A computational workflow for the expansion of heterologous biosynthetic pathways to natural product derivatives

Jasmin Hafner, James Payne, Homa MohammadiPeyhani, Vassily Hatzimanikatis () and Christina Smolke ()
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Jasmin Hafner: Swiss Federal Institute of Technology (EPFL)
James Payne: Stanford University
Homa MohammadiPeyhani: Swiss Federal Institute of Technology (EPFL)
Vassily Hatzimanikatis: Swiss Federal Institute of Technology (EPFL)
Christina Smolke: Stanford University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Plant natural products (PNPs) and their derivatives are important but underexplored sources of pharmaceutical molecules. To access this untapped potential, the reconstitution of heterologous PNP biosynthesis pathways in engineered microbes provides a valuable starting point to explore and produce novel PNP derivatives. Here, we introduce a computational workflow to systematically screen the biochemical vicinity of a biosynthetic pathway for pharmaceutical compounds that could be produced by derivatizing pathway intermediates. We apply our workflow to the biosynthetic pathway of noscapine, a benzylisoquinoline alkaloid (BIA) with a long history of medicinal use. Our workflow identifies pathways and enzyme candidates for the production of (S)-tetrahydropalmatine, a known analgesic and anxiolytic, and three additional derivatives. We then construct pathways for these compounds in yeast, resulting in platforms for de novo biosynthesis of BIA derivatives and demonstrating the value of cheminformatic tools to predict reactions, pathways, and enzymes in synthetic biology and metabolic engineering.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22022-5

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DOI: 10.1038/s41467-021-22022-5

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