Department of Chemistry, Princeton University, Princeton, NJ, USA.
Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
Nat Chem Biol. 2022 Oct;18(10):1135-1143. doi: 10.1038/s41589-022-01090-8. Epub 2022 Aug 11.
Microbial natural products comprise diverse architectures that are generated by equally diverse biosynthetic strategies. In peptide natural products, amino acid sidechains are frequently used as sites of modification to generate macrocyclic motifs. Backbone amide groups, among the most stable of biological moieties, are rarely used for this purpose. Here we report the discovery and biosynthesis of bicyclostreptins-peptide natural products from Streptococcus spp. with an unprecedented structural motif consisting of a macrocyclic β-ether and a heterocyclic sp-sp linkage between a backbone amide nitrogen and an adjacent α-carbon. Both reactions are installed, in that order, by two radical S-adenosylmethionine (RaS) metalloenzymes. Bicyclostreptins are produced at nM concentrations and are potent growth regulation agents in Streptococcus thermophilus. Our results add a distinct and unusual chemotype to the growing family of ribosomal peptide natural products, expand the already impressive catalytic scope of RaS enzymes, and provide avenues for further biological studies in human-associated streptococci.
微生物天然产物具有多样的结构，这些结构是由同样多样的生物合成策略产生的。在肽类天然产物中，氨基酸侧链经常被用作修饰位点，以生成大环结构。在生物分子中，酰胺基团是最稳定的基团之一，很少用于此目的。在这里，我们报告了来自链球菌属的双环肽的发现和生物合成，它们具有前所未有的结构模式，由一个大环β-醚和一个在酰胺氮和相邻α-碳之间的杂环 sp-sp 键组成。这两个反应按顺序由两个自由基 S-腺苷甲硫氨酸（RaS）金属酶进行安装。双环肽以纳摩尔浓度产生，并且是嗜热链球菌中有效的生长调节剂。我们的结果为核糖体肽天然产物不断增长的家族增添了一个独特而不寻常的化学型，扩展了 RaS 酶已经令人印象深刻的催化范围，并为与人类相关的链球菌的进一步生物学研究提供了途径。
