On the mechanism and rate of gold incorporation into thiol-dependent flavoreductases.
On the mechanism and rate of gold incorporation into thiol-dependent flavoreductases.
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DOI：
10.1016/j.jinorgbio.2011.11.005
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发表时间：
2012-03
影响因子：
3.9
通讯作者：
Bellelli, Andrea
中科院分区：
文献类型：
--
作者：
Saccoccia, Fulvio;Angelucci, Francesco;Boumis, Giovanna;Brunori, Maurizio;Miele, Adriana E.;Williams, David L.;Bellelli, Andrea
NADPH依赖性黄素还原酶是重要的药物靶点。在它们的酶循环过程中，产生对过渡金属具有高亲和力的硫醇盐和硒酸盐。金诺芬（AF）是一种含金化合物，被世界卫生组织列为抗风湿药物，并被指示作为开发新的抗癌和抗寄生虫药物的支架。AF抑制含硒半胱氨酸的黄素还原酶（硫氧还蛋白还原酶和硫氧还蛋白谷胱甘肽还原酶）比不含硒的黄素还原酶（谷胱甘肽还原酶）更有效;这种偏好归因于硒对金的高亲和力。我们解决了3D结构的含硒硫氧还蛋白葡萄糖还原酶从人类寄生虫曼氏血吸虫与Au复合，我们的结果挑战了这一观点：我们认为，反应的相对速度，而不是相对亲和力，取决于存在的Sec残基，这似乎决定AF的选择性。
NADPH-dependent flavoreductases are important drug targets. During their enzymatic cycle thiolates and selenolates that have high affinity for transition metals are generated. Auranofin (AF), a gold-containing compound, is classified by the World Health Organization as an antirheumatic agent and it is indicated as the scaffold for the development of new anticancer and antiparasitic drugs. AF inhibits selenocysteine-containing flavoreductases (thioredoxin reductase and thioredoxin glutathione reductase) more effectively than non Se-containing ones (glutathione reductase); this preference has been ascribed to the high affinity of selenium for gold. We solved the 3D structure of the Se-containing Thioredoxin Glutathione Reductase from the human parasite Schistosoma mansoni complexed with Au and our results challenge this view: we believe that the relative velocity of the reaction rather than the relative affinity, depends on the presence of Sec residues, which appear to dictate AF selectivity.
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