Nitro versus Hydroxamate in Siderophores of Pathogenic Bacteria: Effect of Missing Hydroxylamine Protection in Malleobactin Biosynthesis
Nitro versus Hydroxamate in Siderophores of Pathogenic Bacteria: Effect of Missing Hydroxylamine Protection in Malleobactin Biosynthesis
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DOI：
10.1002/anie.201303196
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发表时间：
2013-08-05
影响因子：
16.6
通讯作者：
Hertweck, Christian
中科院分区：
文献类型：
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作者：
Franke, Jakob;Ishida, Keishi;Hertweck, Christian
铁载体作为致病细菌的毒力因子起着重要作用。[1]铁载体是已知的最强的铁离子结合剂，这些结构多样的化合物被用来清除人体或动物宿主中难于溶解的铁。引人注目的是，臭名昭著的人类病原菌，如鼠疫耶尔森菌，是毁灭性黑死病流行的病原体，在没有铁载体的情况下完全失去了它们的毒力。[2]因此，了解病原体S的铁载体结构和相应的生物合成机制被认为是新的治疗方法的先决条件，如靶向致病因子和使用铁载体-药物结合物的特洛伊木马策略。[3]在过去的20年里，许多研究致力于阐明马尔氏伯克霍尔氏菌和伪马雷伯克霍尔德氏菌的铁载体，[4-7]这些传染病的病原体腺体[8]和融液病[9]感染这些b-蛋白细菌通常是致命的。[10]因此，这两个物种都被归类为潜在的生物战剂，事实上，马利氏杆菌在世界大战中被滥用来杀死敌马和骡子。[11，12]虽然人们很早就知道假马利氏杆菌和马利氏杆菌产生两种类型的铁载体，即毕氏杆菌(1和2‘-epi-1，图1)和Malleobactin(2)，[4]令人惊讶的是，后者的结构仍然不明。据推测，Malleobactin可能与洋葱伯克霍尔德氏菌复合体(BCC)产生的鸟杆菌素(3-5，方案1)、羟甲酸铁载体(BCC)有关。[5，6]在这里，我们揭示了Malleobactin的异常结构和绝对构型，并揭示了一种前所未有的脂肪族硝基氨基酸的生物起源。为了初步了解编码的铁载体的结构差异，我们比较了鸟动蛋白和踝乳蛋白生物合成的基因座。[6，13]这两种类型的基因簇共享四模块非核糖体多肽合成酶(NRPS)和辅助酶的基因。此外，推测的氨基酸剪裁酶(鸟氨酸单加氧酶、[14]天冬氨酸b-羟基酶、[15]N-甲酰基转移酶[16])、铁载体受体和转运体的基因都存在于两种类型的基因簇中。然而，我们注意到，属于B.Mallei家族的细菌的基因座含有一个额外的假设蛋白基因(MBAM)，但缺乏orbK和orbL的同源基因(图1A，黄色开放阅读框架(ORF))。后者编码酰基转移酶，虽然它们的生化功能尚未被研究，但人们可能认为它们是将酰基单位加载到N-末端鸟氨酸残基上所必需的。[13]我们得出结论，鸟球菌素和Malleobactin的替代模式不同。
Siderophores play a major role as virulence factors of pathogenic bacteria.[1] Known as the strongest Fe3+-binding agents, these structurally diverse compounds are used to scavenge scarcely soluble iron from the human or animal hosts. Strikingly, infamous human pathogenic bacteria like Yersinia pestis, the causative agent of devastating black death epidemics, completely lose their virulence in the absence of a siderophore.[2] Thus, knowledge of a pathogen s siderophore structures and of the corresponding biosynthetic machineries is considered a prerequisite for new therapeutic approaches such as targeting pathogenicity factors and Trojan horse strategies using siderophore–drug conjugates.[3] Over the past two decades, much research has been devoted to elucidating the siderophores of Burkholderia mallei and Burkholderia pseudomallei,[4–7] the causative agents of the infectious diseases glanders [8] and melioidosis.[9] Infections with these b-proteobacteria are often lethal, even with the best treatment available.[10] Both species have thus been categorized as potential biological warfare agents, and indeed B. mallei has been abused in World WarI to kill enemy horses and mules.[11, 12] Although it has long been known that B. pseudomallei and B. mallei produce two types of siderophores, pyochelin (1 and 2’’-epi-1, Figure 1) and malleobactin (2),[4] surprisingly, the structure of the latter has remained obscure. It was only a matter of speculation that malleobactin could be related to the ornibactins (3–5, Scheme1), hydroxamate siderophores produced by the Burkholderia cepacia complex (Bcc).[5, 6] Here we disclose the unusual structure and absolute configuration of malleobactin, the siderophore of the human pathogenic B. mallei family and reveal the biogenetic origin of an unprecedented aliphatic nitro amino acid. To gain first insights into the structural deviations of the encoded siderophores, we compared the gene loci for ornibactin and malleobactin biosynthesis.[6, 13] Both types of gene clusters share genes for a tetramodular nonribosomal peptide synthetase (NRPS) and accessory enzymes. Furthermore, genes for putative amino acid tailoring enzymes (ornithine monooxygenase,[14] aspartic acid b-hydroxylase,[15] N-formyltransferase [16]), siderophore receptors and transporters are present in both types of gene clusters. However, we noted that the gene loci in bacteria belonging to the B. mallei family harbor an additional gene for a hypothetical protein (mbaM), but lack orthologues of orbK and orbL (Figure 1 A, yellow open reading frames (orfs)). The latter genes code for acyltransferases, and although their biochemical function has not yet been studied, one may assume that they are required for loading acyl units onto the N-terminal ornithine residue.[13] We concluded that ornibactins and malleobactin differ in their substitution patterns.