Horseradish peroxidase catalyzed nitric oxide formation from hydroxyurea
Horseradish peroxidase catalyzed nitric oxide formation from hydroxyurea
复制标题
DOI：
10.1021/ja012271v
复制
发表时间：
2002-04-03
影响因子：
15
通讯作者：
King, SB
中科院分区：
文献类型：
--
作者：
Huang, JM;Sommers, EM;King, SB
羟基脲代表了镰状细胞性贫血和许多癌症的批准治疗。化学发光和电子顺磁共振光谱研究表明，辣根过氧化物酶催化过氧化氢存在下，从羟基脲形成一氧化氮。气相色谱顶空分析和红外光谱也揭示了在该反应中一氧化二氮的产生，这为硝酰基（一氧化氮的单电子还原形式）提供了证据。这些反应也会产生二氧化碳、氨、亚硝酸盐和硝酸盐。在不存在过氧化氢或辣根过氧化物酶的情况下，这些产物都不会在1小时内形成。电子顺磁共振光谱和捕获研究表明，在此反应过程中的氮氧自由基和C-亚硝基物种的中介。吸收光谱表明，辣根过氧化物酶的化合物I和II作为单电子氧化剂的羟基脲。由Angeli盐产生的硝酰基与辣根过氧化物酶铁反应产生辣根过氧化物酶亚铁-一氧化氮复合物。电子顺磁共振实验与一氧化氮特异性陷阱揭示聊天辣根过氧化物酶是能够氧化硝酰基一氧化氮。一个机理模型，其中包括所观察到的氮氧自由基和C-亚硝基化合物的中间体已被转发来解释所观察到的产品分布。这些研究表明，羟基脲和过氧化物酶的直接一氧化氮生成反应可能有助于该药物的整体药理学特性。
Hydroxyurea represents an approved treatment for sickle cell anemia and a number of cancers. Chemiluminescence and electron paramagnetic resonance spectroscopic studies show horseradish peroxidase catalyzes the formation of nitric oxide from hydroxyurea in the presence of hydrogen peroxide. Gas chromatographic headspace analysis and infrared spectroscopy also reveal the production of nitrous oxide in this reaction, which provides evidence for nitroxyl, the one-electron reduced form of nitric oxide. These reactions also generate carbon dioxide, ammonia, nitrite, and nitrate. None of these products form within 1 h in the absence of hydrogen peroxide or horseradish peroxidase. Electron paramagnetic resonance spectroscopy and trapping studies show the intermediary of a nitroxide radical and a C-nitroso species during this reaction. Absorption spectroscopy indicates that both compounds I and II of horseradish peroxidase act as one-electron oxidants of hydroxyurea. Nitroxyl, generated from Angeli's salt, reacts with ferric horseradish peroxidase to produce a ferrous horseradish peroxidase-nitric oxide complex. Electron paramagnetic resonance experiments with a nitric oxide specific trap reveal chat horseradish peroxidase is capable of oxidizing nitroxyl to nitric oxide. A mechanistic model that includes the observed nitroxide radical and C-nitroso compound intermediates has been forwarded to explain the observed product distribution. These studies suggest that direct nitric oxide producing reactions of hydroxyurea and peroxidases may contribute to the overall pharmacological properties of this drug.