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Cryptic Sulfur Incorporation in Thioangucycline Biosynthesis
Author(s) -
Cao Mingming,
Zheng Chengjian,
Yang Dong,
Kalkreuter Edward,
Adhikari Ajeeth,
Liu YuChen,
Rateb Mostafa E.,
Shen Ben
Publication year - 2021
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202015570
Subject(s) - thioether , biosynthesis , sulfur metabolism , sulfur , chemistry , hydrogen sulfide , gene cluster , natural product , biochemistry , enzyme , stereochemistry , gene , combinatorial chemistry , organic chemistry
Sulfur incorporation into natural products is a critical area of biosynthetic studies. Recently, a subset of sulfur‐containing angucyclines has been discovered, and yet, the sulfur incorporation step is poorly understood. In this work, a series of thioether‐bridged angucyclines were discovered, and a cryptic epoxide Michael acceptor intermediate was revealed en route to thioangucyclines (TACs) A and B. However, systematic gene deletion of the biosynthetic gene cluster (BGC) by CRISPR/Cas9 could not identify any gene responsible for the conversion of the epoxide intermediate to TACs. Instead, a series of in vitro and in vivo experiments conclusively showed that the conversion is the result of two non‐enzymatic steps, possibly mediated by endogenous hydrogen sulfide. Therefore, the TACs are proposed to derive from a detoxification process. These results are expected to contribute to the study of both angucyclines and the utilization of inorganic sulfur in natural product biosynthesis.