MECHANISM AND KINETICS OF INHIBITION OF DOPAMINE BETA-HYDROXYLASE BY 2-MERCAPTOETHYLGUANIDINE
MECHANISM AND KINETICS OF INHIBITION OF DOPAMINE BETA-HYDROXYLASE BY 2-MERCAPTOETHYLGUANIDINE
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DOI：
10.1016/0006-2952(73)90182-2
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发表时间：
1973-01-01
影响因子：
5.8
通讯作者：
SMITH, JC
中科院分区：
文献类型：
--
作者：
DILIBERTO, EJ;DISTEFANO, V;SMITH, JC
采用部分纯化的多巴胺β羟基酶制剂，研究了2-巯基乙基胍(MEG)对多巴胺羟基酶(DBH)的抑制作用。随着Cu2+浓度的增加，Meg对DBH的抑制作用逐渐减弱，相同浓度的Meg和Cu2+对胸径生长的抑制作用不明显，支持酶铜结合抑制机理的假说。动力学结果表明，MEG通过两个抑制分子的相互作用抑制纯化的胸径。由于MEG通过结合酶铜来抑制DBH，因此必须在活性部位有两个铜离子才能与这两个MEG分子结合。用几种甲基葡萄糖苷的同系物和其他化合物研究了甲基葡萄糖酯抑制胸径生长的构效关系。基于MEG对胸径抑制的动力学研究获得的信息，SAR与酶活性部位的假设模型相关联。构效关系表明，底物多巴胺(DA)的阴离子中心与β-羟基化中心之间的分子内距离与抑制剂的正电荷与DBH中铜的结合中心之间的分子内距离一致。
The inhibition of dopamine-β-hydroxylase (DBH) by 2-mercaptoethylguanidine (MEG) was studied using a partially purified DBH preparation. The MEG-induced inhibition of DBH decreased progressively with increasing Cu2+concentration; equal concentrations of MEG and Cu2+were without effect, supporting the hypothesis that the mechanism of inhibition is through binding of enzymic Cu. It was shown kinetically that MEG inhibits purified DBH by a two-inhibitor molecule interaction. Since MEG inhibits DBH by binding enzymic Cu, two Cu ions must be available at the active site for binding with the two MEG molecules. Several congeners of MEG and other compounds were used to study the structure-activity relationship (SAR) of the MEG inhibition of DBH. The SAR correlated with a hypothetical model of the enzyme active site based on the information obtained from the kinetic studies of the MEG inhibition of DBH. The structure-activity relationship suggested that the intramolecular distance between the anionic site and the site of β-hydroxylation of the substrate, dopamine (DA), was coincident with the intramolecular distance between the positive charge of the inhibitor and the site of binding of the Cu of DBH.