1. Yeast Platforms for Production and Screening of Bioactive Derivatives of Rauwolscine.
- Author
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Bradley SA, Hansson FG, Lehka BJ, Rago D, Pinho P, Peng H, Adhikari KB, Haidar AK, Hansen LG, Volkova D, Holtz M, Muyo Abad S, Ma X, Koudounas K, Besseau S, Gautron N, Mélin C, Marc J, Birer Williams C, Courdavault V, Jensen ED, Keasling JD, Zhang J, and Jensen MK
- Subjects
- Humans, Biosynthetic Pathways, Yohimbine metabolism, Yohimbine pharmacology, Secologanin Tryptamine Alkaloids metabolism, Indole Alkaloids metabolism, Drug Discovery methods, Saccharomyces cerevisiae metabolism
- Abstract
Monoterpene indole alkaloids (MIAs) make up a highly bioactive class of metabolites produced by a range of tropical and subtropical plants. The corynanthe-type MIAs are a stereochemically complex subclass with therapeutic potential against a large number of indications including cancer, psychotic disorders, and erectile dysfunction. Here, we report yeast-based cell factories capable of de novo production of corynanthe-type MIAs rauwolscine, yohimbine, tetrahydroalstonine, and corynanthine. From this, we demonstrate regioselective biosynthesis of 4 fluorinated derivatives of these compounds and de novo biosynthesis of 7-chlororauwolscine by coexpression of a halogenase with the biosynthetic pathway. Finally, we capitalize on the ability of these cell factories to produce derivatives of these bioactive scaffolds to establish a proof-of-principle drug discovery pipeline in which the corynanthe-type MIAs are screened for bioactivity on human drug targets, expressed in yeast. In doing so, we identify antagonistic and agonistic behavior against the human adrenergic G protein-coupled receptors ADRA2A and ADRA2B, and the serotonergic receptor 5HT4b, respectively. This study thus demonstrates a proto-drug discovery pipeline for bioactive plant-inspired small molecules based on one-pot biocatalysis of natural and new-to-nature corynanthe-type MIAs in yeast.
- Published
- 2024
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