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首页> 外文期刊>Biochemistry >Thiols as Classical and Slow-Binding Inhibitors of IMP-1 and Other Binuclear Metallo-beta-lactamases.
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Thiols as Classical and Slow-Binding Inhibitors of IMP-1 and Other Binuclear Metallo-beta-lactamases.

机译：硫醇是IMP-1和其他双核金属β-内酰胺酶的经典抑制剂和慢结合抑制剂。

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The inhibitory effect of a variety of thiol compounds on the function of binuclear metallo-beta-lactamases, with a particular focus on IMP-1 from Pseudomonas aeruginosa, has been investigated. Thiol inhibitors, depending on their structural features, fall into two categories, one in which inhibition at neutral pH was instantaneous and the other in which inhibition was time-dependent. While mercaptans with anionic substituents in the vicinity of their SH groups exhibited the former type of inhibition, neutral thiols appear to induce a slow, time-dependent isomerization of the initially formed EI complex to a tighter EI complex. Kinetic parameters describing the latter process were obtained by fitting progress curves of substrate hydrolysis using standard and numerical procedures. The failure of charged thiols to exhibit slow binding is suggested to be due to a rapid isomerization of the initial EI complex. Slow binding in the case of neutral thiols was observed only below pH 8. Studies on the pH dependence of catalysis by IMP-1 revealed that (i) enzyme inactivation at low pH is a slow process with presumably two groups with a pK(a) of approximately 5.2 in the protein being responsible for the loss of activity, (ii) inhibition by thiols is independent of pH between pH 5 and 9, and (iii) an apparent enhancement of the catalytic activity of IMP-1 by thiols occurs at pH <5. The last mentioned phenomenon is explained by a model in which mercaptans retard the proton-dependent isomerization of the enzyme. Studies on the thiol-mediated inhibition of the binuclear forms of Bacteroides fragilis (CcrA) and Bacillus cereus (BcII strain 5/B/6) metallo-beta-lactamase have revealed that while CcrA was instantaneously albeit moderately inhibited by mercaptans, BcII mimicked IMP-1 in its interaction with thiols. These differences are proposed to be due partly to the structural divergence of these proteins in the vicinity of Zn2.
机译：研究了多种硫醇化合物对双核金属β-内酰胺酶功能的抑制作用，特别是铜绿假单胞菌的IMP-1。硫醇抑制剂根据其结构特征可分为两类，一类是在中性pH下的抑制作用是瞬时的，另一种是时间依赖性的。尽管在其SH基团附近具有阴离子取代基的硫醇显示出前一种抑制类型，但中性硫醇似乎诱导了最初形成的EI配合物向更紧密的EI配合物的缓慢的，时间依赖性的异构化。通过使用标准程序和数值程序拟合底物水解的进度曲线，可获得描述后一过程的动力学参数。提示带电荷的硫醇未能显示出缓慢的结合是由于初始EI络合物的快速异构化。在中性硫醇的情况下，仅在低于pH 8的情况下才观察到缓慢结合。对IMP-1催化的pH依赖性的研究表明：（i）在低pH值下酶失活是一个缓慢的过程，大概两个带有pK（a）的基团约5.2的蛋白质是造成活性损失的原因;（ii）硫醇的抑制作用独立于pH介于5和9之间的pH;（iii）在pH值下，硫醇对IMP-1的催化活性明显增强<5。最后一个提到的现象是由一个模型解释的，其中硫醇阻止了酶的质子依赖性异构化。巯基介导的对脆弱拟杆菌（CcrA）和蜡状芽孢杆菌（BcII菌株5 / B / 6）金属β-内酰胺酶的双核形式抑制作用的研究表明，尽管CcrA瞬时被硫醇适度抑制，但BcII模仿了IMP -1在与硫醇的相互作用中。提出这些差异部分是由于这些蛋白质在Zn2附近的结构差异所致。

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