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Underground metabolism as a rich reservoir for pathway engineering.

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MOTIVATION Bioproduction of value-added compounds is frequently achieved by utilizing enzymes from other species. However, expression of such heterologous enzymes can be detrimental due to unexpected interactions within the host… Click to show full abstract

MOTIVATION Bioproduction of value-added compounds is frequently achieved by utilizing enzymes from other species. However, expression of such heterologous enzymes can be detrimental due to unexpected interactions within the host cell. Recently, an alternative strategy emerged, which relies on recruiting side activities of host enzymes to establish new biosynthetic pathways. Although such low-level 'underground' enzyme activities are prevalent, it remains poorly explored whether they may serve as an important reservoir for pathway engineering. RESULTS Here we use genome-scale modelling to estimate the theoretical potential of underground reactions in engineering novel biosynthetic pathways in Escherichia coli. We found that biochemical reactions contributed by underground enzyme activities often enhance the in silico production of compounds with industrial importance, including several cases where underground activities are indispensable for production. Most of these new capabilities can be achieved by the addition of one or two underground reactions to the native network, suggesting that only a few side activities need to be enhanced during implementation. Remarkably, we find that the contribution of underground reactions to the production of value-added compounds is comparable to that of heterologous reactions, underscoring their biotechnological potential. Taken together, our genome-wide study demonstrates that exploiting underground enzyme activities could be a promising addition to the toolbox of industrial strain development. AVAILABILITY All scripts and metabolic network reconstructions used in this work are available on GitHub (https://github.com/pappb/Kovacs-et-al-Underground-metabolism). SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

Keywords: reservoir pathway; engineering; pathway engineering; underground metabolism

Journal Title: Bioinformatics
Year Published: 2022

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