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Melleolides from Honey Mushroom Inhibit 5-Lipoxygenase via Cys159

: König, S.; Romp, E.; Krauth, V.; Rühl, M.; Dörfer, M.; Liening, S.; Hofmann, B.; Häfner, A.-K.; Steinhilber, D.; Karas, M.; Garscha, U.; Hoffmeister, D.; Werz, O.


Cell chemical biology 26 (2019), Nr.1, S.60-70
ISSN: 2451-9456
Fraunhofer IME ()

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 Experiments with 5-LO mutants, where select cysteines had been replaced by serine, indicated that the investigated melleolides suppress 5-LO product formation via two distinct modes of action: (1) by direct interference with 5-LO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