Cyclic 5-membered disulfides are not selective substrates of thioredoxin reductase, but are opened nonspecifically.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
01 04 2022
01 04 2022
Historique:
received:
12
01
2021
accepted:
01
03
2022
entrez:
2
4
2022
pubmed:
3
4
2022
medline:
6
4
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35365603
doi: 10.1038/s41467-022-29136-4
pii: 10.1038/s41467-022-29136-4
pmc: PMC8975869
doi:
Substances chimiques
Disulfides
0
Thioredoxin-Disulfide Reductase
EC 1.8.1.9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1754Informations de copyright
© 2022. The Author(s).
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