title: Biosynthesis of diazepinomicin/ECO-4601, a Micromonospora secondary metabolite with a novel ring system.
abstract: The novel microbial metabolite diazepinomicin/ECO-4601 (1) has a unique tricyclic dibenzodiazepinone core, which was unprecedented among microbial metabolites. Labeled feeding experiments indicated that the carbocyclic ring and the ring nitrogen of tryptophan could be incorporated via degradation to the 3-hydroxyanthranilic acid, forming ring A and the nonamide nitrogen of 1. Genomic analysis of the biosynthetic locus indicated that the farnesyl side chain was mevalonate derived, the 3-hydroxyanthranilic acid moiety could be formed directly from chorismate, and the third ring was constructed via 3-amino-5-hydroxybenzoic acid. Successful incorporation of 4,6-D2-3-hydroxyanthranilic acid into ring A of 1 via feeding experiments supports the genetic analysis and the allocation of the locus to this biosynthesis. These studies highlight the enzymatic complexity needed to produce this structural type, which is rare in nature.
authors: Thallion Pharmaceuticals Inc., 7150 Alexander-Fleming, Montréal, Québec, H4S 2C8, Canada. jmcalpine@thallion.com
authors: James B
authors: JB
authors: McAlpine
authors: Arjun H
authors: AH
authors: Banskota
authors: Romila D
authors: RD
authors: Charan
authors: Gerhard
authors: G
authors: Schlingmann
authors: Emmanuel
authors: E
authors: Zazopoulos
authors: Mahmood
authors: M
authors: Piraee
authors: Jeffrey
authors: J
authors: Janso
authors: Valerie S
authors: VS
authors: Bernan
authors: Mustapha
authors: M
authors: Aouidate
authors: Chris M
authors: CM
authors: Farnet
authors: Xidong
authors: X
authors: Feng
authors: Zhizi
authors: Z
authors: Zhao
authors: Guy T
authors: GT
authors: Carter
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D003500:Cyclization; D003984:Dibenzazepines / Q000138:chemical synthesis* / Q000737:chemistry; D008847:Micromonospora / Q000737:chemistry* / Q000235:genetics; D015394:Molecular Structure
chemical_list: D000470:Alkaloids; D003984:Dibenzazepines; C492422:diazepinomicin