Biosynthesis of Natural and Halogenated Plant Monoterpene Indole Alkaloids in Yeast

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2023 Nov 6

PMID 37932529

Authors

Samuel A Bradley

Beata J Lehka

Frederik G Hansson

Khem B Adhikari

Daniela Rago

Paulina Rubaszka

Ahmad K Haidar

Ling Chen

Lea G Hansen

Olga Gudich

Konstantina Giannakou

Bettina Lengger

Ryan T Gill

Yoko Nakamura

Thomas Duge de Bernonville

Konstantinos Koudounas

David Romero-Suarez

Ling Ding

Yijun Qiao

Thomas M Frimurer

Anja A Petersen

Sebastien Besseau

Sandeep Kumar

Nicolas Gautron

Celine Melin

Jillian Marc

Remi Jeanneau

Sarah E OConnor

Vincent Courdavault

Jay D Keasling

Jie Zhang

Michael K Jensen

Affiliations

Soon will be listed here.

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.

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