Rational strain design with minimal phenotype perturbation.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
24 Jan 2024
24 Jan 2024
Historique:
received:
06
12
2022
accepted:
08
01
2024
medline:
25
1
2024
pubmed:
25
1
2024
entrez:
24
1
2024
Statut:
epublish
Résumé
Devising genetic interventions for desired cellular phenotypes remains challenging regarding time and resources. Kinetic models can accelerate this task by simulating metabolic responses to genetic perturbations. However, exhaustive design evaluations with kinetic models are computationally impractical, especially when targeting multiple enzymes. Here, we introduce a framework for efficiently scouting the design space while respecting cellular physiological requirements. The framework employs mixed-integer linear programming and nonlinear simulations with large-scale nonlinear kinetic models to devise genetic interventions while accounting for the network effects of these perturbations. Importantly, it ensures the engineered strain's robustness by maintaining its phenotype close to that of the reference strain. The framework, applied to improve the anthranilate production in E. coli, devises designs for experimental implementation, including eight previously experimentally validated targets. We expect this framework to play a crucial role in future design-build-test-learn cycles, significantly expediting the strain design compared to exhaustive design enumeration.
Identifiants
pubmed: 38267425
doi: 10.1038/s41467-024-44831-0
pii: 10.1038/s41467-024-44831-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
723Subventions
Organisme : EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
ID : 814408
Organisme : EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
ID : 814408
Organisme : Vetenskapsrådet (Swedish Research Council)
ID : 2016-06160
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)
ID : CRSII5_198543
Informations de copyright
© 2024. The Author(s).
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