Melleolides from Honey Mushroom Inhibit 5-Lipoxygenase via Cys159

Cell Chem Biol. 2019 Jan 17;26(1):60-70.e4. doi: 10.1016/j.chembiol.2018.10.010. Epub 2018 Nov 8.


5-Lipoxygenase (5-LO) initiates the biosynthesis of pro-inflammatory leukotrienes from arachidonic acid, which requires the nuclear membrane-bound 5-LO-activating protein (FLAP) for substrate transfer. Here, we identified human 5-LO as a molecular target of melleolides from honey mushroom (Armillaria mellea). Melleolides inhibit 5-LO via an α,β-unsaturated aldehyde serving as Michael acceptor for surface cysteines at the substrate entrance that are revealed as molecular determinants for 5-LO activity. Experiments with 5-LO mutants, where select cysteines had been replaced by serine, indicated that the investigated melleolides suppress 5-LO product formation via two distinct modes of action: (1) by direct interference with 5-LO activity involving two or more of the cysteines 159, 300, 416, and 418, and (2) by preventing 5-LO/FLAP assemblies involving selectively Cys159 in 5-LO. Interestingly, replacement of Cys159 by serine prevented 5-LO/FLAP assemblies as well, implying Cys159 as determinant for 5-LO/FLAP complex formation at the nuclear membrane required for leukotriene biosynthesis.

Keywords: 5-lipoxygenase; 5-lipoxygenase-activating protein; Michael acceptor; leukotriene; melleolide; natural products.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Armillaria / chemistry*
  • Cysteine / metabolism*
  • Dose-Response Relationship, Drug
  • Humans
  • Lipoxygenase Inhibitors / chemistry
  • Lipoxygenase Inhibitors / pharmacology*
  • Molecular Structure
  • Sesquiterpenes / chemistry
  • Sesquiterpenes / pharmacology*
  • Structure-Activity Relationship


  • Lipoxygenase Inhibitors
  • Sesquiterpenes
  • Arachidonate 5-Lipoxygenase
  • Cysteine