基于生物信息学分析从Streptomyces albofaciens JCM 4342中发现2,3-二羟基苯甲酸酯-L-丝氨酸脱水三聚体和二聚体天然产物

背景] 铁是细菌生长的基本元素，而三价铁在自然水环境中几乎无法溶解。细菌已经进化出产生各种铁载体的能力，以促进铁的吸收。对于链霉菌，其特有的铁载体是去铁胺，同时它们也可以产生其他结构的铁载体，如ceolichelin、白霉素、肠杆菌素（enterobactin）和griseobactin。目的] 揭示链霉菌中铁载体生物合成基因簇（Biosynthetic Gene Clusters，BGCs）的分布特点和基因簇特征，并探索其所合成铁载体的化合物结构。方法] 利用生物信息学工具系统地分析308个具有全基因组序列信息的链霉菌中的铁载体生物合成基因簇，并用色谱和波谱方法分离和表征肠杆菌素相关天然产物。结果] 发现Streptomyces albofaciens JCM 4342和其他少数菌株同时含有一个缺少2，3-二羟基苯甲酸（2，3-DHB）生物合成基因的孤立的肠杆菌素生物合成基因簇和另外一个推测可合成griseobactin的基因簇。从S.albofaciens JCM 4342发酵液中鉴定出4个肠杆菌素衍生的天然产物，包括链状2，3-二羟基苯甲酸酯-l-丝氨酸（2，3-DHBS）的三聚体和二聚体以及它们的脱水产物。结论] 2个基因簇间存在一种特别的协同生物合成机制。推测是griseobactin基因簇负责合成2，3-DHB，而孤立的肠杆菌素基因簇编码的生物合成酶可夺取该底物，进而完成上述4种肠杆菌素衍生天然产物的生物合成。

Bioinformatics-directed discovery of dehydrated linear trimer and dimer of 2,3-dihydroxybenzoyl-L-serine from Streptomyces albofaciens JCM 4342

Background] As an essential element for bacterial growth, iron in its ferric form is almost insoluble in aqueous environments. Bacteria have evolved to produce various siderophores to facilitate iron uptake. For Streptomyces, the characteristic siderophores are desferrioxamines, while they can also produce other structurally different siderophores, such as ceolichelin, albomycin, enterobactin, and griseobactin. Objective] We aimed to reveal the distribution and characteristic of siderophore biosynthetic gene clusters (BGCs), and to explore their product structures in streptomycetes. Methods] We systematically investigated the distribution and conservation of siderophore BGCs in 308 annotated Streptomyces genomes using bioinformatics tools. Chromatographic and spectroscopic methods were utilized to isolate and characterize the enterobactin-related natural products. Results] This enabled us to identify an orphan enterobactin BGC, which lacked genes encoding enzymes for the biosynthesis of 2,3-dihydroxybenzoic acid (2,3-DHB), together with a griseobactin BGC in Streptomyces albofaciens JCM 4342 and other strains. Four enterobactin-derived natural products, including linear trimer and dimer of 2,3-dihydroxybenzoyl-L-serine (2,3-DHBS), and their dehydrated products, were identified from S. albofaciens JCM 4342. Conclusion] These results suggested an interesting synergistic biosynthetic mechanism executed by the two BGCs. The orphan enterobactin BGC encoding enzymes hijacked the 2,3-DHB, which was biosynthesized by the griseobactin BGC, to complete biosynthesis of the four aforementioned enterobactin-related natural products.