Cyclic 5-membered disulfides are not selective substrates of thioredoxin reductase, but are opened nonspecifically.

Autor: Felber JG; Department of Pharmacy, Ludwig-Maximilians University Munich, Butenandtstr. 5-13, 81377, Munich, Germany., Poczka L; Department of Pharmacy, Ludwig-Maximilians University Munich, Butenandtstr. 5-13, 81377, Munich, Germany., Scholzen KC; Department of Medical Biochemistry, Karolinska Institutet, Solnavägen 9, 171 77, Stockholm, Sweden., Zeisel L; Department of Pharmacy, Ludwig-Maximilians University Munich, Butenandtstr. 5-13, 81377, Munich, Germany., Maier MS; Department of Pharmacy, Ludwig-Maximilians University Munich, Butenandtstr. 5-13, 81377, Munich, Germany., Busker S; Department of Medical Biochemistry, Karolinska Institutet, Solnavägen 9, 171 77, Stockholm, Sweden.; Pelago Bioscience AB, 171 48, Solna, Sweden., Theisen U; Zoological Institute, Cellular and Molecular Neurobiology, TU Braunschweig, Spielmannstr. 7, 38106, Braunschweig, Germany., Brandstädter C; Interdisciplinary Research Centre (IFZ), Justus-Liebig University Giessen, Heinrich-Buff-Ring 26-32, 35392, Giessen, Germany., Becker K; Interdisciplinary Research Centre (IFZ), Justus-Liebig University Giessen, Heinrich-Buff-Ring 26-32, 35392, Giessen, Germany., Arnér ESJ; Department of Medical Biochemistry, Karolinska Institutet, Solnavägen 9, 171 77, Stockholm, Sweden.; Department of Selenoprotein Research, National Institute of Oncology, 1122, Budapest, Hungary., Thorn-Seshold J; Department of Pharmacy, Ludwig-Maximilians University Munich, Butenandtstr. 5-13, 81377, Munich, Germany., Thorn-Seshold O; Department of Pharmacy, Ludwig-Maximilians University Munich, Butenandtstr. 5-13, 81377, Munich, Germany. oliver.thorn-seshold@cup.lmu.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Apr 01; Vol. 13 (1), pp. 1754. Date of Electronic Publication: 2022 Apr 01.
DOI: 10.1038/s41467-022-29136-4
Abstrakt: The cyclic five-membered disulfide 1,2-dithiolane has been widely used in chemical biology and in redox probes. Contradictory reports have described it either as nonspecifically reduced in cells, or else as a highly specific substrate for thioredoxin reductase (TrxR). Here we show that 1,2-dithiolane probes, such as "TRFS" probes, are nonspecifically reduced by thiol reductants and redox-active proteins, and their cellular performance is barely affected by TrxR inhibition or knockout. Therefore, results of cellular imaging or inhibitor screening using 1,2-dithiolanes should not be interpreted as reflecting TrxR activity, and previous studies may need re-evaluation. To understand 1,2-dithiolanes' complex behaviour, probe localisation, environment-dependent fluorescence, reduction-independent ring-opening polymerisation, and thiol-dependent cellular uptake must all be considered; particular caution is needed when co-applying thiophilic inhibitors. We present a general approach controlling against assay misinterpretation with reducible probes, to ensure future TrxR-targeted designs are robustly evaluated for selectivity, and to better orient future research.
(© 2022. The Author(s).)
Databáze: MEDLINE
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