Expanding the Landscape of Diterpene Structural Diversity through Stereochemically Controlled Combinatorial Biosynthesis

Plant‐derived diterpenoids serve as important pharmaceuticals, food additives, and fragrances, yet their low natural abundance and high structural complexity limits their broader industrial utilization. By mimicking the modularity of diterpene biosynthesis in plants, we constructed 51 functional com...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2016-02, Vol.55 (6), p.2142-2146
Main Authors: Andersen-Ranberg, Johan, Kongstad, Kenneth Thermann, Nielsen, Morten Thrane, Jensen, Niels Bjerg, Pateraki, Irini, Bach, Søren Spanner, Hamberger, Britta, Zerbe, Philipp, Staerk, Dan, Bohlmann, Jörg, Møller, Birger Lindberg, Hamberger, Björn
Format: Article
Language:English
Subjects:
Abundance
biocatalysis
Biosynthesis
Combinatorial analysis
combinatorial biosynthesis
Communication
Communications
Complexity
Construction industry
Construction planning
cyclizations
Diterpenes
Diterpenes - chemistry
Diterpenes - metabolism
Food
Food additives
Food plants
Fragrances
Functional anatomy
Fungi
Industrial plants
Mimicry
Modular construction
Modularity
Molecular Structure
Pharmaceuticals
Plants
Plants (botany)
Saccharomyces cerevisiae
Saccharomyces cerevisiae - enzymology
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - metabolism
Stereoisomerism
terpenes
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Summary:Plant‐derived diterpenoids serve as important pharmaceuticals, food additives, and fragrances, yet their low natural abundance and high structural complexity limits their broader industrial utilization. By mimicking the modularity of diterpene biosynthesis in plants, we constructed 51 functional combinations of class I and II diterpene synthases, 41 of which are “new‐to‐nature”. Stereoselective biosynthesis of over 50 diterpene skeletons was demonstrated, including natural variants and novel enantiomeric or diastereomeric counterparts. Scalable biotechnological production for four industrially relevant targets was accomplished in engineered strains of Saccharomyces cerevisiae. Beyond the horizon: A broad range of cyclic diterpenes, including precursors for therapeutic compounds, was efficiently biosynthesized by combining class I and II diterpene synthase enzymes from diverse species. Stereospecific cyclizations were achieved and scale‐up was demonstrated with efficient biotechnological production.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201510650