Characterization of the Actinonin Biosynthetic Gene Cluster
Characterization of the Actinonin Biosynthetic Gene Cluster
复制标题
DOI：
10.1002/cbic.201800116
复制
发表时间：
2018-06
期刊：
影响因子：
3.2
通讯作者：
F. Wolf;F. Leipoldt;A. Kulik;D. Wibberg;J. Kalinowski;Leonard Kaysser
中科院分区：
文献类型：
--
作者：
F. Wolf;F. Leipoldt;A. Kulik;D. Wibberg;J. Kalinowski;Leonard Kaysser
天然产物放线菌素的羟甲酸根部分对金属蛋白酶活性部位的二价阳离子具有螯合作用，因此可介导金属蛋白酶的抑制作用。由于其抗微生物活性，放线菌素已成为开发新的抗生素候选药物的先导化合物。最近，我们发现了一个与放线菌素生物合成相关的基因簇。在这里，我们通过异源途径表达和基因缺失实验来确认和表征这个簇。我们将生物合成的基因簇分配给放线菌素的生产，并确定了簇的边界。此外，我们确定Acti，一种类似AurF的加氧酶，负责N-羟基化反应，形成异羟甲酸酯弹头。我们的发现为更详细地研究放线菌素的生物合成提供了基础。
The hydroxamate moiety of the natural product actinonin mediates inhibition of metalloproteinases because of its chelating properties towards divalent cations in the active site of those enzymes. Owing to its antimicrobial activity, actinonin has served as a lead compound for the development of new antibiotic drug candidates. Recently, we identified a putative gene cluster for the biosynthesis of actinonin. Here, we confirm and characterize this cluster by heterologous pathway expression and gene‐deletion experiments. We assigned the biosynthetic gene cluster to actinonin production and determine the cluster boundaries. Furthermore, we establish that ActI, an AurF‐like oxygenase, is responsible for the N‐hydroxylation reaction that forms the hydroxamate warhead. Our findings provide the basis for more detailed investigations of actinonin biosynthesis.