Inactivation of NF-kappaB components by covalent binding of (-)-dehydroxymethylepoxyquinomicin to specific cysteine residues

Journal of Medicinal Chemistry
Mizuki YamamotoKazuo Umezawa

Abstract

Previously, we designed and synthesized a potent NF-kappaB inhibitor, DHMEQ. Although DHMEQ showed potent anti-inflammatory and anticancer activities in animals, its molecular target has not been elucidated. In the present study, its target protein was found to be p65 and other Rel homology proteins. We found that (-)-DHMEQ bound to p65 covalently with a 1:1 stoichiometry by conducting SPR and MALDI-TOF MS analyses. MS analysis of the chymotrypsin-digested peptide suggested the binding of (-)-DHMEQ to a Cys residue. Formation of Cys/(-)-DHMEQ adduct in the protein was supported by chemical synthesis of the adduct. Substitution of specific Cys in p65 and other Rel homology proteins resulted in the loss of (-)-DHMEQ binding. (-)-DHMEQ is the first NF-kappaB inhibitor that was proven to bind to the specific Cys by chemical methodology. These findings may explain the highly selective inhibition of NF-kappaB and the low toxic effect of (-)-DHMEQ in cells and animals.

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Citations

Jun 1, 2011·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·Masatoshi TakeiriKazuo Umezawa
Oct 17, 2009·The Journal of Antibiotics·Takao Kataoka
Dec 13, 2012·The Journal of Antibiotics·Yuhei AraiKazuo Umezawa
Jul 23, 2014·PloS One·Mamoru KamoshitaKazuo Tsubota
Dec 1, 2009·Future Medicinal Chemistry·Samedy OukHsiou-Chi Liou
Dec 27, 2013·Chemical & Pharmaceutical Bulletin·Eiko YasuiShinji Nagumo
Aug 17, 2014·Advances in Biological Regulation·Tamami Ukaji, Kazuo Umezawa
Feb 14, 2012·Journal of Crohn's & Colitis·Tohru FunakoshiSatoru Todo
Mar 5, 2013·Biochemical and Biophysical Research Communications·Akira OgasawaraKazuo Umezawa
Jan 19, 2016·Chemico-biological Interactions·C B Rajashekar ReddyArumugam Sivakumar
Sep 18, 2009·Annals of the New York Academy of Sciences·Tetsuo KubotaKazuo Umezawa
Dec 18, 2009·Journal of Molecular Recognition : JMR·Rebecca L Rich, David G Myszka
Mar 13, 2014·TheScientificWorldJournal·Magdy El-SalhyTrygve Hausken
Dec 24, 2008·Biochemical and Biophysical Research Communications·Eriko SuzukiKazuo Umezawa
Sep 26, 2009·Biochemical and Biophysical Research Communications·Tomiteru ToganoRyouichi Horie
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Mar 8, 2012·Organic & Biomolecular Chemistry·Masatoshi TakeiriKazuo Umezawa
Jul 7, 2019·Cancers·Maike Kober-Hasslacher, Marc Schmidt-Supprian
Dec 27, 2013·Journal of Clinical and Experimental Hematopathology : JCEH·Ryouichi Horie

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