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Cyclic 5-membered disulfides are not selective substrates of thioredoxin reductase, but are opened nonspecifically.
Felber, Jan G; Poczka, Lena; Scholzen, Karoline C; Zeisel, Lukas; Maier, Martin S; Busker, Sander; Theisen, Ulrike; Brandstädter, Christina; Becker, Katja; Arnér, Elias S J; Thorn-Seshold, Julia; Thorn-Seshold, Oliver.
Afiliación
  • Felber JG; Department of Pharmacy, Ludwig-Maximilians University Munich, Butenandtstr. 5-13, 81377, Munich, Germany.
  • Poczka L; Department of Pharmacy, Ludwig-Maximilians University Munich, Butenandtstr. 5-13, 81377, Munich, Germany.
  • Scholzen KC; Department of Medical Biochemistry, Karolinska Institutet, Solnavägen 9, 171 77, Stockholm, Sweden.
  • Zeisel L; Department of Pharmacy, Ludwig-Maximilians University Munich, Butenandtstr. 5-13, 81377, Munich, Germany.
  • Maier MS; Department of Pharmacy, Ludwig-Maximilians University Munich, Butenandtstr. 5-13, 81377, Munich, Germany.
  • Busker S; Department of Medical Biochemistry, Karolinska Institutet, Solnavägen 9, 171 77, Stockholm, Sweden.
  • Theisen U; Pelago Bioscience AB, 171 48, Solna, Sweden.
  • Brandstädter C; Zoological Institute, Cellular and Molecular Neurobiology, TU Braunschweig, Spielmannstr. 7, 38106, Braunschweig, Germany.
  • Becker K; Interdisciplinary Research Centre (IFZ), Justus-Liebig University Giessen, Heinrich-Buff-Ring 26-32, 35392, Giessen, Germany.
  • Arnér ESJ; Interdisciplinary Research Centre (IFZ), Justus-Liebig University Giessen, Heinrich-Buff-Ring 26-32, 35392, Giessen, Germany.
  • Thorn-Seshold J; Department of Medical Biochemistry, Karolinska Institutet, Solnavägen 9, 171 77, Stockholm, Sweden.
  • Thorn-Seshold O; Department of Selenoprotein Research, National Institute of Oncology, 1122, Budapest, Hungary.
Nat Commun ; 13(1): 1754, 2022 04 01.
Article en En | MEDLINE | ID: mdl-35365603
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Reductasa de Tiorredoxina-Disulfuro / Disulfuros Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Reductasa de Tiorredoxina-Disulfuro / Disulfuros Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido