Michael acceptor containing drugs are a novel class of 5-lipoxygenase inhibitor targeting the surface cysteines C416 and C418
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...
| Autor Principal: | Piesche, Matthias |
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| Otros Autores: | Maucher, Isabelle V., Rühl, Michael, Kretschmer, Simon B.M., Hofmann, Bettina, Kühn, Benjamin, Fettel, Jasmin, Vogel, Anja, Flügel, Karsten T., Manolikakes, Georg, Hellmuth, Nadine, Häfner, Ann-Kathrin, Golghalyani, Vahid, Ball, Ann-Katrin, Matrone, Carmela, Geisslinger, Gerd, Parnham, Michael J., Karas, Michael, Steinhilber, Dieter, Roos, Jessica, Maier, Thorsten J. |
| Formato: | Artículo |
| Idioma: | English |
| Publicado: |
2017
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| Materias: | |
| Acceso en línea: |
http://repositorio.ucm.cl:8080/handle/ucm/124 |
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| Sumario: |
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. |
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