title: Adenanthin targets proteins involved in the regulation of disulphide bonds.
abstract: Adenanthin has been recently shown to inhibit the enzymatic activities of peroxiredoxins (Prdx) I and II through its functional α,β-unsaturated ketone group serving as a Michael acceptor. A similar group is found in SK053, a compound recently developed by our group to target the thioredoxin-thioredoxin reductase (Trx-TrxR) system. This work provides evidence that next to Prdx I and II adenanthin targets additional proteins including thioredoxin-thioredoxin reductase system as well as protein disulfide isomerase (PDI) that contain a characteristic structural motif, referred to as a thioredoxin fold. Adenanthin inhibits the activity of Trx-TR system and PDI in vitro in the insulin reduction assay and decreases the activity of Trx in cultured cells. Moreover, we identified Trx-1 as an adenanthin binding protein in cells incubated with biotinylated adenanthin as an affinity probe. The results of our studies indicate that adenanthin is a mechanism-selective, rather than an enzyme-specific inhibitor of enzymes containing readily accessible, nucleophilic cysteines. This observation might be of importance in considering potential therapeutic applications of adenanthin to include a range of diseases, where aberrant activity of Prdx, Trx-TrxR and PDI is involved in their pathogenesis.
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Angelika
authors.initials: A
authors.lastname: Muchowicz
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Firczuk
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Chlebowska
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; Genomic Medicine, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Dominika
authors.initials: D
authors.lastname: Nowis
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Stachura
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Barankiewicz
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Trzeciecka
authors.affiliation: Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland.
authors.forename: Szymon
authors.initials: S
authors.lastname: Kłossowski
authors.affiliation: Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland.
authors.forename: Ryszard
authors.initials: R
authors.lastname: Ostaszewski
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Radosław
authors.initials: R
authors.lastname: Zagożdżon
authors.affiliation: Kunming Institute of Botany, Chinese Academy of Science, Kunming, China.
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Pu
authors.affiliation: Kunming Institute of Botany, Chinese Academy of Science, Kunming, China. Electronic address: hdsun@mail.kib.ac.cn.
authors.forename: Han-Dong
authors.initials: HD
authors.lastname: Sun
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; Institute of Physical Chemistry, Polish Academy of Sciences, Department 3, Warsaw, Poland. Electronic address: jakub.golab@wum.edu.pl.
authors.forename: Jakub
authors.initials: J
authors.lastname: Golab
mesh_terms: D045744:Cell Line, Tumor; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism*; D004224:Diterpenes / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D037602:Isodon; D035261:Plant Components, Aerial; D010936:Plant Extracts / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D013879:Thioredoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D004220:Disulfides; D004224:Diterpenes; D010936:Plant Extracts; C491203:TXN protein, human; C466222:adenanthin F; D013879:Thioredoxins
keywords: Adenanthin; Cancer; Peroxiredoxin; Protein disulphide isomerase; Thioredoxin