Abstract:
Lipopeptides represent a large group of microbial natural products that include important antibacterial and antifungal drugs and some of the most-powerful known biosurfactants. The vast majority of lipopeptides comprise cyclic peptide backbones N-terminally equipped with various fatty acyl moieties. The known compounds of this type are biosynthesized by nonribosomal peptide synthetases, giant enzyme complexes that assemble their products in a non-gene-encoded manner. Here, we report the genome-guided discovery of ribosomally derived, fatty-acylated lipopeptides, termed selidamides. Heterologous reconstitution of three pathways, two from cyanobacteria and one from an arctic, ocean-derived alphaproteobacterium, allowed structural characterization of the probable natural products and suggest that selidamides are widespread over various bacterial phyla. The identified representatives feature cyclic peptide moieties and fatty acyl units attached to (hydroxy)ornithine or lysine side chains by maturases of the GCN5-related N-acetyltransferase superfamily. In contrast to nonribosomal lipopeptides that are usually produced as congener mixtures, the three selidamides are selectively fatty acylated with C10, C12, or C16 fatty acids, respectively. These results highlight the ability of ribosomal pathways to emulate products with diverse, nonribosomal-like features and add to the biocatalytic toolbox for peptide drug improvement and targeted discovery.
摘要:
脂肽代表一大组微生物天然产物,其包括重要的抗细菌和抗真菌药物以及一些最强大的已知生物表面活性剂。绝大多数脂肽包含N-末端配备有各种脂肪酰基部分的环状肽主链。这种类型的已知化合物是由非核糖体肽合成酶生物合成的,巨大的酶复合物,以非基因编码的方式组装它们的产物。这里,我们报道了核糖体来源的基因组指导发现,脂肪酰化脂肽,称为硒酰胺。三种途径的异源重建,两个来自蓝细菌,一个来自北极,海洋衍生的α变形杆菌,允许对可能的天然产物进行结构表征,并表明硒酰胺广泛分布在各种细菌门上。鉴定的代表特征在于通过GCN5相关的N-乙酰转移酶超家族的成熟酶连接至(羟基)鸟氨酸或赖氨酸侧链的环状肽部分和脂肪酰基单元。与通常作为同源混合物产生的非核糖体脂肽相反,三种硒酰胺被C10、C12或C16脂肪酸选择性脂肪酰化,分别。这些结果突出了核糖体途径模拟不同产品的能力,非核糖体样特征,并添加到生物催化工具箱中,用于肽药物的改进和靶向发现。