金在硫醇依赖性黄素还原酶中的掺入机制和速率。
On the mechanism and rate of gold incorporation into thiol-dependent flavoreductases.
机构信息
Department of Biochemical Sciences A. Rossi Fanelli, Sapienza University of Rome, Rome, Italy.
出版信息
J Inorg Biochem. 2012 Mar;108:105-11. doi: 10.1016/j.jinorgbio.2011.11.005. Epub 2011 Nov 27.
Abstract
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.
摘要
NADPH 依赖型黄素还原酶是重要的药物靶点。在其酶循环中，会产生对过渡金属具有高亲和力的硫醇盐和硒醇盐。金诺芬（AF）是一种含金的化合物，世界卫生组织将其归类为抗风湿药，并被指定为开发新型抗癌和抗寄生虫药物的支架。AF 比非硒含有的黄素还原酶（硫氧还蛋白还原酶和硫氧还蛋白谷胱甘肽还原酶）更有效地抑制含硒的黄素还原酶（硒代半胱氨酸）；这种偏好归因于硒与金的高亲和力。我们解决了来自人类寄生虫曼氏血吸虫的含硒硫氧还蛋白谷胱甘肽还原酶与 Au 复合物的 3D 结构，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 Sec 残基的存在，Sec 残基似乎决定了 AF 的选择性。
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