Lead poisoning and the inactivation of 5-aminolevulinate dehydratase as modeled by the tris(2-mercapto-1-phenylimidazolyl)hydroborato lead complex, {[TmPh]Pb}[ClO4]
Lead poisoning and the inactivation of 5-aminolevulinate dehydratase as modeled by the tris(2-mercapto-1-phenylimidazolyl)hydroborato lead complex, {[TmPh]Pb}[ClO4]
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DOI：
10.1021/ja001530y
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发表时间：
2000-07-26
影响因子：
15
通讯作者：
Parkin, G
中科院分区：
文献类型：
--
作者：
Bridgewater, BM;Parkin, G
铅是环境中最常见的有毒金属污染物，因为它现在和以前在电池、汽油、管道和油漆等方面的使用。因此，人们正作出相当大的努力来解决这个环境问题。在这方面，铅的毒理学特性与它与蛋白质的相互作用有关，特别是与5-氨基乙酰酸脱水酶（ALAD）的相互作用。4-6铅对后一种酶的影响尤其有害，因为ALAD负责将5-氨基乙酰丙酸（ALA）不对称二聚化成卟啉原，卟啉原是血红素合成所必需的单吡啶。因此，ALAD的失活不仅会导致贫血，因为它会抑制血红素的形成，从而抑制血红蛋白的形成，而且还会导致ALA（一种神经病原体）的积累。7,8 ALAD是一种锌依赖性酶，10，在本文中，我们通过研究对PbII的合成类似物的反应性来解决ALAD铅失活的问题。最近的晶体学研究表明，酵母ALAD的催化位点具有[(Cys) 3ZnII-(OH2)]的组成。7,11,12由于大多数锌酶的活性位点（与结构位点相反）包括至少一个组氨酸配体，因此这种组合物必须被认为是真正不寻常的。13,14此外，由于含硫配体倾向于桥接多个锌中心，具有富硫配位环境的单核四面体锌配合物模拟了上述结构
Lead is the most commonly encountered toxic metal pollutant in the environment as a result of its current and previous use in, for example, batteries, gasoline, plumbing, and paints. 1 Considerable effort is, therefore, being directed toward solving this environmental problem. 2 In this regard, the toxicological properties of lead3 are associated with its interactions with proteins and, in particular, 5-aminolevulinate dehydratase (ALAD). 4-6 The influence of lead on the latter enzyme is particularly harmful because ALAD is responsible for the asymmetric dimerization of 5-aminolevulinic acid (ALA) to porphobilinogen, a monopyrrole which is essential for heme synthesis. 7-9 Thus, not only does inactivation of ALAD result in anemia because it inhibits the formation of heme, and hence hemoglobin, but it also results in a build-up of ALA, a neuropathogenic agent. 7, 8 ALAD is a zinc-dependent enzyme, 10 and, in this paper, we address aspects of lead inactivation of ALAD by investigating the reactivity of a synthetic analogue towards PbII.Recent crystallographic studies have demonstrated that the catalytic site of yeast ALAD possesses the composition [(Cys) 3ZnII-(OH2)]. 7, 11, 12 Such a composition must be regarded as truly unusual since the active sites (as opposed to structural sites) of most zinc enzymes include at least one histidine ligand. 13, 14 Furthermore, due to the proclivity of sulfur containing ligands to bridge more than one zinc center, mononuclear tetrahedral zinc complexes with sulfur-rich coordination environments that mimic the aforemen-