Biosynthesis of Complex Indole Alkaloids: Elucidation of the Concise Pathway of Okaramines

Chen-Yu Lai; I-Wen Lo; Ranuka T Hewage; Yi-Chen Chen; Chien-Ting Chen; Chi-Fang Lee; Steven Lin; Man-Cheng Tang; Hsiao-Ching Lin

doi:10.1002/anie.201705501

Biosynthesis of Complex Indole Alkaloids: Elucidation of the Concise Pathway of Okaramines

Angew Chem Int Ed Engl. 2017 Aug 1;56(32):9478-9482. doi: 10.1002/anie.201705501. Epub 2017 Jul 6.

Authors

Chen-Yu Lai¹, I-Wen Lo¹, Ranuka T Hewage¹, Yi-Chen Chen¹, Chien-Ting Chen¹, Chi-Fang Lee¹, Steven Lin¹, Man-Cheng Tang², Hsiao-Ching Lin¹

Affiliations

¹ Institute of Biological Chemistry, Academia Sinica, Taipei115, Taiwan R.O.C.
² Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, 90095, USA.

PMID: 28631282
DOI: 10.1002/anie.201705501

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) 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.

Keywords: alkaloids; biosynthesis; okaramines.

Publication types

Research Support, Non-U.S. Gov't