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

Melleolides from Honey Mushroom Inhibit 5-Lipoxygenase via Cys159.

Author information

1
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743 Jena, Germany.
2
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 Frankfurt, Germany.
3
Department of Pharmaceutical Microbiology at the Hans Knöll Institute, Friedrich-Schiller-University Jena, 07745 Jena, Germany.
4
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743 Jena, Germany. Electronic address: oliver.werz@uni-jena.de.

Abstract

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 Experiments with 5-LO mutants, where select cysteines had been replaced by serine, indicated that the investigated melleolides suppress 5-LO product formation via two distinct modes of action: (1) by direct interference with 5-LO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

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