Natural Combinatorial Biosynthesis Involving Two Clusters for the Synthesis of Three Pyrrolamides in Streptomyces netropsis
Natural Combinatorial Biosynthesis Involving Two Clusters for the Synthesis of Three Pyrrolamides in Streptomyces netropsis
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DOI：
10.1021/cb500652n
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发表时间：
2015-02-01
影响因子：
4
通讯作者：
Lautru, Sylvie
中科院分区：
文献类型：
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作者：
Vingadassalon, Audrey;Lorieux, Florence;Lautru, Sylvie
吡咯酰胺类化合物是一个次级代谢产物小家族，已知它们能够以非共价键结合DNA小沟，具有一定的序列特异性。迄今为止，只有一个单一的吡咯酰胺生物合成基因簇已被报道，指导合成的刚果杀菌素（netropsin）在链霉菌ambofaciens。在这项研究中，我们通过鉴定和表征链霉菌DSM 40846中负责产生偏端霉素的基因簇，提高了我们对吡咯胺生物合成的理解。我们发现，该菌株产生两个其他pyrrollamides，良好的特点congocidine和congocidine/偏端霉素杂交，我们命名为disgocidine。S. netropsis DSM 40846基因组分析导致鉴定两个不同的吡咯酰胺样生物合成基因簇。我们在这里表明，这两个集群是依赖于三个吡咯酰胺分子的生产。此外，基于对这些簇的详细功能分析，我们提出了一种生物合成途径，以刚果西定和偏端霉素和一个更新的模型吡咯酰胺组装。地戈西定的合成，偏端霉素/刚果西定杂合物，似乎构成了两个相关的生物合成途径之间的自然组合生物合成的第一个例子。最后，我们分析了两个生物合成基因簇的基因组背景，并建议目前相互依赖的集群的结果从两个祖先的独立pyrrolamide基因簇的共同进化。
The pyrrolamides constitute a small family of secondary metabolites that are known for their ability to bind noncovalently to the DNA minor groove with some sequence specificity. To date, only a single pyrrolamide biosynthetic gene cluster has been reported, directing the synthesis of congocidine (netropsin) in Streptomyces ambofaciens. In this study, we improve our understanding of pyrrolamide biosynthesis through the identification and characterization of the gene cluster responsible for the production of distamycin in Streptomyces netropsis DSM40846. We discover that the strain produces two other pyrrolamides, the well-characterized congocidine and a congocidine/distamycin hybrid that we named disgocidine. S. netropsis DSM40846 genome analysis led to the identification of two distinct pyrrolamide-like biosynthetic gene clusters. We show here that these two clusters are reciprocally dependent for the production of the three pyrrolamide molecules. Furthermore, based on detailed functional analysis of these clusters, we propose a biosynthetic route to congocidine and distamycin and an updated model for pyrrolamide assembly. The synthesis of disgocidine, the distamycin/congocidine hybrid, appears to constitute the first example of natural combinatorial biosynthesis between two related biosynthetic pathways. Finally, we analyze the genomic context of the two biosynthetic gene clusters and suggest that the presently interdependent clusters result from the coevolution of two ancestral independent pyrrolamide gene clusters.