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

Keywords: CRISPR; Controlled proteolysis; Dynamic metabolic control; High-throughput metabolic engineering; Metabolic valves; Process robustness; Scalability; Standardization; Two-stage

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