The colibactin warhead crosslinks DNA.
The colibactin warhead crosslinks DNA.
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人类微生物群的成员越来越多地与人类健康和疾病状态相关，但大多数调节宿主-微生物相互作用的潜在微生物代谢物仍在很大程度上未被探索。人类结肠中存在的大肠杆菌菌株通过一种未知的小分子介导过程与引发炎症诱导的结直肠癌有关。负责的非核糖体肽-聚酮杂交途径编码“大肠杆菌蛋白”，这是一个很大程度上未被表征的小分子家族。由于这种途径的高不稳定性，能够启动癌症形成的基因毒性小分子仍然难以捉摸。在代谢组学分析的指导下，我们采用核磁共振波谱和生物信息学指导的同位素标记研究相结合的方法来表征大肠杆菌蛋白战斗部，这是一种前所未有的取代螺环结构。弹头在体外交联双链DNA，为大肠杆菌蛋白的DNA损伤活性提供了直接的实验证据。这些数据支持了大肠杆菌素生物合成及其作用模式的意想不到的模型。
Members of the human microbiota are increasingly being correlated to human health and disease states, but the majority of the underlying microbial metabolites that regulate host-microbe interactions remain largely unexplored. Select strains of E. coli present in the human colon have been linked to initiating inflammation-induced colorectal cancer through an unknown small molecule-mediated process. The responsible nonribosomal peptide-polyketide hybrid pathway encodes “colibactin,” a largely uncharacterized family of small molecules. Genotoxic small molecules from this pathway capable of initiating cancer formation have remained elusive due to their high instability. Guided by metabolomic analyses, here we employ a combination of NMR spectroscopy and bioinformatics-guided isotopic labeling studies to characterize the colibactin warhead, an unprecedented substituted spirobicyclic structure. The warhead crosslinks duplex DNA in vitro, providing direct experimental evidence for colibactin’s DNA-damaging activity. The data support unexpected models for both colibactin biosynthesis and its mode of action.
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影响因子：
16.6
作者：
Arthur, Janelle C.;Gharaibeh, Raad Z.;Muehlbauer, Marcus;Perez-Chanona, Ernesto;Uronis, Joshua M.;McCafferty, Jonathan;Fodor, Anthony A.;Jobin, Christian
通讯作者：
Jobin, Christian
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56.9
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