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Recently, a subset of sulfur\u2010containing angucyclines has been discovered, and yet, the sulfur incorporation step is poorly understood. In this work, a series of thioether\u2010bridged 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\u2010enzymatic 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.<\/jats:p>","DOI":"10.1002\/anie.202015570","type":"journal-article","created":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T14:00:42Z","timestamp":1611064842000},"page":"7140-7147","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Cryptic Sulfur Incorporation in Thioangucycline Biosynthesis"],"prefix":"10.1002","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1386-8717","authenticated-orcid":false,"given":"Mingming","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Chemistry Department of Molecular Medicine Natural Products Discovery Center at Scripps Research The Scripps Research Institute  Jupiter FL 33458 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