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Biosynthesis of Complex Indole Alkaloids: Elucidation of the Concise Pathway of Okaramines
Author(s) -
Lai ChenYu,
Lo IWen,
Hewage Ranuka T.,
Chen YiChen,
Chen ChienTing,
Lee ChiFang,
Lin Steven,
Tang ManCheng,
Lin HsiaoChing
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201705501
Subject(s) - azetidine , indole test , biosynthesis , stereochemistry , chemistry , gene cluster , ring (chemistry) , biochemistry , gene , organic chemistry
The okaramines are a class of complex indole alkaloids isolated from Penicillium and Aspergillus species. Their potent insecticidal activity arises from selectively activating glutamate‐gated chloride channels (GluCls) in invertebrates, not affecting human ligand‐gated anion channels. Okaramines B ( 1 ) and D ( 2 ) contain a polycyclic skeleton, including an azocine ring and an unprecedented 2‐dimethyl‐3‐methyl‐azetidine ring. Owing to their complex scaffold, okaramines have inspired many total synthesis efforts, but the enzymology of the okaramine biosynthetic pathway remains unexplored. Here, we identified and characterized the biosynthetic gene cluster ( oka ) of 1 and 2 , then elucidated the pathway with target gene inactivation, heterologous reconstitution, and biochemical characterization. Notably, we characterized an α‐ketoglutarate‐dependent non‐heme Fe II dioxygenase that forged the azetidine ring on the okaramine skeleton.