Arsenite (Trisenox) Bridges the Redox Centers of Thioredoxin Reductase
6 affiliations
- 1Department of Geological Sciences, University of Saskatchewan, 114 Science Place, Saskatoon, Saskatchewan, Canada, S7N 5E2
- 2Canadian Light Source, University of Saskatchewan, 44 Innovation Blvd, Saskatoon, Saskatchewan, Canada, S7N 2V3
- 3Stanford Synchrotron Radiation Lightsource
- 4Stanford University
- 5Toxicology Centre
- 6University of Saskatchewan
Abstract
Arsenic trioxide (Trisenox) is an effective treatment for acute promyelocytic leukemia and is being explored for broader anticancer applications, yet our understanding of the molecular basis of its anticancer activity remains incomplete. Under physiological conditions arsenic trioxide forms arsenite, As(OH)3, which has been proposed to target the thioredoxin system. Here, we investigate the structural basis of arsenite interaction with mammalian thioredoxin reductase 1 (TrxR1, TXNRD1), a flavoenzyme selenoprotein essential for maintaining cellular redox homeostasis. Arsenic and selenium K-edge X-ray absorption spectroscopy, including highenergy resolution fluorescence detected (HERFD)-XAS, were combined with site-directed mutagenesis and density functional theory calculations. Wild-type TrxR1 forms a well-defined As(SeR)(SR)2 coordination environment in which arsenite binds the catalytic selenocysteine residue Sec498 and bridges the C-terminal and N-terminal redox centers of the enzyme. Replacement of Sec498 by cysteine yields an As(OH)(SR)2 species, whereas substitution by serine abolishes detectable binding. These results provide the first direct structural characterization of arsenite bound to TrxR1 and reveal a mechanism by which arsenite inhibits catalysis through crosslinking of the enzyme's redox centers. The findings establish a molecular basis for targeting of the thioredoxin system by arsenic trioxide and provide new insight into the chemistry underlying its anticancer activity.
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BibTeX
@misc{rengifo2026arsenite,
title = {{Arsenite (Trisenox) Bridges the Redox Centers of Thioredoxin Reductase}},
author = {Emerita Mendoza Rengifo and Clinton Kidman and Linda I. Vogt and Julien J. H. Cotelesage and Thomas Kroll and Dimosthenis Sokaras and Qing Cheng and Elias S. J. Arnér and Graham N. George and Ingrid J. Pickering},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010443/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010443/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Arsenite (Trisenox) Bridges the Redox Centers of Thioredoxin Reductase
AU - Emerita Mendoza Rengifo
AU - Clinton Kidman
AU - Linda I. Vogt
AU - Julien J. H. Cotelesage
AU - Thomas Kroll
AU - Dimosthenis Sokaras
AU - Qing Cheng
AU - Elias S. J. Arnér
AU - Graham N. George
AU - Ingrid J. Pickering
PY - 2026
DA - 2026/10/14
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010443/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010443/v1
AB - Arsenic trioxide (Trisenox) is an effective treatment for acute promyelocytic leukemia and is being explored for broader anticancer applications, yet our understanding of the molecular basis of its anticancer activity remains incomplete. Under physiological conditions arsenic trioxide forms arsenite, As(OH)3, which has been proposed to target the thioredoxin system. Here, we investigate the structural basis of arsenite interaction with mammalian thioredoxin reductase 1 (TrxR1, TXNRD1), a flavoenzyme selenoprotein essential for maintaining cellular redox homeostasis. Arsenic and selenium K-edge X-ray absorption spectroscopy, including highenergy resolution fluorescence detected (HERFD)-XAS, were combined with site-directed mutagenesis and density functional theory calculations. Wild-type TrxR1 forms a well-defined As(SeR)(SR)2 coordination environment in which arsenite binds the catalytic selenocysteine residue Sec498 and bridges the C-terminal and N-terminal redox centers of the enzyme. Replacement of Sec498 by cysteine yields an As(OH)(SR)2 species, whereas substitution by serine abolishes detectable binding. These results provide the first direct structural characterization of arsenite bound to TrxR1 and reveal a mechanism by which arsenite inhibits catalysis through crosslinking of the enzyme's redox centers. The findings establish a molecular basis for targeting of the thioredoxin system by arsenic trioxide and provide new insight into the chemistry underlying its anticancer activity.
ER -