Uncovering the unexplored diversity of thioamidated ribosomal peptides in Actinobacteria using the RiPPER genome mining tool
Uncovering the unexplored diversity of thioamidated ribosomal peptides in Actinobacteria using the RiPPER genome mining tool
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DOI：
10.1093/nar/gkz192
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发表时间：
2019-05-21
影响因子：
14.9
通讯作者：
Truman, Andrew W.
中科院分区：
文献类型：
--
作者：
Santos-Aberturas, Javier;Chandra, Govind;Truman, Andrew W.
通过基因组挖掘合理发现新的特化代谢物是寻找新的生物活性分子的一种非常有前途的策略。核糖体合成和翻译后修饰肽（RiPPs）是一类主要的天然产物，来源于遗传编码的前体肽。然而，由于在所有途径中缺乏共同的生物合成特征，RiPP基因簇特别难以进行可靠的生物信息学预测。在这里，我们描述了RiPPER，一个新的工具，用于家族独立鉴定RiPP前体肽，并应用该方法在放线菌中寻找新的硫胺化RiPP。到目前为止，硫胺化被认为是一种罕见的翻译后修饰，它是由古细菌中的一对蛋白质（YcaO和TfuA）催化的。在放线菌中，硫代病毒酰胺样分子是一类细胞毒性ripp，具有多种硫代酰胺，被认为是由YcaO-TfuA蛋白引入的。使用RiPPER，我们发现先前描述的编码YcaO和TfuA蛋白的RiPP基因簇在放线菌中广泛存在，并且编码高度多样化的前体肽，这些前体肽被预测会产生硫胺化的RiPP。为了说明这一策略，我们描述了一种新的结构类硫胺化天然产物的首次合理发现，即来自varsoviensis链霉菌的硫代varsolins。
The rational discovery of new specialized metabolites by genome mining represents a very promising strategy in the quest for new bioactive molecules. Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a major class of natural product that derive from genetically encoded precursor peptides. However, RiPP gene clusters are particularly refractory to reliable bioinformatic predictions due to the absence of a common biosynthetic feature across all pathways. Here, we describe RiPPER, a new tool for the family-independent identification of RiPP precursor peptides and apply this methodology to search for novel thioamidated RiPPs in Actinobacteria. Until now, thioamidation was believed to be a rare post-translational modification, which is catalyzed by a pair of proteins (YcaO and TfuA) in Archaea. In Actinobacteria, the thioviridamide-like molecules are a family of cytotoxic RiPPs that feature multiple thioamides, which are proposed to be introduced by YcaO-TfuA proteins. Using RiPPER, we show that previously undescribed RiPP gene clusters encoding YcaO and TfuA proteins are widespread in Actinobacteria and encode a highly diverse landscape of precursor peptides that are predicted to make thioamidated RiPPs. To illustrate this strategy, we describe the first rational discovery of a new structural class of thioamidated natural products, the thiovarsolins from Streptomyces varsoviensis.