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

• Published in: Angewandte Chemie Vol. 135; no. 14
• 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: 27.03.2023
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202216989

Abstract 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 Fe II /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 abstraction and water nucleophilic attack from the opposite face of the resultant iminium cation intermediate.