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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The data that support the findings of this study are available from the corresponding author upon reasonable request. All genomic sequences are available at NCBI under BioProject ID PRJNA485586.
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This research was supported in part by a grant from National Science Foundation (MCB-1139318) for JP-US “Metabolomics for Low Carbon Society” (received by J.C.L.), and Japan Science and Technology’s Strategic International Collaborative Research Program (received by E.F). S.F.-G. acknowledges support from a QCB Collaboratory Postdoctoral Fellowship, and the QCB Collaboratory community directed by M. Pellegrini.
The authors declare no competing interests.
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Pontrelli, S., Fricke, R.C.B., Teoh, S.T. et al. Metabolic repair through emergence of new pathways in Escherichia coli. Nat Chem Biol 14, 1005–1009 (2018). https://doi.org/10.1038/s41589-018-0149-6
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