Conjugation of urate-derived electrophiles to proteins during normal metabolism and inflammation.

Autor: Turner R; From the Centre for Free Radical Research.; the Department of Pathology and Biomedical Science., Brennan SO; the Department of Pathology and Biomedical Science., Ashby LV; From the Centre for Free Radical Research.; the Department of Pathology and Biomedical Science., Dickerhof N; From the Centre for Free Radical Research.; the Department of Pathology and Biomedical Science., Hamzah MR; From the Centre for Free Radical Research.; the Department of Pathology and Biomedical Science., Pearson JF; the Biostatistics and Computational Biology Unit, and., Stamp LK; the Department of Medicine, University of Otago Christchurch, P.O. Box 4345, Christchurch 8011, New Zealand., Kettle AJ; From the Centre for Free Radical Research, tony.kettle@otago.ac.nz.; the Department of Pathology and Biomedical Science.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2018 Dec 21; Vol. 293 (51), pp. 19886-19898. Date of Electronic Publication: 2018 Nov 01.
DOI: 10.1074/jbc.RA118.005237
Abstrakt: Urate is often viewed as an antioxidant. Here, we present an alternative perspective by showing that, when oxidized, urate propagates oxidative stress. Oxidation converts urate to the urate radical and the electrophilic products dehydrourate, 5-hydroxyisourate, and urate hydroperoxide, which eventually break down to allantoin. We investigated whether urate-derived electrophiles are intercepted by nucleophilic amino acid residues to form stable adducts on proteins. When urate was oxidized in the presence of various peptides and proteins, two adducts derived from urate ( M r 167 Da) were detected and had mass additions of 140 and 166 Da, occurring mainly on lysine residues and N-terminal amines. The adduct with a 140-Da mass addition was detected more frequently and was stable. Dehydrourate ( M r 166 Da) also formed transient adducts with cysteine residues. Urate-derived adducts were detected on human serum albumin in plasma of healthy donors. Basal adduct levels increased when neutrophils were added to plasma and stimulated, and relied on the NADPH oxidase, myeloperoxidase, hydrogen peroxide, and superoxide. Adducts of oxidized urate on serum albumin were elevated in plasma and synovial fluid from individuals with gout and rheumatoid arthritis. We propose that rather than acting as an antioxidant, urate's conversion to electrophiles contributes to oxidative stress. The addition of urate-derived electrophiles to nucleophilic amino acid residues, a process we call oxidative uratylation, will leave a footprint on proteins that could alter their function when critical sites are modified.
(© 2018 Turner et al.)
Databáze: MEDLINE
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