Zinc-bound thiolate-disulfide exchange:: A strategy for inhibiting metallo-β-lactamases
Zinc-bound thiolate-disulfide exchange:: A strategy for inhibiting metallo-β-lactamases
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DOI：
10.1021/ic025624f
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发表时间：
2003-03-10
影响因子：
4.6
通讯作者：
Lippard, SJ
中科院分区：
文献类型：
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作者：
Boerzel, H;Koeckert, M;Lippard, SJ
合成了单核硫代锌配合物[(Tp(PhMe))Zn(S-R)]，其中Tp（PhMe）为氢化三(（3-甲基-5-苯基）吡唑硼酸盐，而（S-R）为苯基硫代、4-硝基苯基硫代、4-三氟甲基苯基硫代、4-氯苯硫代、苯基硫代、2-甲基苯基硫代、4-甲基苯基硫代、4-甲氧基苯基硫代或4-羟基苯基硫代。班级的代表成员也有结构特征。苯硫酸盐配合物与多种二苯基和二吡啶基二硫化物发生硫酸-二硫化物交换反应。动力学研究表明，对于大多数研究的二硫化物，该反应在络合物和二硫化物中都表现出饱和行为。结合对配位硫代酸盐稳定性的研究，提出了锌配位硫代酸盐的反应机理。当让游离的苄基硫醇与同样的二硫化物反应时，反应速度比锌-硫酸盐络合物慢20-200倍，这取决于所使用的特定二硫化物。由于大多数金属- β -内酰胺酶含有一种或多种半胱氨酸残基，其中活性位点的半胱氨酸残基与锌配合，因此本研究扩展到检查二硫化物是否可以通过选择性氧化金属结合的半胱氨酸来用作这些酶的抑制剂。允许与脆弱拟杆菌中的金属- β -内酰胺酶CcrA反应的几种二硫化物是该酶的中度至强效不可逆抑制剂。
The mononuclear zinc thiolate complexes [(Tp(PhMe))Zn(S-R)], where Tp(PhMe) is hydrotris((3-methyl-5-phenyl)pyrazolyl)borate and (S-R) is benzyl thiolate, 4-nitrophenylthiolate, 4-trifluoromethylphenylthiolate, 4-chlorophenylthiolate, phenylthiolate, 2-methylphenylthiolate, 4-methylphenylthiolate, 4-methoxyphenylthiolate, or 4-hydroxyphenylthiolate, were synthesized. Representative members of the class were also characterized structurally. The benzyl thiolate complex undergoes a thiolate-disulfide exchange reaction with a variety of diphenyl and dipyridyl disulfides. Kinetic studies revealed that the reaction shows saturation behavior in both complex and disulfide for most of the disulfides studied. Combined with studies of the lability of the coordinated thiolate, a mechanism is proposed where the reactive species is the zinc-coordinated thiolate. When the free benzyl thiol was allowed to react with the same disulfides, the reaction was slower by a factor of 20-200 than that for the zinc-thiolate complex, depending on the particular disulfide employed. Since most metallo-beta-lactamases contain one or more cysteine residues, the one in the active site being coordinated to zinc, the present study was extended to examine whether disulfides can be used as inhibitors of these enzymes by selective oxidation of the metal-bound cysteine. Several disulfides allowed to react with metallo-beta-lactamase CcrA from Bacteroides fragilis were moderate to potent irreversible inhibitors of the enzyme.