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首页> 外文期刊>Journal of Molecular Biology >The anti-cancer drug chlorambucil as a substrate for the human polymorphic enzyme glutathione transferase P1-1: kinetic properties and crystallographic characterisation of allelic variants.
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The anti-cancer drug chlorambucil as a substrate for the human polymorphic enzyme glutathione transferase P1-1: kinetic properties and crystallographic characterisation of allelic variants.

机译：抗癌药苯丁酸氮芥作为人多态酶谷胱甘肽转移酶P1-1的底物：等位基因变体的动力学性质和晶体学表征。

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摘要

The commonly used anti-cancer drug chlorambucil is the primary treatment for patients with chronic lymphocytic leukaemia. Chlorambucil has been shown to be detoxified by human glutathione transferase Pi (GST P1-1), an enzyme that is often found over-expressed in cancer tissues. The allelic variants of GST P1-1 are associated with differing susceptibilities to leukaemia and differ markedly in their efficiency in catalysing glutathione (GSH) conjugation reactions. Here, we perform detailed kinetic studies of the allelic variants with the aid of three representative co-substrates. We show that the differing catalytic properties of the variants are highly substrate-dependent. We show also that all variants exhibit the same temperature stability in the range 10 degrees C to 45 degrees C. We have determined the crystal structures of GST P1-1 in complex with chlorambucil and its GSH conjugate for two of these allelic variants that have different residues at positions 104 and 113. Chlorambucil is found to bindin a non-productive mode to the substrate-binding site (H-site) in the absence of GSH. This result suggests that under certain stress conditions where GSH levels are low, GST P1-1 can inactivate the drug by sequestering it from the surrounding medium. However, in the presence of GSH, chlorambucil binds in the H-site in a productive mode and undergoes a conjugation reaction with GSH present in the crystal. The crystal structure of the GSH-chlorambucil complex bound to the *C variant is identical with the *A variant ruling out the hypothesis that primary structure differences between the variants cause structural changes at the active site. Finally, we show that chlorambucil is a very poor inhibitor of the enzyme in contrast to ethacrynic acid, which binds to the enzyme in a similar fashion but can act as both substrate and inhibitor.
机译：常用的抗癌药物苯丁酸氮芥是慢性淋巴细胞性白血病患者的主要治疗方法。苯丁酸氮芥已被人类谷胱甘肽转移酶Pi（GST P1-1）排毒，该酶通常在癌症组织中过度表达。 GST P1-1的等位基因变体与白血病的敏感性不同，并且在催化谷胱甘肽（GSH）偶联反应中的效率也显着不同。在这里，我们借助三个代表性的共底物对等位基因变体进行详细的动力学研究。我们表明，变体的不同催化性能是高度依赖于底物的。我们还表明，所有变体在10摄氏度至45摄氏度的范围内均表现出相同的温度稳定性。我们已经确定了与苯丁酸氮芥及其GSH缀合物复合的GST P1-1的晶体结构，其中两个等位基因变体具有不同的在104和113位残基上发现残基。苯丁酸氮芥在没有GSH的情况下以非生产方式结合到底物结合位点（H位点）。该结果表明，在某些应激条件下，其中GSH含量较低，GST P1-1可以通过与周围介质隔离来使药物失活。但是，在存在谷胱甘肽的情况下，苯丁酸氮芥以生产方式在H位结合，并与晶体中存在的谷胱甘肽发生共轭反应。与* C变体结合的GSH-苯丁酸氮芥复合物的晶体结构与* A变体相同，排除了以下假​​设：变体之间的一级结构差异会导致活性位点发生结构变化。最后，我们证明苯丁酸氮芥与该酶相比，是一种非常差的酶抑制剂，而乙炔酸以相似的方式与该酶结合，但可以同时充当底物和抑制剂。

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