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Strategies for microbial synthesis of high-value phytochemicals

Abstract

Phytochemicals are of great pharmaceutical and agricultural importance, but often exhibit low abundance in nature. Recent demonstrations of industrial-scale production of phytochemicals in yeast have shown that microbial production of these high-value chemicals is a promising alternative to sourcing these molecules from native plant hosts. However, a number of challenges remain in the broader application of this approach, including the limited knowledge of plant secondary metabolism and the inefficient reconstitution of plant metabolic pathways in microbial hosts. In this Review, we discuss recent strategies to achieve microbial biosynthesis of complex phytochemicals, including strategies to: (1) reconstruct plant biosynthetic pathways that have not been fully elucidated by mining enzymes from native and non-native hosts or by enzyme engineering; (2) enhance plant enzyme activity, specifically cytochrome P450 activity, by improving efficiency, selectivity, expression or electron transfer; and (3) enhance overall reaction efficiency of multi-enzyme pathways by dynamic control, compartmentalization or optimization with the host’s metabolism. We also highlight remaining challenges to — and future opportunities of — this approach.

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Fig. 1: Strategies to reconstruct plant biosynthetic pathways that are not fully elucidated.
Fig. 2: Strategies to enhance plant cytochrome P450 activity in microbial hosts.
Fig. 3: Strategies to enhance the overall efficiency of multi-enzyme pathways within a microbial cell.

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Acknowledgements

We thank J. Payne for valuable feedback in the preparation of the manuscript. This work was supported by the National Institutes of Health (grant to C.D.S., AT007886) and Novartis Institutes for Biomedical Research (grant to C.D.S., IC2013-1373). C.D.S. is a Chan Zuckerberg Biohub investigator.

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S. L., Y. L. and C. D. S. contributed to discussions and wrote the manuscript. S. L. and Y. L. contributed equally.

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Correspondence to Christina D. Smolke.

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Li, S., Li, Y. & Smolke, C.D. Strategies for microbial synthesis of high-value phytochemicals. Nature Chem 10, 395–404 (2018). https://doi.org/10.1038/s41557-018-0013-z

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