2. Academic Validation
  3. Activation of the NLRP3 Inflammasome by Hyaboron, a New Asymmetric Boron-Containing Macrodiolide from the Myxobacterium Hyalangium minutum

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

  • ACS Chem Biol. 2018 Oct 19;13(10):2981-2988. doi: 10.1021/acschembio.8b00659.
Frank Surup 1 2,  Dhruv Chauhan 3,  Jutta Niggemann 1,  Eva Bartok 4,  Jennifer Herrmann 5 2,  Matthias Keck 1,  Wiebke Zander 1,  Marc Stadler 1 2,  Veit Hornung 3 6,  Rolf Müller 1 5 2
Affiliations

Affiliations

  • 1 Department Microbial Drugs , Helmholtz Center for Infection Research (HZI) , Inhoffenstraße 7 , 38124 Braunschweig , Germany.
  • 2 German Centre for Infection Research (DZIF) , partner site Hannover-Braunschweig , Inhoffenstraße 7 , Braunschweig , 38124 , Germany.
  • 3 Gene Center and Department of Biochemistry , Ludwig-Maximilians-Universität München , Munich, Feodor-Lynen-Straße 25 , Munich , 81377 , Germany.
  • 4 Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital , University of Bonn , Sigmund-Freud-Straße 25 , Bonn , 53127 , Germany.
  • 5 Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research and Department of Pharmacy , Saarland University Campus , Building E8.1 , Saarbrücken , 66123 , Germany.
  • 6 Center for Integrated Protein Science (CIPSM) , Ludwig-Maximilians-Universität München, Munich , Feodor-Lynen-Straße 25 , Munich , 81377 , Germany.
PMID: 30183250 DOI: 10.1021/acschembio.8b00659
Abstract

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.

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