Structure and biosynthesis of unusual polyamine and polyagmatine natural products

罕见多胺和多胍丁胺天然产物的结构和生物合成

• 批准号: 245509096
• 负责人: Professor Dr. Helge Björn Bode
• 金额: --
• 依托单位: Abteilung Naturstoffe in Organismischen Interaktionen
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/245509096?language=en
• 关键词: Structure; biosynthesis; unusual; polyamine; polyagmatine

Entomopathogenic bacteria of the genera Photorhabdus and Xenorhabdus have been proven to be a rich source for novel natural products. However, their structure and biosynthesis is often still unknown. Therefore the biosynthesis of two structurally very unusual natural product classes will be investigated in detail in this project:1. Polyamine natural products with similarity to zeamine.Zeamine is only one of three known members of a highly unusual class of natural products with broad antimicrobial activity. It is a linear long-chain amine (>30 carbon atoms in length) with additional amine substituents. Biochemically, this unusual structure in likely to be derived from a pathways similar to the biosynthesis of polyunsaturated fatty acids but it represents a new subtype of this biosynthesis. From Xenorhabdus budapestensis we have identified and elucidated the structure of another member of this class of compounds, which was named xenoGUFamine. In this compound the polyamine moiety is attached to a nonribosomally made cyclic peptide with the cyclisation mechanism being unknown. XenoGUFamine also shows broad antimicrobial activity but is also highly cytotoxic. Preliminary work revealed that several Xenorhabdus but also Photorhabdus strains that live in symbiosis with nematodes and are entomopathogenic are able to produce similar compounds. Subsequent analysis of the genome sequences of several of these bacteria also led to the identification of the respective biosynthesis gene clusters.2. Polyagmatine natural products with similarity to nemaucin.The only known members of this second unusual class of natural products are phleomycin G, nemaucin and cabanillasin. Nemaucin and cabanillasin have been isolated from Xenorhabdus cabanillasii and were described in patents by a French company because they also show a broad and potent antimicrobial activity similar to the polyamines. Nemaucin has a peptide moiety very similar to that of xenoGUFamine but carries a polyagmatine instead of the polyamine moiety. Currently nothing in known about the biosynthesis of this highly unusual polyagmatine moiety.In this project additional members of these very unusual classes of natural products, which obviously is very common in entomopathogenic bacteria, will be identified and their structures will be elucidated. The respective biosynthesis gene clusters will be identified and analysed and selected enzymes will be characterized in vitro. Additionally, the biological activity of these compounds will be investigated in more detail and first experiments regarding the mode of action of these compounds will be performed.

photohabdus属和Xenorhabdus属昆虫病原细菌已被证明是新型天然产物的丰富来源。然而，它们的结构和生物合成往往仍然未知。因此，本项目将详细研究两类结构非常不寻常的天然产物的生物合成：1。与玉米胺相似的多胺天然产物。玉米胺是一种非常不寻常的具有广泛抗菌活性的天然产物的三种已知成员之一。它是一个线性长链胺（bbb30碳原子的长度）与额外的胺取代基。从生物化学角度来看，这种不寻常的结构可能来源于类似于多不饱和脂肪酸生物合成的途径，但它代表了这种生物合成的一种新亚型。从Xenorhabdus budapestensis中，我们已经鉴定并阐明了这类化合物的另一个成员的结构，并将其命名为xenoGUFamine。在该化合物中，多胺部分附着在非核糖体制造的环肽上，其环化机制尚不清楚。XenoGUFamine也显示出广泛的抗菌活性，但也具有高度的细胞毒性。初步研究表明，一些与线虫共生并具有昆虫致病性的Xenorhabdus和Photorhabdus菌株能够产生类似的化合物。随后对这些细菌基因组序列的分析也导致了各自生物合成基因簇的鉴定。聚氨酰胺与链毛蛋白相似的天然产物。这第二种不寻常的天然产物的唯一已知成员是静脉霉素G， nemaucin和cabanillasin。Nemaucin和cabanillasin已经从Xenorhabdus cabanillasii中分离出来，并由一家法国公司申请专利，因为它们也显示出与多胺相似的广泛而有效的抗菌活性。Nemaucin的肽段与xenoGUFamine的肽段非常相似，但携带的是聚氨酰胺而不是多胺部分。目前对这种极不寻常的聚聚丁氨酸片段的生物合成还一无所知。在这个项目中，这些非常不寻常的天然产物类别的其他成员，显然在昆虫致病细菌中非常常见，将被鉴定并阐明它们的结构。将鉴定和分析各自的生物合成基因簇，并在体外对选定的酶进行表征。此外，将更详细地研究这些化合物的生物活性，并进行有关这些化合物作用方式的首次实验。