Discovery of ( ±)-Penindolenes Reveals an Unusual Indole Ring Cleavage Pathway Catalyzed by P450 Monooxygenase

Angew Chem Int Ed Engl. 2024 Apr 18:e202403963. doi: 10.1002/anie.202403963. Online ahead of print.ABSTRACT(±)-Penindolenes A-D (1-4), the first representatives of indole terpenoids featuring a γ-lactam skeleton, were isolated from the mangrove-derived endophytic fungus Penicillium brocae MA-231. Our bioactivity tests revealed their potent antimicrobial and acetylcholinesterase inhibitory activities. The biosynthetic reactions by the five enzymes PbaABCDE leading to γ-lactam ring formation were identified with heterologous expression and in vitro enzymatic assays. Remarkably, the cytochrome P450 monooxygenase PbaB and its homolog in Aspergillus oryzae catalyzed the 2,3-cleavage of the indole ring to generate two keto groups in 1, in different manners from well-known tryptophan dioxygenases. This is the first example of the oxidative cleavage of indole by a P450 monooxygenase. In addition, rare secondary amide bond formation by the glutamine synthetase-like enzyme PbaD was reported. These findings will contribute to the engineered biosynthesis of unnatural, bioactive indole terpenoids.PMID:38635317 | DOI:10.1002/anie.202403963

Source: Angewandte Chemie - April 18, 2024 Category: Chemistry Authors: Ling-Hong Meng Takayoshi Awakawa Xiao-Ming Li Zhiyang Quan Sui-Qun Yang Bin-Gui Wang Ikuro Abe Source Type: research