Structure and Function of Salmochelins and Microcins M/H47

对于许多致病细菌来说，铁的供应是一个关键因素，因为在它们的宿主中，铁与蛋白质结合。在低铁生长条件下，大肠杆菌会分泌一种铁载体(铁络合剂)，称为肠杆菌素(肠球蛋白)。特定的高亲和力转运系统允许摄取铁-肠肌动蛋白，以供应生长所需的铁。自1970年以来，一直认为肠杆菌素是沙门氏菌菌株的主要铁载体。然而，我们最近发现，Salmochelin是一种二葡萄糖基化的肠杆菌素，是大多数沙门氏菌株分泌的主要铁载体。Salmochelin的合成和利用由iroBCDEN基因编码。在计划中的项目中，将对新型Salmochelin及其降解产物的化学结构进行表征。此外，还将用化学和遗传方法研究和表征基因产物在生物合成、运输和降解中的功能和活性。由于ENTO蛋白在哺乳动物体内通过血清蛋白和NGAL Lipocalin在炎症中强烈结合，宿主的这些固有防御机制似乎使ENTO蛋白成为病原菌的劣势铁载体。因此，将考察Salmochelin与白蛋白和NGAL Lipocalin的结合特性。该项目的第二部分集中在几个产生沙莫契林的大肠杆菌菌株分泌的微粘菌素H47和M。这些微囊素杀死了广泛的不同的大肠杆菌菌株，并使用与Salmochelin和Enterobactin相同的儿茶酚类铁载体受体。此外，在微霉素H47和M生物合成的基因簇中还发现了与iroB和irod同源的基因mcML和mcmK。随着这些微球蛋白结构的阐明，对其可能的修饰以及对微球蛋白功能的研究将会有更多的结论。

For many pathogenic bacteria iron supply is a critical factor since in their host iron is bound to proteins. Under low iron growth conditions E. coli secretes a siderophore (iron complexing agent) called enterobactin (enterochelin). Specific high affinity transport systems allow the uptake of iron-enterobactin in order to supply the iron necessary for growth. Since 1970 it has been assumed that enterobactin is a major siderophore of Salmonella strains. However, we recently showed that salmochelin, a diglucosylated enterobactin is the principal siderophore secreted by most Salmonella strains. Synthesis and utilization of salmochelin is encoded by the iroBCDEN genes. In the planned project, the chemical structures of novel salmochelins and its degradation products will be characterized. Furthermore, the functions and activities of the gene products in biosynthesis, transport and degradation will be studied and characterized with chemical and genetic methods. Since, enterobactin is avidly bound in the mammal by serum albumins and in inflammation by NGAL lipocalin, these innate defense mechanisms of the host seem to make enterobactin an inferior siderophore for pathogenic bacteria. Therefore, the binding properties of salmochelins to albumins and NGAL lipocalin will be examined. The second part of the project is focused on microcins H47 and M secreted by several salmochelin producing E. coli strains. These microcins kill a broad spectrum of different E. coli strains and use the same catecholate siderophore receptors as salmochelins and enterobactin. Furthermore, the genes mcmL and mcmK, which are homologs of iroB and iroD, are found in the gene cluster for microcin H47 and M biosynthesis. With the structure elucidation of these microcins conclusions are expected on the putative modification by McmL and McmK and on the function of microcins.