Biosynthesis of Complex Indole Alkaloids: Elucidation of the Concise Pathway of Okaramines. Issue 32 (6th July 2017)

• Record Type: Journal Article
• Authors: Lai, Chen‐Yu; Lo, I‐Wen; Hewage, Ranuka T.; Chen, Yi‐Chen; Chen, Chien‐Ting; Lee, Chi‐Fang; Lin, Steven; Tang, Man‐Cheng; Lin, Hsiao‐Ching
• Is Part Of: Angewandte Chemie international edition. Volume 56:Issue 32(2017)
• Page Start: 9478
• Page End: 9482
• Publication Date: 2017-07-06
• Subjects: alkaloids -- biosynthesis -- okaramines; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201705501
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: 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 ) of1 and2, 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. Abstract : Okaramines are a class of complex indole alkaloids and potential insecticidal agents that activate glutamate‐gated chloride channels (GluCls) in invertebrates selectively over human ligand‐gated anion channels. The biosynthesis pathway was mapped with genetic inactivation, pathway enzyme reconstitution in a yeast heterologous system, and biochemical characterization.