Biosynthesis of natural and halogenated plant monoterpene indole alkaloids in yeast
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Published:2023-11-06
Issue:12
Volume:19
Page:1551-1560
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ISSN:1552-4450
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Container-title:Nature Chemical Biology
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language:en
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Short-container-title:Nat Chem Biol
Author:
Bradley Samuel A., Lehka Beata J., Hansson Frederik G., Adhikari Khem B., Rago Daniela, Rubaszka Paulina, Haidar Ahmad K., Chen Ling, Hansen Lea G.ORCID, Gudich Olga, Giannakou Konstantina, Lengger BettinaORCID, Gill Ryan T., Nakamura Yoko, de Bernonville Thomas DugéORCID, Koudounas KonstantinosORCID, Romero-Suarez DavidORCID, Ding Ling, Qiao YijunORCID, Frimurer Thomas M.ORCID, Petersen Anja A., Besseau SébastienORCID, Kumar Sandeep, Gautron NicolasORCID, Melin Celine, Marc Jillian, Jeanneau Remi, O’Connor Sarah E.ORCID, Courdavault VincentORCID, Keasling Jay D., Zhang JieORCID, Jensen Michael K.ORCID
Abstract
AbstractMonoterpenoid 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.
Funder
EC | Horizon 2020 Framework Programme Novo Nordisk Fonden Danmarks Grundforskningsfond
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Molecular Biology
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