Department of Chemistry, Department of Molecular Medicine, Natural Products Discovery Center at Scripps Research, The Scripps Research Institute, Jupiter, FL, 33458, USA.
Angew Chem Int Ed Engl. 2021 Mar 22;60(13):7140-7147. doi: 10.1002/anie.202015570. Epub 2021 Feb 17.
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.
硫在天然产物中的掺入是生物合成研究的一个关键领域。最近，人们发现了一组含硫的蒽环类化合物，但硫掺入步骤仍未被充分了解。在这项工作中，发现了一系列硫醚桥连的蒽环类化合物，并揭示了在形成硫蒽环类化合物（TACs）A 和 B 的过程中存在隐环氧化物迈克尔受体中间产物。然而，通过 CRISPR/Cas9 对生物合成基因簇（BGC）进行系统的基因缺失，无法确定任何负责将环氧化物中间产物转化为 TACs 的基因。相反，一系列体外和体内实验的结果明确表明，这种转化是两个非酶步骤的结果，可能由内源性硫化氢介导。因此，TACs 被认为是一种解毒过程的产物。这些结果有望为蒽环类化合物的研究以及天然产物生物合成中无机硫的利用做出贡献。
