Hydroxylation with Unusual Stereoinversion Catalyzed by an FeII/2‐OG Dependent Oxidase and 3,6‐Diene‐2,5‐diketopiperazine Formation in the Biosynthesis of Brevianamide K

• Published in: Angewandte Chemie International Edition Vol. 62; no. 14; pp. e202216989 - n/a
• Main Authors: Xu, Zhuo‐Zheng, Zhuang, Zheng, Cai, Runlin, Lin, Guo‐Qiang, She, Zhigang, Zhao, Qunfei, He, Qing‐Li
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 27.03.2023
• Edition: International ed. in English
• Subjects: 2,5-Diketopiperazine; Biosynthesis; Dehydration; Fungi; Heme; Hydrogen atoms; Hydroxylation; Natural products; Oxidase; Oxidases; Stereoinversion
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202216989

Natural products with the 3,6‐diene‐2,5‐diketopiperazine core are widely distributed in nature; however, the biosynthetic mechanism of 3,6‐diene‐2,5‐diketopiperazine in fungi remains to be further elucidated. Through heterologous expression and biochemical investigation of an FeII/2‐oxoglutarate‐dependent oxidase (AspE) and a heme‐dependent P450 enzyme (AspF), we report that AspE, AspF and subsequent dehydration account for the formation of the 3,6‐diene‐2,5‐diketopiperazine substructure of brevianamide K from Aspergillus sp. SK‐28, a symbiotic fungus of mangrove plant Kandelia candel. More interestingly, in‐depth investigation of the enzymatic mechanism showed that AspE promotes hydroxylation of brevianamide Q with unprecedented stereoinversion through hydrogen atom ion and water nucleophilic attack from the opposite face of the resultant iminium cation intermediate. Unlike the known biosynthetic pathways for the 3,6‐diene‐2,5‐diketopiperazine substructure in bacteria, double‐bond installation by heme‐dependent AspF, unprecedented stereoinversion upon hydroxylation by FeII/2‐OG‐dependent AspE, and subsequent dehydration lead to the formation of the 3,6‐diene‐2,5‐diketopiperazine substructure of brevianamide K in the fungus Aspergillus sp. SK‐28.