The cyanobacterial genus Microcystis is known to produce an elaborate array of structurally unique and biologically active natural products, including hazardous cyanotoxins. Cytotoxic aeruginoguanidines represent a yet unexplored family of peptides featuring a trisubstituted benzene unit and farnesylated arginine derivatives. In this study, we aimed at assigning these compounds to a biosynthetic gene cluster by utilizing biosynthetic attributes deduced from public genomes of Microcystis and the sporadic distribution of the metabolite in axenic strains of the Pasteur Culture Collection of Cyanobacteria. By integrating genome mining with untargeted metabolomics using liquid chromatography with mass spectrometry, we linked aeruginoguanidine (AGD) to a nonribosomal peptide synthetase gene cluster and coassigned a significantly smaller product to this pathway, microguanidine (MGD), previously only reported from two Microcystis blooms. Further, a new intermediate class of compounds named microguanidine amides was uncovered, thereby further enlarging this compound family. The comparison of structurally divergent AGDs and MGDs reveals an outstanding versatility of this biosynthetic pathway and provides insights into the assembly of the two compound subfamilies. Strikingly, aeruginoguanidines and microguanidines were found to be as widespread as the hepatotoxic microcystins, but the occurrence of both toxin families appeared to be mutually exclusive.

中文翻译：

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在形成花的蓝细菌属微囊藻中独特的生物合成途径联合组装细胞毒性铜绿胍和微胍。

众所周知，蓝藻属微囊藻产生一系列精心设计的结构独特且具有生物活性的天然产物，包括有害的蓝毒素。细胞毒性铜绿胍代表了一个尚未开发的肽家族，其特征在于三取代的苯单元和法呢基化的精氨酸衍生物。在这项研究中，我们旨在通过利用微囊藻的公共基因组推导的生物合成属性，以及蓝藻的巴斯德培养物集合的无菌菌株的代谢产物的零星分布，将这些化合物分配到生物合成基因簇中。通过使用液相色谱和质谱技术将基因组挖掘与非靶向代谢组学整合在一起，我们将铜绿胍（AGD）与非核糖体肽合成酶基因簇相连，并向该途径分配了一个明显较小的产物，即微胍（MGD），以前仅从两次微囊藻的开花中报道过。此外，发现了新的中间类别的化合物，称为微胍酰胺，从而进一步扩大了该化合物家族。在结构上不同的AGDs和MGDs的比较揭示了这种生物合成途径的杰出多功能性，并提供了对这两个化合物亚家族的组装的见解。令人惊讶的是，发现铜绿胍和微胍与肝毒性微囊藻毒素一样广泛，但是两个毒素家族的出现似乎是互斥的。发现了一种新的中间类别的化合物，称为微胍酰胺，从而进一步扩大了该化合物家族。在结构上不同的AGDs和MGDs的比较揭示了这种生物合成途径的杰出多功能性，并提供了对这两个化合物亚家族的组装的见解。令人惊讶的是，发现铜绿胍和微胍与肝毒性微囊藻毒素一样广泛，但是两个毒素家族的出现似乎是互斥的。发现了一种新的中间类别的化合物，称为微胍酰胺，从而进一步扩大了该化合物家族。在结构上不同的AGDs和MGDs的比较揭示了这种生物合成途径的杰出多功能性，并提供了对这两个化合物亚家族的组装的见解。令人惊讶的是，发现铜绿胍和微胍与肝毒性微囊藻毒素一样广泛，但是两个毒素家族的出现似乎是互斥的。