Structure of bifunctional variediene synthase yields unique insight on biosynthetic diterpene assembly and cyclization

Eliott S. Wenger and David W. Christianson ()
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Eliott S. Wenger: University of Pennsylvania
David W. Christianson: University of Pennsylvania

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract An unusual family of bifunctional terpene synthases has been identified in which a prenyltransferase assembles 5-carbon precursors to form C20 geranylgeranyl diphosphate (GGPP), which is then converted into a polycyclic product by a cyclase. Here, we report the cryo-EM structure of a massive, 495-kD bifunctional terpene synthase, variediene synthase from Emericella variecolor (EvVS). The structure reveals a hexameric prenyltransferase core sandwiched between two triads of cyclases. Surprisingly, GGPP is not channeled intramolecularly from the prenyltransferase to the cyclase, but instead is channeled intermolecularly to a non-native cyclase as indicated by substrate competition experiments. These results inform our understanding of carbon management in the greater family of bifunctional terpene synthases, hundreds of which have been identified in fungi. Using sequence similarity networks, we also report the identification of bifunctional terpene synthases in an animal, Adineta steineri, a bdelloid rotifer indigenous to freshwater environments.

Date: 2025
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DOI: 10.1038/s41467-025-60537-3

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