Dataset Information

Biosynthesis of natural and halogenated plant monoterpene indole alkaloids in yeast.

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.

SUBMITTER: Bradley SA

PROVIDER: S-EPMC10667104 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Biosynthesis of natural and halogenated plant monoterpene indole alkaloids in yeast.

Bradley Samuel A SA Lehka Beata J BJ Hansson Frederik G FG Adhikari Khem B KB Rago Daniela D Rubaszka Paulina P Haidar Ahmad K AK Chen Ling L Hansen Lea G LG Gudich Olga O Giannakou Konstantina K Lengger Bettina B Gill Ryan T RT Nakamura Yoko Y de Bernonville Thomas Dugé TD Koudounas Konstantinos K Romero-Suarez David D Ding Ling L Qiao Yijun Y Frimurer Thomas M TM Petersen Anja A AA Besseau Sébastien S Kumar Sandeep S Gautron Nicolas N Melin Celine C Marc Jillian J Jeanneau Remi R O'Connor Sarah E SE Courdavault Vincent V Keasling Jay D JD Zhang Jie J Jensen Michael K MK

Nature chemical biology 20231106 12

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 ...[more]

PMID: 37932529

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Project description:The natural diversity of plant metabolism has long been a source for human medicines. One group of plant-derived compounds, the monoterpene indole alkaloids (MIAs), includes well-documented therapeutic agents used in the treatment of cancer (vinblastine, vincristine, camptothecin), hypertension (reserpine, ajmalicine), malaria (quinine), and as analgesics (7-hydroxymitragynine). Our understanding of the biochemical pathways that synthesize these commercially relevant compounds is incomplete due in part to a lack of molecular, genetic, and genomic resources for the identification of the genes involved in these specialized metabolic pathways. To address these limitations, we generated large-scale transcriptome sequence and expression profiles for three species of Asterids that produce medicinally important MIAs: Camptotheca acuminata, Catharanthus roseus, and Rauvolfia serpentina. Using next generation sequencing technology, we sampled the transcriptomes of these species across a diverse set of developmental tissues, and in the case of C. roseus, in cultured cells and roots following elicitor treatment. Through an iterative assembly process, we generated robust transcriptome assemblies for all three species with a substantial number of the assembled transcripts being full or near-full length. The majority of transcripts had a related sequence in either UniRef100, the Arabidopsis thaliana predicted proteome, or the Pfam protein domain database; however, we also identified transcripts that lacked similarity with entries in either database and thereby lack a known function. Representation of known genes within the MIA biosynthetic pathway was robust. As a diverse set of tissues and treatments were surveyed, expression abundances of transcripts in the three species could be estimated to reveal transcripts associated with development and response to elicitor treatment. Together, these transcriptomes and expression abundance matrices provide a rich resource for understanding plant specialized metabolism, and promotes realization of innovative production systems for plant-derived pharmaceuticals.

Dataset Information

Biosynthesis of natural and halogenated plant monoterpene indole alkaloids in yeast.

Publications

Biosynthesis of natural and halogenated plant monoterpene indole alkaloids in yeast.

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