Nitro-oleic Acid, a Novel and Irreversible Inhibitor of Xanthine Oxidoreductase
Nitro-oleic Acid, a Novel and Irreversible Inhibitor of Xanthine Oxidoreductase
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DOI：
10.1074/jbc.m802402200
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发表时间：
2008-12-26
影响因子：
4.8
通讯作者：
Tarpey, Margaret M.
中科院分区：
文献类型：
--
作者：
Kelley, Eric E.;Batthyany, Carlos I.;Tarpey, Margaret M.
黄嘌呤氧化还原酶（XOR）产生促炎氧化剂和次级硝化物质，抑制XOR证明在多种疾病中有益。亲电硝化脂肪酸衍生物，如硝基油酸（OA-NO2），显示出具有多效性的抗炎作用。硝基-油酸以浓度依赖性方式抑制XOR活性，IC 50为0.6 μ M，限制嘌呤氧化和超氧化物的形成（O-2（柱上的中心点））。OA-NO2对酶的抑制作用不会被巯基试剂（包括谷胱甘肽、β-巯基乙醇和二硫苏糖醇）逆转。结构-功能研究表明，羧酸部分，硝化在9或10个烯碳，和不饱和是需要XOR抑制。酶营业额和竞争性再活化的研究表明，在钼辅因子的电子转移反应的抑制占OA-NO2诱导的抑制。重要的是，OA-NO2更有效地抑制细胞相关的XOR依赖性O-2（（条形图上的中心点））。比别嘌呤醇产量高。结合起来，这些数据建立了一个新的作用OA-NO2在抑制XOR衍生的氧化剂形成。
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 mu M, limiting both purine oxidation and formation of superoxide (O-2((center dot) over bar).). 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 O-2((center dot) over bar). production than does allopurinol. Combined, these data establish a novel role for OA-NO2 in the inhibition of XOR-derived oxidant formation.