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Nat Chem Biol. 2018 Nov;14(11):1005-1009. doi: 10.1038/s41589-018-0149-6. Epub 2018 Oct 16.

Metabolic repair through emergence of new pathways in Escherichia coli.

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Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Biotechnology, Graduate School of Engineering, Osaka University, Suita, Osaka, Japan.
Microbiology Division, Institute of Biological Sciences, College of Arts and Sciences, University of the Philippines Los Baños, Los Baños, Laguna, Philippines.
Institute of Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA.
Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.


Escherichia coli can derive all essential metabolites and cofactors through a highly evolved metabolic system. Damage of pathways may affect cell growth and physiology, but the strategies by which damaged metabolic pathways can be circumvented remain intriguing. Here, we use a ΔpanD (encoding for aspartate 1-decarboxylase) strain of E. coli that is unable to produce the β-alanine required for CoA biosynthesis to demonstrate that metabolic systems can overcome pathway damage by extensively rerouting metabolic pathways and modifying existing enzymes for unnatural functions. Using directed cell evolution, rewiring and repurposing of uracil metabolism allowed formation of an alternative β-alanine biosynthetic pathway. After this pathway was deleted, a second was evolved that used a gain-of-function mutation on ornithine decarboxylase (SpeC) to alter reaction and substrate specificity toward an oxidative decarboxylation-deamination reaction. After deletion of both pathways, yet another independent pathway emerged using polyamine biosynthesis, demonstrating the vast capacity of metabolic repair.


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