Direct Observation of Methylmercury and Auranofin Binding to Selenocysteine in Thioredoxin Reductase

Pickering, Ingrid J.; Cheng, Qing; Rengifo, Emérita Mendoza; Nehzati, Susan; Dolgova, Natalia V.; Kroll, Thomas; Sokaras, Dimosthenis; George, Graham N.; Arnér, Elias S.  J.

doi:10.1021/acs.inorgchem.9b03072

Direct Observation of Methylmercury and Auranofin Binding to Selenocysteine in Thioredoxin Reductase

Journal Article · Wed Feb 12 00:00:00 EST 2020 · Inorganic Chemistry

DOI:https://doi.org/10.1021/acs.inorgchem.9b03072· OSTI ID:1617012

^[1]; ^[2]; Rengifo, Emérita Mendoza ^[1]; ^[1]; ^[1]; Kroll, Thomas ^[3]; Sokaras, Dimosthenis ^[3]; ^[1]; ^[2]

Univ. of Saskatchewan, Saskatoon, SK (Canada)
Karolinska Inst., Stockholm (Sweden)
SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

Selenoenzymes, containing a selenocysteine (Sec) residue, fulfill important roles in biology. The mammalian thioredoxin reductase selenoenzymes are key regulators of antioxidant defense and redox signaling and are inhibited by methylmercury species and by the gold-containing drug auranofin. It has been proposed that such inhibition is mediated by metal binding to Sec in the enzyme. However, direct structural observations of these classes of inhibitors binding to selenoenzymes have been few to date. Here we therefore have used extended X-ray absorption fine structure as a direct structural probe to investigate binding to the selenium site in recombinant rat thioredoxin reductase 1 (TrxR1). The results demonstrate for the first time the direct and complete binding of the metal atom of the inhibitors to the selenium atom in TrxR1 for both methylmercury and auranofin, indicating that TrxR1 inhibition indeed can be attributed to such direct metal–selenium binding.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1617012

Journal Information:: Inorganic Chemistry, Journal Name: Inorganic Chemistry Journal Issue: 5 Vol. 59; ISSN 0020-1669

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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