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

Jan G. Felber, Lena Poczka, Karoline C. Scholzen, Lukas Zeisel, Martin S. Maier, Sander Busker, Ulrike Theisen, Christina Brandstädter, Katja Becker, Elias S. J. Arnér, Julia Thorn-Seshold and Oliver Thorn-Seshold ()
Additional contact information
Jan G. Felber: Ludwig-Maximilians University Munich
Lena Poczka: Ludwig-Maximilians University Munich
Karoline C. Scholzen: Karolinska Institutet
Lukas Zeisel: Ludwig-Maximilians University Munich
Martin S. Maier: Ludwig-Maximilians University Munich
Sander Busker: Karolinska Institutet
Ulrike Theisen: Cellular and Molecular Neurobiology, TU Braunschweig
Christina Brandstädter: Justus-Liebig University Giessen
Katja Becker: Justus-Liebig University Giessen
Elias S. J. Arnér: Karolinska Institutet
Julia Thorn-Seshold: Ludwig-Maximilians University Munich
Oliver Thorn-Seshold: Ludwig-Maximilians University Munich

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-29136-4

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