Cryptic sulfur incorporation in thioangucycline biosynthesis

Mingming Cao, Chengjian Zheng, Dong Yang, Edward Kalkreuter, Ajeeth Adhikari, Yu-Chen Liu, Mostafa E. Rateb, Ben Shen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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 languageEnglish
Number of pages8
JournalAngewandte Chemie (International ed. in English)
Early online date19 Jan 2021
Publication statusE-pub ahead of print - 19 Jan 2021
Externally publishedYes


  • angucycline
  • biosynthetic gene cluster
  • sulfur incorporation
  • epoxide
  • detoxification products

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