Terpendole E, a Kinesin Eg5 Inhibitor, Is a Key Biosynthetic Intermediate of Indole-Diterpenes in the Producing Fungus Chaunopycnis alba

SummaryTerpendole E is the first natural product inhibitor of kinesin Eg5. Because terpendole E production is unstable, we isolated and analyzed the terpendole E biosynthetic gene cluster, which consists of seven genes encoding three P450 monooxygenases (TerP, TerQ, and TerK), an FAD-dependent monooxygenase (TerM), a terpene cyclase (TerB), and two prenyltransferases (TerC and TerF). Gene knockout and feeding experiments revealed that terpendole E is a key intermediate in terpendole biosynthesis and is produced by the action of the key enzyme TerQ from paspaline, a common biosynthetic intermediate of indole-diterpenes. TerP converts terpendole E to a downstream intermediate specific to terpendole biosynthesis and converts paspaline to shunt metabolites. We successfully overproduced terpendole E by disrupting the terP gene. We propose that terpendole E is a key biosynthetic intermediate of terpendoles and related indole-diterpenes.

Graphical AbstractFigure optionsDownload high-quality image (212 K)Download as PowerPoint slideHighlights
► The terpendole biosynthetic gene cluster was isolated
► Terpendole E is a key biosynthetic intermediate of indole-diterpenes
► Terpendole E was overproduced by gene knockout of the bispecific enzyme TerP
► Indole-diterpene biosynthetic pathways can be classified into two groups