McCaughey Catherine S, van Santen Jeffrey A, van der Hooft Justin J J, Medema Marnix H, Linington Roger G
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Bioinformatics Group, Wageningen University, Wageningen, the Netherlands.
Nat Chem Biol. 2022 Mar;18(3):295-304. doi: 10.1038/s41589-021-00949-6. Epub 2021 Dec 30.
Major advances in genome sequencing and large-scale biosynthetic gene cluster (BGC) analysis have prompted an age of natural product discovery driven by genome mining. Still, connecting molecules to their cognate BGCs is a substantial bottleneck for this approach. We have developed a mass-spectrometry-based parallel stable isotope labeling platform, termed IsoAnalyst, which assists in associating metabolite stable isotope labeling patterns with BGC structure prediction to connect natural products to their corresponding BGCs. Here we show that IsoAnalyst can quickly associate both known metabolites and unknown analytes with BGCs to elucidate the complex chemical phenotypes of these biosynthetic systems. We validate this approach for a range of compound classes, using both the type strain Saccharopolyspora erythraea and an environmentally isolated Micromonospora sp. We further demonstrate the utility of this tool with the discovery of lobosamide D, a new and structurally unique member of the family of lobosamide macrolactams.
基因组测序和大规模生物合成基因簇（BGC）分析的重大进展推动了一个由基因组挖掘驱动的天然产物发现时代。然而，将分子与其同源BGCs联系起来是这种方法的一个重大瓶颈。我们开发了一种基于质谱的平行稳定同位素标记平台，称为IsoAnalyst，它有助于将代谢物稳定同位素标记模式与BGC结构预测相关联，从而将天然产物与其相应的BGCs联系起来。在这里，我们表明IsoAnalyst可以快速将已知代谢物和未知分析物与BGCs相关联，以阐明这些生物合成系统的复杂化学表型。我们使用模式菌株红色糖多孢菌和环境分离的小单孢菌属验证了这种方法适用于一系列化合物类别。我们进一步通过发现洛博酰胺D（一种新的、结构独特的洛博酰胺大环内酯家族成员）证明了该工具的实用性。
