These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
2 files

Cyclic 5-Membered Disulfides Are Not Selective Substrates of Thioredoxin Reductase, but Are Opened Nonspecifically by Thiols

submitted on 23.12.2020, 14:18 and posted on 24.12.2020, 06:48 by Jan Felber, Lena Poczka, Sander Busker, Ulrike Theisen, Lukas Zeisel, Martin S. Maier, Kristina Loy, Christina Brandstädter, Karoline Scholzen, Katja Becker, Elias Arnér, Julia Ahlfeld, Oliver Thorn-Seshold

The cyclic five-membered disulfide 1,2-dithiolane has been used as the key element in numerous chemical biology probes. Contradictory views of this disulfide motif populate the literature: some reports describe it as being nonspecifically reduced, others as a highly specific substrate for thioredoxin reductase (TrxR). We show that 1,2-dithiolanes are nonspecifically reduced by a broad range of thiol reductants and redox-active proteins, and that their cellular performance is barely affected by TrxR inhibition or knockout. We conclude that inhibitor screenings and probe designs treating 1,2-dithiolanes as TrxR-selective substrates should be treated with caution and previous interpretations may need careful re-evaluation. Considering ring-opening polymerisation, and stringently interpreting assays involving the thiophilic gold-based inhibitor auranofin, are critical to assess 1,2-dithiolane’s true behaviour. We present an approach to control against assay misinterpretation with reducible probes, to ensure that future TrxR-targeted designs are robustly evaluated for selectivity, and to better orient redox probe research in the future.


Email Address of Submitting Author


Ludwig-Maximilians University Munich



ORCID For Submitting Author


Declaration of Conflict of Interest

no conflict of interest

Version Notes

version 4.41