title: Terpendole E, a kinesin Eg5 inhibitor, is a key biosynthetic intermediate of indole-diterpenes in the producing fungus Chaunopycnis alba.
abstract: 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.
authors.affiliation: Chemical Biology Core Facility, Chemical Biology Department, RIKEN Advanced Science Institute, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Motoyama
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirota
authors.forename: Masashi
authors.initials: M
authors.lastname: Ueki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism*; D001203:Ascomycota / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D004224:Diterpenes / Q000378:metabolism*; D005800:Genes, Fungal; D006801:Humans; D007211:Indoles / Q000378:metabolism*; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D005810:Multigene Family
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D007211:Indoles; C470243:KIF11 protein, human; C477863:terpendole E; D016547:Kinesins