Affiliation:
1. State Key Laboratory of Mycology Institute of Microbiology Chinese Academy of Sciences Beijing 100101 P. R. China
2. Savaid Medical School University of Chinese Academy of Sciences Beijing 100049 P. R. China
3. Institut für Pharmazeutische Biologie und Biotechnologie Fachbereich Pharmazie Philipps-Universität Marburg 35037 Marburg Germany
4. State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences Peking Union Medical College Beijing 100050 P. R. China
Abstract
AbstractFungal 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.
Funder
National Key Research and Development Program of China
National Natural Science Foundation of China
Deutsche Forschungsgemeinschaft
China Postdoctoral Science Foundation
Subject
General Chemistry,Catalysis
Cited by
7 articles.
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