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Michael acceptor containing drugs are a novel class of 5-lipoxygenase inhibitor targeting the surface cysteines C416 and C418

: Maucher, I.V.; Rühl, M.; Kretschmer, S.B.M.; Hofmann, B.; Kühn, B.; Fettel, J.; Vogel, A.; Flügel, K.-T.; Manolikakes, G.; Hellmuth, N.; Häfner, A.-K.; Golghalyani, V.; Ball, A.K.; Piesche, M.; Matrone, C.; Geisslinger, G.; Parnham, M.J.; Karas, M.; Steinhilber, D.; Roos, J.; Maier, T.J.


Biochemical pharmacology 125 (2017), pp.55-74
ISSN: 0006-2952
ISSN: 1873-2968
Deutsche Forschungsgemeinschaft DFG
Journal Article
Fraunhofer IME ()

Recently, we published that nitro-fatty acids (NFA) are potent electrophilic molecules which inhibit 5-lipoxygenase (5-LO) by interacting catalytically with cysteine residues next to a substrate entry channel. The electrophilicity is derived from an intramolecular Michael acceptor moiety consisting of an electron-withdrawing group in close proximity to a double bond. The potential of the Michael acceptor moiety to interact with functionally relevant cysteines of proteins potentially renders them effective and sustained enzyme activity modulators. We screened a large library of naturally derived and synthetic electrophilic compounds to investigate whether other types of Michael acceptor containing drugs suppress 5-LO enzyme activity. The activity was measured by assessing the effect on the 5-LO product formation of intact human polymorphonuclear leukocytes. We demonstrated that a number of structurally different compounds were suppressive in the activity assays and showed that Michael acceptors of the quinone and nitro-alkene group produced the strongest inhibition of 5-LO product formation. Reactivity with the catalytically relevant cysteines 416 and 418 was confirmed using mutated recombinant 5-LO and mass spectrometric analysis (MALDI-MS). In the present study, we show for the first time that a number of well-recognized naturally occurring or synthetic anti-inflammatory compounds carrying a Michael acceptor, such as thymoquinone (TQ), the paracetamol metabolite NAPQI, the 5-LO inhibitor AA-861, and bardoxolone methyl (also known as RTA 402 or CDDO-methyl ester) are direct covalent 5-LO enzyme inhibitors that target the catalytically relevant cysteines 416 and 418.