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Computational design and construction of an Escherichia coli strain engineered to produce a non-standard amino acid

Ali R. Zomorrodi, Colin Hemez, Pol Arranz-Gibert, Terrence Wu, Farren J. Isaacs, View ORCID ProfileDaniel Segrè
doi: https://doi.org/10.1101/2022.04.02.486821
Ali R. Zomorrodi
1Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA
2Harvard Medical School, Boston, MA
3Bioinformatics Graduate Program, Boston University, Boston, MA
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Colin Hemez
4Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT
5Systems Biology Institute, Yale University, West Haven, CT
6Department of Biomedical Engineering, Yale University, New Haven, CT
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Pol Arranz-Gibert
4Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT
5Systems Biology Institute, Yale University, West Haven, CT
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Terrence Wu
7Yale West Campus Analytical Core, 600 West Campus Drive, West Haven
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Farren J. Isaacs
4Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT
5Systems Biology Institute, Yale University, West Haven, CT
6Department of Biomedical Engineering, Yale University, New Haven, CT
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  • For correspondence: dsegre@bu.edu farren.isaacs@yale.edu
Daniel Segrè
3Bioinformatics Graduate Program, Boston University, Boston, MA
8Department of Biology, Boston University, Boston, MA
9Department of Biomedical Engineering, Boston University, Boston, MA
10Biological Design Center, Boston University, Boston, MA
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  • ORCID record for Daniel Segrè
  • For correspondence: dsegre@bu.edu farren.isaacs@yale.edu
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Summary

Introducing heterologous pathways into host cells constitutes a promising strategy for synthesizing nonstandard amino acids (nsAAs) to enable the production of proteins with expanded chemistries. However, this strategy has proven challenging as the expression of heterologous pathways can disrupt cellular homeostasis of the host cell. Here, we sought to optimize the heterologous production of the nsAA para-aminophenylalanine (pAF) in Escherichia coli. First, we incorporated a heterologous pAF biosynthesis pathway into a genome-scale model of E. coli metabolism, and computationally identified metabolic interventions in the host’s native metabolism to improve pAF production. Next, we explored different ways of imposing these flux interventions experimentally and found that the upregulation of flux in chorismate biosynthesis pathway through the elimination of feedback inhibition mechanisms could significantly raise pAF titers (∼20 fold) while maintaining a reasonable pAF yield-growth rate trade-off. Overall, this study provides a promising strategy for the biosynthesis of nsAAs in engineered cells.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted April 02, 2022.
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Computational design and construction of an Escherichia coli strain engineered to produce a non-standard amino acid
Ali R. Zomorrodi, Colin Hemez, Pol Arranz-Gibert, Terrence Wu, Farren J. Isaacs, Daniel Segrè
bioRxiv 2022.04.02.486821; doi: https://doi.org/10.1101/2022.04.02.486821
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Computational design and construction of an Escherichia coli strain engineered to produce a non-standard amino acid
Ali R. Zomorrodi, Colin Hemez, Pol Arranz-Gibert, Terrence Wu, Farren J. Isaacs, Daniel Segrè
bioRxiv 2022.04.02.486821; doi: https://doi.org/10.1101/2022.04.02.486821

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