Biosynthesis of natural and halogenated plant monoterpene indole alkaloids in yeast

Bradley, Samuel A.; Lehka, Beata J.; Hansson, Frederik G.; Adhikari, Khem B.; Rago, Daniela; Rubaszka, Paulina; Haidar, Ahmad K.; Chen, Ling; Hansen, Lea Gram; Gudich, Olga; Giannakou, Konstantina; Lengger, Bettina; Gill, Ryan T.; Nakamura, Yoko; de Bernonville, Thomas Dugé; Koudounas, Konstantinos; Romero-Suarez, David; Ding, Ling; Qiao, Yijun; Frimurer, Thomas M.; Petersen, Anja A.; Besseau, Sébastien; Kumar, Sandeep; Gautron, Nicolas; Melin, Celine; Marc, Jillian; Jeanneau, Remi; O’Connor, Sarah E.; Courdavault, Vincent; Keasling, Jay D.; Zhang, Jie; Jensen, Michael Krough

doi:10.1038/s41589-023-01430-2

Title: Biosynthesis of natural and halogenated plant monoterpene indole alkaloids in yeast

Journal Article · 06 November 2023 · Nature Chemical Biology

DOI: https://doi.org/10.1038/s41589-023-01430-2 · OSTI ID:2367187

Bradley, Samuel A. ^[1]; Lehka, Beata J. ^[1]; Hansson, Frederik G. ^[1]; Adhikari, Khem B. ^[1]; Rago, Daniela ^[1]; Rubaszka, Paulina ^[1]; Haidar, Ahmad K. ^[1]; Chen, Ling ^[1];

^[1]; Gudich, Olga ^[1]; Giannakou, Konstantina ^[1];

^[1]; Gill, Ryan T. ^[1]; Nakamura, Yoko ^[2];

^[3];

^[1]; Ding, Ling ^[1];

^[1];

^[4] more »

Technical Univ. of Denmark, Lyngby (Denmark)
Max Planck Institute for Chemical Ecology, Jena (Germany)
University of Tours (France)
Univ. of Copenhagen (Denmark)
Axyntis, Pithiviers (France)
Technical Univ. of Denmark, Lyngby (Denmark); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Joint BioEnergy Institute and Environmental Genomics and Systems Biology Division; Univ. of California, Berkeley, CA (United States); Shenzhen Institutes of Advance Technologies (China)

Monoterpenoid indole alkaloids (MIAs) represent a large class of plant natural products with marketed pharmaceutical activities against a wide range of indications, including cancer, malaria and hypertension. Halogenated MIAs have shown improved pharmaceutical properties; however, synthesis of new-to-nature halogenated MIAs remains a challenge. Here we demonstrate a platform for de novo biosynthesis of two MIAs, serpentine and alstonine, in baker’s yeast Saccharomyces cerevisiae and deploy it to systematically explore the biocatalytic potential of refactored MIA pathways for the production of halogenated MIAs. From this, we demonstrate conversion of individual haloindole derivatives to a total of 19 different new-to-nature haloserpentine and haloalstonine analogs. Furthermore, by process optimization and heterologous expression of a modified halogenase in the microbial MIA platform, we document de novo halogenation and biosynthesis of chloroalstonine. Together, this study highlights a microbial platform for enzymatic exploration and production of complex natural and new-to-nature MIAs with therapeutic potential.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-05CH11231; SC0018368

OSTI ID:: 2367187

Journal Information:: Nature Chemical Biology, Vol. 19; ISSN 1552-4450

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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