{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Geological Sciences, University of Saskatchewan, 114 Science Place, Saskatoon, Saskatchewan, Canada, S7N 5E2",
    "Canadian Light Source, University of Saskatchewan, 44 Innovation Blvd, Saskatoon, Saskatchewan, Canada, S7N 2V3",
    "Stanford Synchrotron Radiation Lightsource",
    "Stanford University",
    "Toxicology Centre",
    "University of Saskatchewan"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Emerita Mendoza Rengifo"
    },
    {
      "affs": [
        0
      ],
      "name": "Clinton Kidman"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Linda I. Vogt"
    },
    {
      "affs": [
        0
      ],
      "name": "Julien J. H. Cotelesage"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Thomas Kroll"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Dimosthenis Sokaras"
    },
    {
      "name": "Qing Cheng"
    },
    {
      "name": "Elias S. J. Arnér"
    },
    {
      "affs": [
        0,
        4,
        5
      ],
      "name": "Graham N. George",
      "orcid": "0000-0002-0420-7493"
    },
    {
      "affs": [
        0,
        1,
        4,
        5
      ],
      "name": "Ingrid J. Pickering"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e0ytcj57qdrf2.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15010443/v1",
  "fulltext_url": null,
  "id": "e0ytcj57qdrf2",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010443/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Redox biology and oxidative stress"
    ]
  ],
  "openalex": "W7221806363",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15010443/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-14",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/e0ytcj57qdrf2.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:24Z",
      "native_id": "10.26434/chemrxiv.15010443",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010443/v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Redox biology and oxidative stress",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Arsenite (Trisenox) Bridges the Redox Centers of Thioredoxin Reductase",
  "title_text": "Arsenite (Trisenox) Bridges the Redox Centers of Thioredoxin Reductase",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:24Z",
  "url": "https://research.draconitic.com/paper/e0ytcj57qdrf2",
  "venue": "ChemRxiv",
  "versions": []
}