Reconstitution of a 10-gene pathway for synthesis of the plant alkaloid dihydrosanguinarine in Saccharomyces cerevisiae

Benzylisoquinoline alkaloids (BIAs) represent a large class of plant secondary metabolites, including pharmaceuticals such as morphine, codeine and their derivatives. Large-scale production of BIA-based pharmaceuticals is limited to extraction and derivatization of alkaloids that accumulate in plant...

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Bibliographic Details
Published in:Nature communications 2014-02, Vol.5 (1), p.3283-3283, Article 3283
Main Authors: Fossati, Elena, Ekins, Andrew, Narcross, Lauren, Zhu, Yun, Falgueyret, Jean-Pierre, Beaudoin, Guillaume A. W., Facchini, Peter J, Martin, Vincent J. J.
Format: Article
Language:English
Subjects:
631/61/338/318
Alkaloids - biosynthesis
Benzophenanthridines - biosynthesis
Genes, Plant
Genetic Vectors
Humanities and Social Sciences
Isoquinolines
multidisciplinary
Papaver - genetics
Papaver - metabolism
Plasmids
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - metabolism
Science
Science (multidisciplinary)
Tetrahydropapaveroline - metabolism
Transformation, Genetic - genetics
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Summary:Benzylisoquinoline alkaloids (BIAs) represent a large class of plant secondary metabolites, including pharmaceuticals such as morphine, codeine and their derivatives. Large-scale production of BIA-based pharmaceuticals is limited to extraction and derivatization of alkaloids that accumulate in planta . Synthesis of BIAs in microbial hosts could bypass such limitations and transform both industrial production of BIAs with recognized value and research into uncharacterized BIAs. Here we reconstitute a 10-gene plant pathway in Saccharomyces cerevisiae that allows for the production of dihydrosanguinarine and its oxidized derivative sanguinarine from ( R,S )-norlaudanosoline. Synthesis of dihydrosanguinarine also yields the side-products N -methylscoulerine and N -methylcheilanthifoline, the latter of which has not been detected in plants. This work represents the longest reconstituted alkaloid pathway ever assembled in yeast and demonstrates the feasibility of the production of high-value alkaloids in microbial systems. Benzylisoquinoline alkaloids are a group of plant secondary metabolites with important pharmaceutical applications. Here, the authors have reconstituted a 10-gene alkaloid pathway in Saccharomyces cerevisiae , demonstrating the feasibility of producing commercially important alkaloids in microbial systems.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms4283