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

24 December 2020, Version 1


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.


disulfide moiety
redox activity
redox biology
redox biochemistry
probe candidate drug targets
Thioredoxin Reductase Inhibitors
thioredoxin reductase activity
thioredoxin reductase
Thioredoxin Redox Properties
thioredoxin superfamily enzymes
dithiolane groups
dithiolane-containing polymers
dithiolane-containing cyclic carbon...
Dithiolane Containing Amino

Supplementary materials

Felber (Thorn-Seshold) - Cyclic 5-membered disulfides are not selective substrates for TrxR - Supp v4.41


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