@article{df9cc1c3fd274ffc8569977c8ca8375f,
title = "Biosynthesis of Indole Diterpene Lolitrems: Radical-Induced Cyclization of an Epoxyalcohol Affording a Characteristic Lolitremane Skeleton",
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.",
keywords = "cyclization, cytochrome P450, lolitrem, natural products, radical reactions",
author = "Yulu Jiang and Taro Ozaki and Mei Harada and Tadachika Miyasaka and Hajime Sato and Kazunori Miyamoto and Junichiro Kanazawa and Chengwei Liu and Maruyama, {Jun ichi} and Masaatsu Adachi and Atsuo Nakazaki and Toshio Nishikawa and Masanobu Uchiyama and Atsushi Minami and Hideaki Oikawa",
note = "Funding Information: This work was supported by JSPS KAKENHI (B) (No. 19H02891 (H.O.), No. 19H02896 (T.N.)), JSPS KAKENHI (S) (No. 17H06173 (M.U.)), JSPS Grant‐in‐Aid for Scientific Research on Innovative Areas (No. 16H06446 (A.M.), No. 19H04635 (T.O.), No. 17H05430 (M.U.), No. 17H06406 (T.N.), No. 19H04644 (J.M.)). Allotment of computational resource (Project G19012) from HOKUSAI BigWaterfall (RIKEN) is gratefully acknowledged. We are grateful to Dr. H. Osada and Dr. T. Motoyama (RIKEN) for the helpful discussion about terpendole biosynthesis and Prof. D. Takemoto (Nagoya University) for the genomic DNA sample of a lolitrem producer. We also thank S. Yamaguchi (Nagoya University) for the preparation of compound . 22 Funding Information: This work was supported by JSPS KAKENHI (B) (No. 19H02891 (H.O.), No. 19H02896 (T.N.)), JSPS KAKENHI (S) (No. 17H06173 (M.U.)), JSPS Grant-in-Aid for Scientific Research on Innovative Areas (No. 16H06446 (A.M.), No. 19H04635 (T.O.), No. 17H05430 (M.U.), No. 17H06406 (T.N.), No. 19H04644 (J.M.)). Allotment of computational resource (Project G19012) from HOKUSAI BigWaterfall (RIKEN) is gratefully acknowledged. We are grateful to Dr. H. Osada and Dr. T. Motoyama (RIKEN) for the helpful discussion about terpendole biosynthesis and Prof. D. Takemoto (Nagoya University) for the genomic DNA sample of a lolitrem producer. We also thank S. Yamaguchi (Nagoya University) for the preparation of compound 22. Publisher Copyright: {\textcopyright} 2020 Wiley-VCH GmbH",
year = "2020",
month = oct,
day = "5",
doi = "10.1002/anie.202007280",
language = "English",
volume = "59",
pages = "17996--18002",
journal = "Angewandte Chemie - International Edition",
issn = "1433-7851",
publisher = "John Wiley and Sons Ltd",
number = "41",
}