The Oxidation of Selenocysteine Is Involved in the Inactivation of Glutathione Peroxidase by Nitric Oxide Donor
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Glutathione peroxidase (GPx) was inactivated by S-nitroso-N-acetyl-D, L-penicillamine (SNAP), a nitric oxide donor (Asahi, M., Fujii, J., Suzuki, K., Seo, H. G., Kuzuya, T., Hori, M., Tada, M., Fujii, S., and Taniguchi, N. (1995) J. Biol. Chem. 270, 21035-21039). The structural basis of the inactivation was studied. We also show that 3-morpholinosydnonimine N-ethylcarbamide, a peroxynitrite precursor, as well as synthetic peroxynitrite also inactivated bovine GPx. The degree of incorporation of a sulfhydryl reagent, n-octyldithionitrobenzoic acid, into GPx decreased after pretreatment with SNAP as evidenced by mass spectrometry. To identify the modification site of this enzyme by SNAP, both SNAP-pretreated and untreated GPxs were reacted with n-octyldithionitrobenzoic acid and digested with lysylendopeptidase, and the resulting peptides were subjected to mass spectrometry. This technique identified a bridge between two peptides, one of which contains Sec45 at the catalytic center and Cys74, and the other contains Cys91. Although there are two possible combinations, selenocysteine 45 (Sec45) and Cys91 or Cys74 and Cys91, the tertiary structure of GPx indicates that a cross-link between Sec45 and Cys91 is more feasible. This is consistent with the experimental evidence that SNAP specifically inactivates GPx, in which Sec45 forms the catalytic center. Thus, we conclude that SNAP mainly oxidized Sec45 to form a selenenyl sulfide (Se-S) with a free thiol, leading to the inactivation of the enzyme. These data suggest that nitric oxide and its derivatives directly inactivate GPx in a specific manner via the production of a selenenyl sulfide, resulting in an increase in intracellular peroxides that are responsible for cellular damage.
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The redox-active selenocysteine site may also be a target for other free radical-mediated reactions, forming Se-NO in the presence of nitric oxide.
“The redox-active Sec site may also be a target for other free radical-mediated reactions, forming Se-NO in the presence of NO· (19, 20).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [20]
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- Authors
- Asahi, M., Fujii, J., Takao, T., Kuzuya, T., Hori, M., Shimonishi, Y., & Taniguchi, N.
- Affiliations
- The University of Osaka (JP)
- Institute for Protein Research, The University of Osaka (JP)
- Corresponding author
- Taniguchi, Naoyuki
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1997-08
- Volume
- 272
- Issue
- 31
- Pages
- 19152-19157
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1966593481
- Cited by
- 122
- References
- 48
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 1 · 2020: 2 · 2019: 4 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 2 · 2014: 3 · 2013: 5 · 2012: 4
- FWCI
- 3.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Japan Foundation for Aging and Health
- Institute for Protein Research, Osaka University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Organoselenium and organotellurium chemistry
- Keywords
- glutathione peroxidase, nitric oxide donors, enzyme inactivation, peroxynitrite, sulfhydryl modification, catalytic site
- MeSH terms
- Amino Acid Sequence, Glutathione Peroxidase, Molecular Sequence Data, Molsidomine, Nitrates, Nitric Oxide, Nitroprusside, Oxidation-Reduction, Apoptosis, Selenocysteine
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