Metals are important cofactors in the metabolic processes of cyanobacteria, including photosynthesis, cellular respiration, DNA replication, and the biosynthesis of primary and secondary metabolites. In adaptation to the marine environment, cyanobacteria use metallophores to acquire trace metals when necessary as well as to reduce potential toxicity from excessive metal concentrations. Leptochelins A–C were identified as structurally novel metallophores from three geographically dispersed cyanobacteria of the genus Leptothoe. Determination of the complex structures of these metabolites presented numerous challenges, but they were ultimately solved using integrated data from NMR, mass spectrometry and deductions from the biosynthetic gene cluster. The leptochelins are comprised of halogenated linear NRPS-PKS hybrid products with multiple heterocycles that have potential for hexadentate and tetradentate coordination with metal ions. The genomes of the three leptochelin producers were sequenced, and retrobiosynthetic analysis revealed one candidate biosynthetic gene cluster (BGC) consistent with the structure of leptochelin. The putative BGC is highly homologous in all three Leptothoe strains, and all possess genetic signatures associated with metallophores. Postcolumn infusion of metals using an LC-MS metabolomics workflow performed with leptochelins A and B revealed promiscuous binding of iron, copper, cobalt, and zinc, with greatest preference for copper. Iron depletion and copper toxicity experiments support the hypothesis that leptochelin metallophores may play key ecological roles in iron acquisition and in copper detoxification. In addition, the leptochelins possess significant cytotoxicity against several cancer cell lines.

中文翻译：

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Leptochelins A–C，由地理分散的海洋蓝藻细藻菌株产生的细胞毒性金属载体


金属是蓝细菌代谢过程中的重要辅助因子，包括光合作用、细胞呼吸、DNA复制以及初级和次级代谢物的生物合成。为了适应海洋环境，蓝藻在必要时使用金属载体来获取微量金属，并减少金属浓度过高的潜在毒性。 Leptochelins A–C 被鉴定为结构新颖的金属载体，来自三种地理上分散的细藻属蓝细菌。确定这些代谢物的复杂结构提出了许多挑战，但最终利用核磁共振、质谱分析和生物合成基因簇推论的综合数据解决了这些问题。轻螯素由卤化线性 NRPS-PKS 杂化产物组成，具有多个杂环，具有与金属离子进行六齿和四齿配位的潜力。对三种细螯素生产者的基因组进行了测序，逆转录生物合成分析揭示了一个与细螯素结构一致的候选生物合成基因簇（BGC）。假定的 BGC 在所有三种细毛菌菌株中都高度同源，并且都具有与金属载体相关的遗传特征。使用轻螯素 A 和 B 进行的 LC-MS 代谢组学工作流程进行的柱后金属注入显示铁、铜、钴和锌的混杂结合，其中铜的结合最为优先。铁消耗和铜毒性实验支持这样的假设：细螯素金属载体可能在铁获取和铜解毒中发挥关键的生态作用。此外，leptochelins 对多种癌细胞系具有显着的细胞毒性。