Inhibition by methylated organo-arsenicals of the respiratory 2-oxo-acid dehydrogenases.
Inhibition by methylated organo-arsenicals of the respiratory 2-oxo-acid dehydrogenases.
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DOI：
10.1016/j.jorganchem.2008.12.028
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发表时间：
2009-03-15
影响因子：
2.3
通讯作者：
Martin BD
中科院分区：
文献类型：
--
作者：
Bergquist ER;Fischer RJ;Sugden KD;Martin BD
通过饮用水或吸入摄入的无机砷通过生物甲基化途径代谢成有机砷代谢物。现在人们认识到，这种以前被认为是解毒的代谢可能对增加砷的毒性有同样多的或更多的贡献。一种被认为是砷及其有机砷代谢产物的毒性作用方式是通过与蛋白质结合，使其酶活性失活。经典的案例被认为是丙酮酸脱氢酶复合体的硫辛酸辅助因子的近端1，3个巯基对砷的亲和力。测定了蛋白质中羟基与砷的化学计量比为2：1，并用游离的D，L-硫辛酸合成了砷的络合物。这个位点对于砷结合的相对重要性已经受到了质疑，因为使用了甲基化的双功能砷络合物，这表明活性位点组氨酸的甲基化也可能是重要的，以及砷通过促进线粒体过氧化氢的产生间接抑制丙酮酸脱氢酶复合体。为了将直接三价亚砷酸盐的毒性与过氧化氢和活性氧的毒性区分开来，我们研究了在不产生过氧化氢但使硫辛酸基团处于还原状态的砷化合物的条件下对PDH络合物的抑制作用。我们还研究了砷化合物对α-酮戊二酸脱氢酶复合体的抑制作用。我们发现，只有三价砷化合物才能抑制这两种脱氢酶复合体的活性，而且只有在硫辛酸处于还原状态时才能抑制。亚砷酸盐对两种酶复合体的抑制作用大致相同，而单甲基亚砷酸盐对PDH复合体的抑制程度大于KGDH复合体--尽管两种复合体对该复合体的抑制都非常敏感。预孵化时间较长时，才能观察到二甲基砷对两种络合物的抑制作用。观察到还原砷对所有络合物的累积抑制，表明抑制的结合模式取决于硫辛酸处于还原状态。
Inorganic arsenic that is ingested through drinking water or inhalation is metabolized by biological methylation pathways into organoarsenical metabolites. It is now becoming understood that this metabolism that was formerly considered to be detoxification may contribute as much or more to increasing the toxicity of arsenic. One proposed mode of the toxic action of arsenic and its organoarsenic metabolites is through its binding to proteins and inactivating their enzymatic activity. The classic case has been considered the affinity of the proximal 1,3 sulfhydryl groups of the lipoic acid cofactor of the pyruvate dehydrogenase complex for arsenic. A 2:1 stoichiometry of sulfhydryl to arsenic groups has been measured in proteins and arsenical complexes can be synthesized using free D,L-lipoic acid. The relative importance of this site for arsenic binding has come in to question through the use of methylating bifunctional arsenic complexes that suggested the methylation of an active site histidine may also be important, and the suggestion that arsenic inhibits the pyruvate dehydrogenase complex indirectly by elevating mitochondrial hydrogen peroxide generation. In order to separate the effects of direct trivalent arsenite toxicity from that of hydrogen peroxide and activated oxygen, we studied the inhibition of the PDH complex under conditions that did not generate hydrogen peroxide but did expose the lipoic acid group in its reduced state to arsenicals. We also studied the effects of arsenicals in the inhibition of the α-ketoglutarate dehydrogenase complex. We found that only trivalent arsenical compounds inhibited the activity of both dehydrogenase complexes and only when the lipoic acid was in its reduced form. Arsenite inhibited both enzyme complexes approximately equivalently while monomethylarsenite inhibited the PDH complex to a greater extent than the KGDH complex – although both complexes were very sensitive to inhibition by this complex. Dimethylarsenite inhibition of both complexes was only observed with longer pre-incubation periods. Cumulative inhibition by the reduced arsenical was observed for all complexes indicating a binding mode of inhibition that is dependent upon lipoic acid being in its reduced state.
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