Affiliation:
1. Innovation Research Institute of Traditional Chinese Medicine Shanghai University of Traditional Chinese Medicine 1200 Cailun Road Shanghai 201203 China
2. School of Chemistry Sun Yat-Sen University Guangzhou 510275 China
Abstract
AbstractNatural 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 abstraction and water nucleophilic attack from the opposite face of the resultant iminium cation intermediate.
Funder
National Natural Science Foundation of China
Shanghai Municipal Health Commission
Shanghai Municipal Education Commission