Pretrichodermamide A Biosynthesis Reveals the Hidden Diversity of Epidithiodiketopiperazines

作者：Jie Fan, Huomiao Ran, Peng‐Lin Wei, Yuanyuan Li, Huan Liu, Shu‐Ming Li, Youcai Hu, Wen‐Bing Yin · 发表于：Angewandte Chemie International Edition · 年份：2023 · DOI：10.1002/anie.202217212 · 被引用次数：22 · 研究领域：Microbial Natural Products and Biosynthesis、Fungal Biology and Applications、Alkaloids: synthesis and pharmacology

Fungal epidithiodiketopiperazines (ETPs) possess large structural diversity and complexity due to modifications of the cyclodipeptide skeleton. Elucidation of the biosynthetic pathway of pretrichodermamide A (1) in Trichoderma hypoxylon revealed a flexible catalytic machinery of multiple enzymes for generating ETP diversity. Seven tailoring enzymes encoded by the tda cluster are involved in 1 biosynthesis, that is, four P450s TdaB and TdaQ for 1,2-oxazine formation, TdaI for C7'-hydroxylation, and TdaG for C4, C5-epoxidation, two methyltransferases TdaH for C6'- and TdaO for C7'-O-methylation, and a reductase TdaD for furan opening. Gene deletions led to the identification of 25 novel ETPs, including 20 shunt products, indicating the catalytic promiscuity of Tda enzymes. Particularly, TdaG and TdaD accept various substrates and catalyze regiospecific reactions at different stages of 1 biosynthesis. Our study not only uncovers a hidden library of ETP alkaloids, but also helps to understand the hidden chemical diversity of natural products by pathway manipulation.