Discovery and Biosynthesis of Streptosactin, a Sactipeptide with an Alternative Topology Encoded by Commensal Bacteria in the Human Microbiome
Discovery and Biosynthesis of Streptosactin, a Sactipeptide with an Alternative Topology Encoded by Commensal Bacteria in the Human Microbiome
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DOI：
10.1021/jacs.0c05546
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发表时间：
2020-09-23
影响因子：
15
通讯作者：
Seyedsayamdost, Mohammad R.
中科院分区：
文献类型：
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作者：
Bushin, Leah B.;Covington, Brett C.;Seyedsayamdost, Mohammad R.
哺乳动物微生物组编码数千个生物合成基因簇（BGC），代表了天然产物研究的新前沿。我们最近在哺乳动物微生物组链球菌中发现了大量的群体感应调节的BGC，它们编码核糖体合成和后修饰肽（RIPPs），并含有一种或多种自由基S-腺苷甲硫氨酸（RaS）酶，这是一个多功能的超家族，已知可以催化生物学中一些最不寻常的反应。在目前的工作中，我们针对一个广泛的链球菌RiPP BGC组，并阐明其编码的RaS酶进行的反应，并确定其肽天然产物，我们命名为streptosactin。链球菌素是第一个从链球菌中鉴定出来的乳糖肽;它含有两个连续的四个氨基酸的sactionine大环，这是该化合物家族的不寻常拓扑结构。生物活性测定揭示了对生产菌株及其携带相同BGC的最近亲属的有效但窄谱的活性，表明链菌素可能是嗜热链球菌的长期怀疑的杀同胞剂。我们的研究结果突出了哺乳动物链球菌作为一个不寻常的酶化学和生物活性天然产物的丰富来源。
Mammalian microbiomes encode thousands of biosynthetic gene clusters (BGCs) and represent a new frontier in natural product research. We recently found an abundance of quorum sensing-regulated BGCs in mammalian microbiome streptococci that code for ribosomally synthesized and post-translationally modified peptides (RiPPs) and contain one or more radical S-adenosylmethionine (RaS) enzymes, a versatile superfamily known to catalyze some of the most unusual reactions in biology. In the current work, we target a widespread group of streptococcal RiPP BGCs and elucidate both the reaction carried out by its encoded RaS enzyme and identify its peptide natural product, which we name streptosactin. Streptosactin is the first sactipeptide identified from Streptococcus spp.; it contains two sequential four amino acid sactionine macrocycles, an unusual topology for this compound family. Bioactivity assays reveal potent but narrow-spectrum activity against the producing strain and its closest relatives that carry the same BGC, suggesting streptosactin may be a long-suspected fratricidal agent of Streptococcus thermophilus. Our results highlight mammalian streptococci as a rich source of unusual enzymatic chemistries and bioactive natural products.