An enzymatic dual-oxa Diels–Alder reaction constructs the oxygen-bridged tricyclic acetal unit of (–)-anthrabenzoxocinone
- Author(s)
- Xiaoli Yan, Xinying Jia, Zhenyao Luo, Shunjia Ji, Meng Jie Zhang, Hui Zhang, Mingjia Yu, Julien Orts, Kai Jiang, Zhi Lin, Zixin Deng, Xu Dong Kong, Bostjan Kobe, Yi Lei Zhao, Mehdi Mobli, Xudong Qu
- Abstract
The hetero-Diels–Alder (HDA) reaction is a key method for synthesizing six-membered heterocyclic rings in natural products and bioactive compounds. Despite its importance in synthetic chemistry, naturally occurring enzymatic HDA reactions are rare and limited to a single heteroatom. Here we report Abx(−)F, a bifunctional vicinal oxygen chelate (VOC)-like protein that catalyses dehydration and dual-oxa Diels–Alder reactions to stereoselectively form the oxygen-bridged tricyclic acetal of (–)-anthrabenzoxocinone ((−)-ABX). Isotope assays and density functional theory calculations reveal a dehydration-coordinated, concerted HDA mechanism. The crystal structure of Abx(−)F and NMR complex structures of Abx(−)F with its substrate analogue and (−)-ABX define the reaction’s structural basis. Mutational analysis identifies Asp17 as a general base that mediates dehydration, forming an o-quinone methide intermediate for stereoselective dual-oxa HDA. This work establishes the molecular and structural basis of a polyheteroatomic Diels–Alderase, paving the way for designing polyheteroatomic DA enzymatic tools. (Figure presented.)
- Organisation(s)
- Department of Pharmaceutical Sciences
- External organisation(s)
- State Key Laboratory of Microbial Metabolism, Wuhan University, Shanghai Jiao Tong University, National University of Singapore (NUS), University of Queensland
- Journal
- Nature Chemistry
- Volume
- 17
- Pages
- 1058-1066
- No. of pages
- 9
- ISSN
- 1755-4330
- DOI
- https://doi.org/10.1038/s41557-025-01804-0
- Publication date
- 07-2025
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 106041 Structural biology
- ASJC Scopus subject areas
- General Chemistry, General Chemical Engineering
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/e705eb3c-d871-4843-af37-0b958ded64f2