Biosynthesis of diazepinomicin/ECO-4601, a Micromonospora secondary metabolite with a novel ring system.
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.
McAlpine
James B
JB
Thallion Pharmaceuticals Inc., 7150 Alexander-Fleming, Montréal, Québec, H4S 2C8, Canada. jmcalpine@thallion.com
Banskota
Arjun H
AH
Charan
Romila D
RD
Schlingmann
Gerhard
G
Zazopoulos
Emmanuel
E
Piraee
Mahmood
M
Janso
Jeffrey
J
Bernan
Valerie S
VS
Aouidate
Mustapha
M
Farnet
Chris M
CM
Feng
Xidong
X
Zhao
Zhizi
Z
Carter
Guy T
GT
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
D000470:Alkaloids; D003984:Dibenzazepines; C492422:diazepinomicin