Journal
CHEMISTRY & BIOLOGY
Volume 19, Issue 12, Pages 1611-1619Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2012.10.010
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Funding
- Chemical Biology Project of RIKEN
- Program for Promotion of Basic and Applied Researches for Innovations in Bio-oriented Industry
- Grants-in-Aid for Scientific Research [21404009, 23580125] Funding Source: KAKEN
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Terpendole 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.
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