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Cell Syst. 2016 May 25;2(5):335-46. doi: 10.1016/j.cels.2016.04.004. Epub 2016 May 19.

Characterizing Strain Variation in Engineered E. coli Using a Multi-Omics-Based Workflow.

Author information

1
Joint Bioenergy Institute (JBEI), 5885 Hollis Street, Emeryville, CA 94608, USA; Department of Bioengineering, University of California, San Diego, San Diego, CA 92093, USA; Biological Systems & Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
2
Joint Bioenergy Institute (JBEI), 5885 Hollis Street, Emeryville, CA 94608, USA; Biological Systems & Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
3
Joint Bioenergy Institute (JBEI), 5885 Hollis Street, Emeryville, CA 94608, USA; Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
4
Department of Bioengineering, University of California, San Diego, San Diego, CA 92093, USA.
5
Joint Bioenergy Institute (JBEI), 5885 Hollis Street, Emeryville, CA 94608, USA.
6
Department of Bioengineering, University of California, San Diego, San Diego, CA 92093, USA; Biological Systems & Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
7
Joint Bioenergy Institute (JBEI), 5885 Hollis Street, Emeryville, CA 94608, USA; Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
8
Joint Bioenergy Institute (JBEI), 5885 Hollis Street, Emeryville, CA 94608, USA; Biological Systems & Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2970 Horsholm, Denmark; Department of Chemical & Biomolecular Engineering, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA.
9
Department of Bioengineering, University of California, San Diego, San Diego, CA 92093, USA; The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2970 Horsholm, Denmark. Electronic address: palsson@eng.ucsd.edu.
10
Joint Bioenergy Institute (JBEI), 5885 Hollis Street, Emeryville, CA 94608, USA; Biological Systems & Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Electronic address: tslee@lbl.gov.

Abstract

Understanding the complex interactions that occur between heterologous and native biochemical pathways represents a major challenge in metabolic engineering and synthetic biology. We present a workflow that integrates metabolomics, proteomics, and genome-scale models of Escherichia coli metabolism to study the effects of introducing a heterologous pathway into a microbial host. This workflow incorporates complementary approaches from computational systems biology, metabolic engineering, and synthetic biology; provides molecular insight into how the host organism microenvironment changes due to pathway engineering; and demonstrates how biological mechanisms underlying strain variation can be exploited as an engineering strategy to increase product yield. As a proof of concept, we present the analysis of eight engineered strains producing three biofuels: isopentenol, limonene, and bisabolene. Application of this workflow identified the roles of candidate genes, pathways, and biochemical reactions in observed experimental phenomena and facilitated the construction of a mutant strain with improved productivity. The contributed workflow is available as an open-source tool in the form of iPython notebooks.

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