Helmholtz Institute for Pharmaceutical Research Saarland, Saarland University, 66123 Saarbruecken, Germany.
J Nat Prod. 2023 Oct 27;86(10):2258-2269. doi: 10.1021/acs.jnatprod.3c00097. Epub 2023 Sep 20.
Dereplication and genome mining in LU18118 combined with heterologous expression of selected biosynthetic gene clusters (BGCs) led to the discovery of various threonine-16:0dioic acids named lipothrenins. Lipothrenins consist of the core elements l-Thr, d--Thr, or Dhb, which are linked to hexadecanedioic acid by an amide bond. The main compound lipothrenin A () carries the -hydroxylated d- form of threonine and expresses a siderophore activity. The lipothrenin BGC was analyzed by a series of deletion experiments. As a result, a variety of interesting genes involved in the recruitment and selective activation of linear 16:0dioic acids, amide bond formation, and the epimerization of l-Thr were revealed. Furthermore, a diiron -oxygenase was identified that may be directly involved in the monooxygenation of the amide bond. This is divergent from the usual hydroxamate formation mechanism in siderophores, which involves hydroxylation of the free amine prior to amide bond formation. Siderophore activity was observed for all -hydroxylated lipothrenins by application of the CAS assay method.
去重复化和基因组挖掘 LU18118，并对选定的生物合成基因簇（BGCs）进行异源表达，导致了各种苏氨酸-16:0 二酸的发现，被命名为脂硫素。脂硫素由核心元素 l-Thr、d-Thr 或 Dhb 组成，通过酰胺键与十六烷二酸相连。主要化合物脂硫素 A () 携带 - 羟基化的 d- 形式的苏氨酸，并表现出铁载体活性。脂硫素 BGC 通过一系列缺失实验进行了分析。结果揭示了多种涉及线性 16:0 二酸的募集和选择性激活、酰胺键形成以及 l-Thr 的差向异构化的有趣基因。此外，鉴定了一种可能直接参与酰胺键单加氧的二铁 - 氧合酶。这与铁载体中通常的羟肟酸形成机制不同，后者涉及在酰胺键形成之前对游离胺进行羟化。通过应用 CAS 测定方法，观察到所有 - 羟基化的脂硫素都具有铁载体活性。
