反应的动力学和机理与血清白蛋白金诺芬(及其模拟异丙酯)在体外。
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Roberts JR,小J, Schliesman B,帕森斯DJ,肖CF第三
反应的动力学和机理与血清白蛋白金诺芬(及其模拟异丙酯)在体外。
Inorg化学。1996年1月17日,35 (2):424 - 433。
- PubMed ID
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11666224 (在PubMed]
- 文摘
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第一个详细的动力学分析和机械的解释之间的反应药物血清白蛋白和第二代黄金金诺芬(Et (3) PAuSATg = (triethylphosphine) (2、3、4, 6-tetra-O-acetyl-1-beta-D-glucopyranosato-S)金(我)及其triisopropylphosphine模拟,知识产权(3)PAuSATg,体外报告。反应了使用Penefsky旋转列和NMR饱和转移的方法。Penefsky色谱条件下0.4 - -0.6毫米白蛋白和广泛的Et (3) PAuSATg浓度,两相的反应。快速阶段显然是白蛋白的一级反应速率常数(k (1) = 3.4 + / - 0.3 x 10 (-) (-) (1) (2) s]略有减少,成为中间级黄金浓度较低,[Et (3) PAuSATg] < [AlbSH];它占大约95%的非盟(I)结合。小,慢一步[k (2) = 2.3 + / - 0.3 x 10 s(-)(-)(3)(1)),只占5%的反应,也是一阶对白蛋白,和零阶金诺芬。知识产权(3)PAuSATg,只有第一步是观察,k (1) = (1.4 + / - 0.1) x 10 s(-)(-)(2)(1),和一阶白蛋白和独立的知识产权(3)PAuSATg浓度。(31)P-NMR饱和转移实验利用知识产权(3)PAuSATg,在平衡条件下,产生向前的二阶速率常数(1.2 x 10 (2) M s(-)(-)(1)(1))和反向(3.9 x 10 (1) M s(-)(-)(1)(1)方向。一个多步机制涉及构象上改变白蛋白物种了。白蛋白域IA开场伴随Cys-34重排,使灵巧的黄金绑定和交换,然后关闭。 In conjunction with the steady-state approximation, this mechanism accounts for the different reaction orders observed under the two set of conditions. The rate-determining conformational change of albumin governs the reaction as monitored by the Penefsky columns. Rapid second order exchange of R(3)PAuSATg at the exposed Cys-34 residue is observed under the NMR conditions. The mechanism predicts that under physiological conditions where [Et(3)PAuSATg] is 10-25 &mgr;M, the reaction will be second order and rapid with a rate constant of 8 +/- 2 x 10(2) M(-)(1) s(-)(1). The Penefsky spun columns revealed a previously unreported and novel binding mechanism, association of auranofin in the pocket of albumin-disulfide species, which was confirmed by Hummel-Dreyer gel chromatographic techniques under equilibrium conditions. This albumin-auranofin complex (AlbSSR-Et(3)PAuSATg) is weakly bound and readily dissociates during conventional gel exclusion chromatography.