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Yeast Platforms for Production and Screening of Bioactive Derivatives of Rauwolscine.
Bradley, Samuel A; Hansson, Frederik G; Lehka, Beata J; Rago, Daniela; Pinho, Pedro; Peng, Huadong; Adhikari, Khem B; Haidar, Ahmad K; Hansen, Lea G; Volkova, Daria; Holtz, Maxence; Muyo Abad, Sergi; Ma, Xin; Koudounas, Konstantinos; Besseau, Sébastien; Gautron, Nicolas; Mélin, Céline; Marc, Jillian; Birer Williams, Caroline; Courdavault, Vincent; Jensen, Emil D; Keasling, Jay D; Zhang, Jie; Jensen, Michael K.
Afiliação
  • Bradley SA; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Lyngby, Denmark.
  • Hansson FG; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Lyngby, Denmark.
  • Lehka BJ; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Lyngby, Denmark.
  • Rago D; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Lyngby, Denmark.
  • Pinho P; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Lyngby, Denmark.
  • Peng H; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Lyngby, Denmark.
  • Adhikari KB; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Lyngby, Denmark.
  • Haidar AK; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Lyngby, Denmark.
  • Hansen LG; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Lyngby, Denmark.
  • Volkova D; Biomia ApS, DK-2100 Copenhagen, Denmark.
  • Holtz M; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Lyngby, Denmark.
  • Muyo Abad S; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Lyngby, Denmark.
  • Ma X; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Lyngby, Denmark.
  • Koudounas K; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Lyngby, Denmark.
  • Besseau S; EA2106 Biomolécules et Biotechnologies Végétales, Université de Tours, F-37200 Tours, France.
  • Gautron N; EA2106 Biomolécules et Biotechnologies Végétales, Université de Tours, F-37200 Tours, France.
  • Mélin C; EA2106 Biomolécules et Biotechnologies Végétales, Université de Tours, F-37200 Tours, France.
  • Marc J; EA2106 Biomolécules et Biotechnologies Végétales, Université de Tours, F-37200 Tours, France.
  • Birer Williams C; EA2106 Biomolécules et Biotechnologies Végétales, Université de Tours, F-37200 Tours, France.
  • Courdavault V; EA2106 Biomolécules et Biotechnologies Végétales, Université de Tours, F-37200 Tours, France.
  • Jensen ED; EA2106 Biomolécules et Biotechnologies Végétales, Université de Tours, F-37200 Tours, France.
  • Keasling JD; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Lyngby, Denmark.
  • Zhang J; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Lyngby, Denmark.
  • Jensen MK; Joint BioEnergy Institute, Emeryville, California 94608,United States.
ACS Synth Biol ; 13(5): 1498-1512, 2024 05 17.
Article em En | MEDLINE | ID: mdl-38635307
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Saccharomyces cerevisiae Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Saccharomyces cerevisiae Idioma: En Ano de publicação: 2024 Tipo de documento: Article