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

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

Angew Chem Int Ed Engl. 2020 Jul 16;:

Authors: Jiang Y, Ozaki T, Harada M, Miyasaka T, Sato H, Miyamoto K, Kanazawa J, Liu C, Maruyama JI, Adachi M, Nakazaki A, Nishikawa T, Uchiyama M, Minami A, Oikawa H

Abstract
Lolitrems are tremorgenic indole diterpenes that exhibit a unique 5/6 bicyclic system of the indoleĀ  moiety. Although genetic analysis has indicated that prenyltransferase LtmE and cytochrome P450 LtmJ are involved in the construction of this unique structure, the detailed mechanism remains to be elucidated. Herein, we reconstitute 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 analog.

PMID: 32677206 [PubMed – as supplied by publisher]

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