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Biosynthesis of natural and halogenated plant monoterpene indole alkaloids in yeast

  • Pharmacie,
  • Santé-Sciences-Technologie,
  • Recherche,
Date(s)

du 7 novembre 2023 au 26 août 2025

Lieu(x)

Site Grandmont

EA2106 BBV - Biomolécules et Biotechnologies végétales

Published in Nature Chemical Biology, this collaborative work demonstrates a scalable de novo manufacturing platform for bioactive monoterpenoid indole alkaloids (MIAs, plant metabolites that possess various medicinal properties) in yeast and provides a foundation for further pathway refactoring toward microbial biosynthesis of both native and new-to-nature MIAs.

Bradley SA, Lehka BJ, Hansson FG, Adhikari KB, Rago D, Rubaszka P, Haidar AK, Chen L, Hansen LG, Gudich O, Giannakou K, Lengger B, Gill RT, Nakamura Y, de Bernonville TD, Koudounas K, Romero-Suarez D, Ding L, Qiao Y, Frimurer TM, Petersen AA, Besseau S, Kumar S, Gautron N, Melin C, Marc J, Jeanneau R, O'Connor SE, Courdavault V, Keasling JD, Zhang J, Jensen MK. Biosynthesis of natural and halogenated plant monoterpene indole alkaloids in yeast. Nat Chem Biol. 2023 Nov 6.
doi: 10.1038/s41589-023-01430-2.
 

Abstract

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.