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Chembiochem. 2019 Jan 2;20(1):111-117. doi: 10.1002/cbic.201800580. Epub 2018 Nov 28.

Diterpene Synthase-Catalyzed Biosynthesis of Distinct Clerodane Stereoisomers.

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Department of Plant Biology, University of California Davis, One Shields Avenue, Davis, CA, 95616, USA.
Department of Chemistry, University of California Davis, One Shields Avenue, Davis, CA, 95616, USA.


The diterpene synthase clerodienyl diphosphate synthase 1 (PvCPS1) from the crop plant switchgrass (Panicum virgatum) stereoselectively converts (E,E,E)-geranylgeranyl diphosphate (GGPP) into the clerodane natural product, cis-trans-clerodienyl diphosphate (CLPP, 1). Structure-guided point mutations of PvCPS1 redirected product stereoselectivity toward the formation of a rare cis-clerodane diastereomer, cis-cis-CLPP (2). Additionally, an alternative cis-clerodane diastereomer, (5S,8S,9R,10R)-13Z-CLPP (3), was produced when treating PvCPS1 and select variants thereof with the cis-prenyl substrate (Z,Z,Z)-nerylneryl diphosphate (NNPP). These results support the hypothesis that substrate configuration and minor active-site alterations impact precatalysis substrate folding in the stereoselective biosynthesis of clerodane diterpenoid scaffolds, and can be employed to provide enzymatic access to a broader range of bioactive clerodane natural products.


clerodane diterpenes; diterpene synthase; plant natural products; protein mutagenesis; terpenoid metabolism


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