Hg(II) Coordination in Human Thioredoxin Reductase 1: Molecular Insights into Mercury Toxicity
Year: 2026
Type: preprint
Abstract: Thioredoxin reductase 1 (TrxR1) is an essential selenoprotein oxidoreductase and a sensitive molecular target of mercury, but the coordination chemistry underlying its inhibition by inorganic Hg(II) remains unknown. We use complementary Hg LIII-edge and Se K-edge X-ray absorption spectroscopy (XAS), high-energy-resolution fluorescence-detected XAS (HERFDXAS), and density functional theory (DFT) to determine the Hg(II) coordination environment in inhibited human TrxR1. Se K-edge EXAFS provides direct evidence for Hg(II) coordination to catalytic Sec498 in wild-type TrxR1, with a Se–Hg distance of 2.44 Å. Hg LIII-edge EXAFS indicates predominantly two-coordinate, near-digonal Se–Hg–S coordination, with Hg–Se and Hg–S distances of 2.43 and 2.37 Å, respectively. Replacement of Sec498 by cysteine or serine gives bis-thiolate Hg(SR)2 coordination, demonstrating that Sec498 is not essential for Hg(II) binding. Hg Lα1 HERFD-XAS independently supports two-coordinate Hg(II) and distinguishes mixed sulfur/selenium coordination in wild-type TrxR1 from the bis-thiolate U498C variant. DFT calculations show that coordination by the adjacent C-terminal Cys497/Sec498 pair and structures involving the N-terminal redox center are compatible with spectroscopy, but do not unambiguously distinguish their relative energies. In contrast, bis-thiolate coordination in U498S, which retains only Cys497 at the C-terminal redox center, supports recruitment of a cysteine from the N-terminal site. These results directly characterize inorganic Hg(II) binding to TrxR1 and demonstrate how the strong, adaptable chalcogen coordination chemistry of Hg(II) enables it to target the catalytic machinery of this essential cellular redox enzyme.
Source: ChemRxiv
Language: English
Subfield: Nutrition and Dietetics
Field: Nursing
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7221788928