Nitro-oleic acid, a novel and irreversible inhibitor of xanthine oxidoreductase.

Published

Journal Article

Xanthine oxidoreductase (XOR) generates proinflammatory oxidants and secondary nitrating species, with inhibition of XOR proving beneficial in a variety of disorders. Electrophilic nitrated fatty acid derivatives, such as nitro-oleic acid (OA-NO2), display anti-inflammatory effects with pleiotropic properties. Nitro-oleic acid inhibits XOR activity in a concentration-dependent manner with an IC50 of 0.6 microM, limiting both purine oxidation and formation of superoxide (O2.). Enzyme inhibition by OA-NO2 is not reversed by thiol reagents, including glutathione, beta-mercaptoethanol, and dithiothreitol. Structure-function studies indicate that the carboxylic acid moiety, nitration at the 9 or 10 olefinic carbon, and unsaturation is required for XOR inhibition. Enzyme turnover and competitive reactivation studies reveal inhibition of electron transfer reactions at the molybdenum cofactor accounts for OA-NO2-induced inhibition. Importantly, OA-NO2 more potently inhibits cell-associated XOR-dependent O2. production than does allopurinol. Combined, these data establish a novel role for OA-NO2 in the inhibition of XOR-derived oxidant formation.

Full Text

Duke Authors

Cited Authors

  • Kelley, EE; Batthyany, CI; Hundley, NJ; Woodcock, SR; Bonacci, G; Del Rio, JM; Schopfer, FJ; Lancaster, JR; Freeman, BA; Tarpey, MM

Published Date

  • December 26, 2008

Published In

Volume / Issue

  • 283 / 52

Start / End Page

  • 36176 - 36184

PubMed ID

  • 18974051

Pubmed Central ID

  • 18974051

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M802402200

Language

  • eng

Conference Location

  • United States