The Diterpenoid Substrate Analogue 19‐nor‐GGPP Reveals Pronounced Methyl Group Effects in Diterpene Cyclisations

The substrate analogue 19‐nor‐geranylgeranyl diphosphate (19‐nor‐GGPP) was synthesised and incubated with 20 diterpene synthases, resulting in the formation of diterpenoids in all cases. A total of 23 different compounds were isolated from these enzyme reactions and structurally characterised, if po...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2024-02, Vol.63 (6), p.e202318375-n/a
Main Authors: Taizoumbe, Kizerbo A., Goldfuss, Bernd, Dickschat, Jeroen S.
Format: Article
Language:English
Subjects:
Alkyl and Aryl Transferases
Biosynthesis
Deuteration
Diterpenes
Diterpenes - chemistry
Enzymes
Group effects
Stereoselective Synthesis
Stereoselectivity
Substrate Analogues
Substrates
Terpenoids
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Summary:The substrate analogue 19‐nor‐geranylgeranyl diphosphate (19‐nor‐GGPP) was synthesised and incubated with 20 diterpene synthases, resulting in the formation of diterpenoids in all cases. A total of 23 different compounds were isolated from these enzyme reactions and structurally characterised, if possible including the experimental determination of absolute configurations through a stereoselective deuteration approach. In several cases the missing 19‐Me group in the substrate analogue resulted in opening of completely new reaction paths towards compounds with novel skeletons. DFT calculations were applied to gain a deeper understanding of these observed methyl group effects in diterpene biosynthesis. 19‐nor‐Geranylgeranyldiphosphate (with a methyl group removed) has been synthesised and converted into diterpene analogues with 20 diterpene synthases. In some cases only the desmethyl derivatives of the natural enzyme products were obtained, but with several enzymes a dramatic change in the reactivity was observed. The newly opened reaction paths to compounds with unknown skeletons reveal an intriguing methyl group effect in diterpene biosynthesis.
ISSN:1433-7851
1521-3773
1521-3773
DOI:10.1002/anie.202318375