Biosynthesis of Indole Diterpene Lolitrems: Radical-Induced Cyclization of an Epoxyalcohol Affording a Characteristic Lolitremane Skeleton.

Angewandte Chemie
Yulu JiangHideaki Oikawa

Abstract

Lolitrems are tremorgenic indole diterpenes that exhibit a unique 5/6 bicyclic system of the indole moiety. Although genetic analysis has indicated that the prenyltransferase LtmE and the cytochrome P450 LtmJ are involved in the construction of this unique structure, the detailed mechanism remains to be elucidated. Herein, we report the reconstitution of the biosynthetic pathway for lolitrems employing a recently established genome-editing technique for the expression host Aspergillus oryzae. Heterologous expression and bioconversion of the various intermediates revealed that LtmJ catalyzes multistep oxidation to furnish the lolitrem core. We also isolated the key reaction intermediate with an epoxyalcohol moiety. This observation allowed us to establish the mechanism of radical-induced cyclization, which was firmly supported by density functional theory calculations and a model experiment with a synthetic analogue.

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Citations

Nov 13, 2020·Proceedings of the Japan Academy. Series B, Physical and Biological Sciences·Hideaki Oikawa
Dec 10, 2020·Natural Product Reports·Robert A Hill, Andrew Sutherland
Mar 13, 2021·Natural Product Reports·Xingwang ZhangShengying Li
Jun 3, 2021·Marine Drugs·Gao-Yang PengWen Zhang

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