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

1 Citation (Scopus)

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 languageEnglish
Pages (from-to)7140-7147
Number of pages8
JournalAngewandte Chemie (International ed. in English)
Volume60
Issue number13
Early online date19 Jan 2021
DOIs
Publication statusPublished - 22 Mar 2021
Externally publishedYes

Keywords

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

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