Temporary inactivation of plasma amine oxidase by alkylhydrazines. A combined enzyme/model study implicates cofactor reduction/reoxidation but cofactor deoxygenation and subsequent reoxygenation in the case of hydrazine itself.
Temporary inactivation of plasma amine oxidase by alkylhydrazines. A combined enzyme/model study implicates cofactor reduction/reoxidation but cofactor deoxygenation and subsequent reoxygenation in the case of hydrazine itself.
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DOI：
10.1021/jo001115o
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发表时间：
2001-02
期刊：
影响因子：
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通讯作者：
Y. Lee;H. Jeon;H. Huang;L. Sayre
中科院分区：
文献类型：
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作者：
Y. Lee;H. Jeon;H. Huang;L. Sayre
一段时间以来，已知肼及其甲基和1，1-二甲基类似物诱导含铜醌依赖性血浆胺氧化酶失活，但活性随时间恢复，表明所有三种抑制剂的代谢。然而，负责活动的损失和恢复的机制尚未调查。在这项研究中，结合酶的研究，在受控气氛下沿着与模型研究，使用5-叔丁基-2-羟基-1，4-苯醌，以模拟2，4，5-三羟基苯丙氨酸醌（TPQ）辅因子的酶表明，酶活性的恢复代表两个不同的O（2）依赖的过程。在甲基肼和1，1-二甲基肼的情况下，我们提出，无活性的甲腙/偶氮形式的酶缓慢地再水合和消除MeN=NH，得到三醇辅因子形式，其在O（2）的存在下立即再氧化为催化活性的醌形式。甲基肼的代谢表示其转化为CH（4）和N（2），1，1-二甲基肼转化为CH（2）=O、CH（4）和N（2）。然而，在肼本身的情况下，我们提出，酶的无活性的腙/偶氮形式反而经历了缓慢的分解，可能是由活性位点铜促进的，得到N（2）和一种新的5-脱氧间苯二酚形式的辅因子。后者经历了一个快速的，但noninstantaneous复氧在C5恢复活性辅因子的形式，也可能介导的活性位点铜。
It has been known for some time that hydrazine and its methyl and 1,1-dimethyl analogues induce inactivation of the copper-containing quinone-dependent plasma amine oxidase but that the activity recovers over time, suggesting metabolism of all three inhibitors. However, the mechanism responsible for loss and regain of activity has not been investigated. In this study a combination of enzyme studies under a controlled atmosphere along with model studies using 5-tert-butyl-2-hydroxy-1,4-benzoquinone to mimic the 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor of the enzyme suggest that regain of enzyme activity represents two different O(2)-dependent processes. In the case of methylhydrazine and 1,1-dimethylhydrazine, we propose that the inactive methylhydrazone/azo form of the enzyme slowly rehydrates and eliminates MeN=NH to give the triol cofactor form, which instantly reoxidizes to the catalytically active quinone form in the presence of O(2). Metabolism of methylhydrazine represents its conversion to CH(4) and N(2), and of 1,1-dimethylhydrazine to CH(2)=O, CH(4), and N(2). In the case of hydrazine itself, however, we propose that the inactive hydrazone/azo form of the enzyme instead undergoes a slow decomposition, probably facilitated by the active-site copper, to give N(2) and a novel 5-desoxy resorcinol form of the cofactor. The latter undergoes a rapid, but noninstantaneous reoxygenation at C5 to restore the active cofactor form, also probably mediated by the active-site copper.