Unique Biosynthetic Pathway in Bloom-Forming Cyanobacterial Genus Microcystis Jointly Assembles Cytotoxic Aeruginoguanidines and Microguanidines
Unique Biosynthetic Pathway in Bloom-Forming Cyanobacterial Genus Microcystis Jointly Assembles Cytotoxic Aeruginoguanidines and Microguanidines
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DOI：
10.1021/acschembio.8b00918
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发表时间：
2019-01-01
影响因子：
4
通讯作者：
Gugger, Muriel
中科院分区：
文献类型：
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作者：
Pancrace, Claire;Ishida, Keishi;Gugger, Muriel
已知蓝藻属微囊藻产生一系列结构独特和具有生物活性的复杂天然产物，包括危险的氰基毒素。细胞毒性铜绿素代表了一个尚未被探索的多肽家族，其特征是一个三取代苯单元和法尼化精氨酸衍生物。在这项研究中，我们的目的是利用微囊藻公共基因组的生物合成属性和代谢物在巴斯德蓝藻培养库中的零星分布，将这些化合物分配到一个生物合成基因簇。通过将基因组挖掘与非靶向代谢组学相结合，我们将铜绿假单胞菌(AGD)连接到一个非核糖体肽合成酶基因簇上，并将一个小得多的产物微胍(MGD)共同分配给这一途径，该产物以前只在两次微囊藻水华中报道过。此外，还发现了一类新的中间体化合物，命名为微钴酰胺，从而进一步扩大了这个化合物家族。结构上不同的AGD和MGDS的比较揭示了这种生物合成途径的突出的多功能性，并为这两个化合物亚家族的组装提供了见解。值得注意的是，铜绿假单胞菌和微双胍被发现与肝毒性微囊藻毒素一样广泛，但这两个毒素家族的出现似乎是相互排斥的。
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.