Abstract
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.
Original language | English |
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Pages (from-to) | 7140-7147 |
Number of pages | 8 |
Journal | Angewandte Chemie (International ed. in English) |
Volume | 60 |
Issue number | 13 |
Early online date | 19 Jan 2021 |
DOIs | |
Publication status | Published - 22 Mar 2021 |
Externally published | Yes |
Keywords
- angucycline
- biosynthetic gene cluster
- sulfur incorporation
- epoxide
- detoxification products