Article ; Online: Cyclic 5-membered disulfides are not selective substrates of thioredoxin reductase, but are opened nonspecifically.
2022 Volume 13, Issue 1, Page(s) 1754
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 ... ...
| 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. |
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| MeSH term(s) | Disulfides/metabolism ; Fluorescence ; Oxidation-Reduction ; Thioredoxin-Disulfide Reductase/metabolism |
| Chemical Substances | Disulfides ; Thioredoxin-Disulfide Reductase (EC 1.8.1.9) |
| Language | English |
| Publishing date | 2022-04-01 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2553671-0 |
| ISSN | 2041-1723 ; 2041-1723 |
| ISSN (online) | 2041-1723 |
| ISSN | 2041-1723 |
| DOI | 10.1038/s41467-022-29136-4 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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