Oxidative Electrocyclization Assembles 2,2-Dimethyl-2H-pyran in Fungal Indole Alkaloids
Chengjie Zhang
State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237 China
These authors contributed equally to this work.
Search for more papers by this authorJingxuan Zhou
State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237 China
These authors contributed equally to this work.
Search for more papers by this authorWei Wang
State Key Laboratory of Engineering Biology for Low-Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308 China
National Center of Technology Innovation for Synthetic Biology, Tianjin, 300308 China
These authors contributed equally to this work.
Search for more papers by this authorMingyu Liu
State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237 China
These authors contributed equally to this work.
Search for more papers by this authorYuanning Li
State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237 China
Institute of Marine Science and Technology, Shandong University, Qingdao, Shandong, 266237 China
Search for more papers by this authorCorresponding Author
Xiang Sheng
State Key Laboratory of Engineering Biology for Low-Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308 China
National Center of Technology Innovation for Synthetic Biology, Tianjin, 300308 China
E-mail: [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Lei Du
State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237 China
E-mail: [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Shengying Li
State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237 China
Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237 China
E-mail: [email protected]; [email protected]; [email protected]
Search for more papers by this authorChengjie Zhang
State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237 China
These authors contributed equally to this work.
Search for more papers by this authorJingxuan Zhou
State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237 China
These authors contributed equally to this work.
Search for more papers by this authorWei Wang
State Key Laboratory of Engineering Biology for Low-Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308 China
National Center of Technology Innovation for Synthetic Biology, Tianjin, 300308 China
These authors contributed equally to this work.
Search for more papers by this authorMingyu Liu
State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237 China
These authors contributed equally to this work.
Search for more papers by this authorYuanning Li
State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237 China
Institute of Marine Science and Technology, Shandong University, Qingdao, Shandong, 266237 China
Search for more papers by this authorCorresponding Author
Xiang Sheng
State Key Laboratory of Engineering Biology for Low-Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308 China
National Center of Technology Innovation for Synthetic Biology, Tianjin, 300308 China
E-mail: [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Lei Du
State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237 China
E-mail: [email protected]; [email protected]; [email protected]
Search for more papers by this authorCorresponding Author
Shengying Li
State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong, 266237 China
Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, Shandong, 266237 China
E-mail: [email protected]; [email protected]; [email protected]
Search for more papers by this authorGraphical Abstract
A berberine bridge-like oxidoreductase mediates oxidative electrocyclization to form the 2,2-dimethyl-2H-pyran (DMP) ring in fungal indole alkaloids. Heterologous gene expression, in vitro enzyme activity reconstitution, and mechanistic studies unveil nature's strategy for pyran formation via enzymatic electrocyclization, expanding biocatalytic pericyclic chemistry.
Abstract
Pericyclic reactions, such as cycloaddition and electrocyclization, are among the most useful approaches for constructing complex natural products with diverse biological activities. While enzymatic pericyclic reactions have been increasingly reported in recent years, there are only a few examples of enzyme-mediated electrocyclization reactions. The 2,2-dimethyl-2H-pyran (DMP) ring plays a significant role in constituting many bioactive fungal and plant natural products. In this study, we characterize the vsc biosynthetic gene cluster of the DMP-containing natural product versicamide A (1) in Aspergillus versicolor DL0022. The biosynthetic route for DMP formation and the biochemical functions of the involved enzymes are fully elucidated. Specifically, we reveal that the berberine bridge-like oxidoreductase VscB mediates a crucial oxidative process, followed by an electrocyclization to form a C─O bridge bond, thereby affording the key DMP ring. Structural simulation, molecular modeling, mutational analysis, and quantum chemical calculations elucidate the oxidative electrocyclization mechanism. The flavin adenine dinucleotide (FAD) cofactor of VscB/NotD' facilitates hydride abstraction at the C25 position of the substrate, while the key amino acid residue E529 acts as a general base to deprotonate the C6 hydroxyl group.
Conflict of Interests
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available in the supplementary material of this article.
Supporting Information
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