Department of Plant and Microbial Biology, University of Zurich, 8008, Zurich, Switzerland.
Department of Chemistry, University of Zurich, 8057, Zurich, Switzerland.
Nat Commun. 2018 Mar 30;9(1):1297. doi: 10.1038/s41467-018-03690-2.
Members of the diazeniumdiolate class of natural compounds show potential for drug development because of their antifungal, antibacterial, antiviral, and antitumor activities. Yet, their biosynthesis has remained elusive to date. Here, we identify a gene cluster directing the biosynthesis of the diazeniumdiolate compound fragin in Burkholderia cenocepacia H111. We provide evidence that fragin is a metallophore and that metal chelation is the molecular basis of its antifungal activity. A subset of the fragin biosynthetic genes is involved in the synthesis of a previously undescribed cell-to-cell signal molecule, valdiazen. RNA-Seq analyses reveal that valdiazen controls fragin biosynthesis and affects the expression of more than 100 genes. Homologs of the valdiazen biosynthesis genes are found in various bacteria, suggesting that valdiazen-like compounds may constitute a new class of signal molecules. We use structural information, in silico prediction of enzymatic functions and biochemical data to propose a biosynthesis route for fragin and valdiazen.
天然化合物的重氮二氧戊环类化合物因其抗真菌、抗菌、抗病毒和抗肿瘤活性而显示出药物开发的潜力。然而，其生物合成至今仍是一个谜。在这里，我们确定了一个基因簇，该基因簇指导伯克霍尔德菌 H111 中重氮二氧戊环化合物 fragin 的生物合成。我们提供的证据表明，fragin 是一种金属载体，金属螯合是其抗真菌活性的分子基础。 fragin 生物合成基因的一部分参与了一种以前未描述的细胞间信号分子 valdiazen 的合成。RNA-Seq 分析表明，valdiazen 控制 fragin 的生物合成，并影响 100 多个基因的表达。在各种细菌中发现了 valdiazen 生物合成基因的同源物，这表明类似 valdiazen 的化合物可能构成一类新的信号分子。我们使用结构信息、酶功能的计算机预测和生化数据来提出 fragin 和 valdiazen 的生物合成途径。
