Bicyclostreptins are radical SAM enzyme-modified peptides with unique cyclization motifs
Bicyclostreptins are radical SAM enzyme-modified peptides with unique cyclization motifs
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DOI：
10.1038/s41589-022-01090-8
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发表时间：
2022-08-11
影响因子：
14.8
通讯作者：
Seyedsayamdost, Mohammad R.
中科院分区：
文献类型：
--
作者：
Bushin, Leah B.;Covington, Brett C.;Seyedsayamdost, Mohammad R.
微生物天然产物包括由同样不同的生物合成策略产生的不同的结构。在多肽天然产物中，氨基酸侧链经常被用来作为大环基序的修饰位点。主链酰胺基团是最稳定的生物基团之一，很少用于此目的。本文报道了从链球菌中发现并生物合成双环链菌素-多肽天然产物。具有前所未有的结构基序，由大环β-乙醚和主链酰胺氮与相邻的α-碳之间的杂环sp(3)-sp(3)连接而成。这两个反应都是由两个自由基S-腺苷蛋氨酸(RAS)金属酶按照这个顺序安装的。双环链菌素是在NM浓度下产生的，是嗜热链球菌的有效生长调节剂。我们的结果为不断增长的核糖体肽天然产物家族增加了一种独特和不同寻常的化学类型，扩大了已经令人印象深刻的RAS酶的催化范围，并为进一步的人类相关链球菌的生物学研究提供了途径。
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 beta-ether and a heterocyclic sp(3)-sp(3) linkage between a backbone amide nitrogen and an adjacent alpha-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.