Bioinorganic and medicinal chemistry: aspects of gold(I)-protein complexes
Bioinorganic and medicinal chemistry: aspects of gold(I)-protein complexes
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DOI：
10.1039/c0dt01057j
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发表时间：
2011-01-01
影响因子：
4
通讯作者：
Mugesh, Govindasamy
中科院分区：
文献类型：
--
作者：
Bhabak, Krishna P.;Bhuyan, Bhaskar J.;Mugesh, Govindasamy
基于金(I)的药物已经成功地用于治疗类风湿性关节炎（RA）好几年了。虽然这些金(I)类药物治疗类风湿性关节炎的确切作用机制尚未明确，但这些化合物与哺乳动物酶的相互作用已被广泛研究。在本文中，我们描述了治疗性金(I)化合物与含有半胱氨酸（Cys）和硒代半胱氨酸（Sec）残基的哺乳动物蛋白的相互作用。由于金(I)对硫和硒具有较高的亲和力，金(I)药物与酶的活化半胱氨酸或硒代半胱氨酸残基迅速反应，形成蛋白-金(I)-硫代酸盐或蛋白-金(I)-硒代酸盐配合物。稳定的金(I)-硫代酸盐/硒酸盐络合物的形成通常会抑制酶的活性。金-硫酸盐/硒酸盐配合物与其他亲核试剂发生广泛的配体交换反应，这种配体交换反应改变了金(I)配合物的抑制作用。因此，金(I)化合物对含半胱氨酸或硒代半胱氨酸蛋白酶活性的影响可能在RA中起重要作用。金(I)化合物与不同酶的相互作用及其抑制酶活性的生化机制可能对类风湿关节炎的治疗具有广泛的医学意义。
Gold(I)-based drugs have been used successfully for the treatment of rheumatoid arthritis (RA) for several years. Although the exact mechanism of action of these gold(I) drugs for RA has not been clearly established, the interaction of these compounds with mammalian enzymes has been extensively studied. In this paper, we describe the interaction of therapeutic gold(I) compounds with mammalian proteins that contain cysteine (Cys) and selenocysteine (Sec) residues. Owing to the higher affinity of gold(I) towards sulfur and selenium, gold(I) drugs rapidly react with the activated cysteine or selenocysteine residues of the enzymes to form protein-gold(I)-thiolate or protein-gold(I)-selenolate complexes. The formation of stable gold(I)-thiolate/selenolate complexes generally lead to inhibition of the enzyme activity. The gold-thiolate/selenolate complexes undergo extensive ligand exchange reactions with other nucleophiles and such ligand exchange reactions alter the inhibitory effects of gold(I) complexes. Therefore, the effect of gold(I) compounds on the enzymatic activity of cysteine-or selenocysteine-containing proteins may play important roles in RA. The interaction of gold(I) compounds with different enzymes and the biochemical mechanism underlying the inhibition of enzymatic activities may have broad medicinal implications for the treatment of RA.