Activation of the NLRP3 Inflammasome by Hyaboron, a New Asymmetric Boron-Containing Macrodiolide from the Myxobacterium Hyalangium minutum,ACS Chemical Biology

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Activation of the NLRP3 Inflammasome by Hyaboron, a New Asymmetric Boron-Containing Macrodiolide from the Myxobacterium Hyalangium minutum
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-09-05 00:00:00 , DOI: 10.1021/acschembio.8b00659
Frank Surup _{1,

2} , Dhruv Chauhan ₃ , Jutta Niggemann ₁ , Eva Bartok ₄ , Jennifer Herrmann _{2,

5} , Matthias Keck ₁ , Wiebke Zander ₁ , Marc Stadler _{1,

2} , Veit Hornung _{3,

6} , Rolf Müller _{1,

2,

5}

Affiliation

A Natural Compound Library containing myxobacterial secondary metabolites was screened in murine macrophages for novel activators of IL-1β maturation and secretion. The most potent of three hits in total was a so far undescribed metabolite, which was identified from the myxobacterium Hyalangium minutum strain Hym3. While the planar structure of 1 was elucidated by high resolution mass spectrometry and NMR data yielding an asymmetric boron containing a macrodiolide core structure, its relative stereochemistry of all 20 stereocenters of the 42-membered ring was assigned by rotating frame Overhause effect spectroscopy correlations, ¹H,¹H, and ¹H,¹³C coupling constants, and by comparison of ¹³C chemical shifts to those of the structurally related metabolites tartrolon B-D. The absolute stereochemistry was subsequently assigned by Mosher’s and Marfey’s methods. Further functional studies revealed that hyaboron and other boronated natural compounds resulted in NLRP3 inflammasome dependent IL-1β maturation, which is most likely due to their ability to act as potassium ionophores. Moreover, besides its inflammasome-stimulatory activity in human and mouse cells, hyaboron (1) showed additional diverse biological activities, including antibacterial and antiparasitic effects.

中文翻译：

Hyaboron，一种新的不对称的含硼透明质酸杆菌的不对称含硼大环内酯对NLRP3炎性体的激活

在小鼠巨噬细胞中筛选了含有黏细菌次生代谢产物的天然化合物文库，以寻找IL-1β成熟和分泌的新型激活剂。总共三个命中最有力的是迄今为止从未描述的代谢物，该代谢物是从粘杆菌透明质酸菌Hym3菌株中鉴定出来的。通过高分辨率质谱法和NMR数据阐明了1的平面结构，得到了一个不对称的含大环糊精核心结构的硼，但通过旋转框架Overhause效应光谱相关性，确定了其42个环的全部20个立体中心的相对立体化学，¹ H，¹ H和¹ H，¹³C耦合常数，并通过¹³ C化学位移与结构相关代谢物tartrolon BD的化学位移进行比较。随后通过Mosher和Marfey的方法确定了绝对立体化学。进一步的功能研究表明，hyaboron和其他含硼天然化合物导致NLRP3炎性体依赖的IL-1β成熟，这很可能是由于它们具有钾离子载体的功能。此外，除了其在人和小鼠细胞中的炎性体刺激活性外，hyaboron（1）还表现出其他多种生物活性，包括抗菌和抗寄生虫作用。

更新日期：2018-09-05

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