Biosynthesis of Indole Diterpene Lolitrems: Radical-Induced Cyclization of an Epoxyalcohol Affording a Characteristic Lolitremane Skeleton
Biosynthesis of Indole Diterpene Lolitrems: Radical-Induced Cyclization of an Epoxyalcohol Affording a Characteristic Lolitremane Skeleton
复制标题
DOI：
10.1002/anie.202007280
复制
发表时间：
2020-10-05
影响因子：
16.6
通讯作者：
Oikawa, Hideaki
中科院分区：
文献类型：
--
作者：
Jiang, Yulu;Ozaki, Taro;Oikawa, Hideaki
Lolitrems是一种震颤性吲哚二萜，具有独特的吲哚部分5/6双环系统。虽然遗传分析表明异戊烯基转移酶LtmE和细胞色素P450 LtmJ参与了这种独特结构的构建，但详细的机制仍有待阐明。在此，我们报告了重组的生物合成途径lolitrems采用最近建立的基因组编辑技术的表达宿主曲霉。各种中间体的异源表达和生物转化表明，LtmJ催化多步氧化，以提供lolitrem核心。我们还分离出关键的反应中间体与环氧醇部分。这一观察使我们能够建立自由基诱导的环化的机制，这是坚决支持的密度泛函理论计算和模型实验与合成类似物。
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.