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首页> 外文期刊>Bioorganic and Medicinal Chemistry >On the active site for hydrolysis of aryl amides and choline esters by human cholinesterases
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On the active site for hydrolysis of aryl amides and choline esters by human cholinesterases

机译：在人胆碱酯酶水解芳基酰胺和胆碱酯的活性位点上

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Cholinesterases, in addition to their well-known esterase action, also show an aryl acylamidase (AAA) activity whereby they catalyze the hydrolysis of amides of certain aromatic amines. The biological function of this catalysis is not known. Furthermore, it is not known whether the esterase catalytic site is involved in the AAA activity of cholinesterases. It has been speculated that the AAA activity, especially that of butyrylcholinesterase (BuChE), may be important in the development of the nervous system and in pathological processes such as formation of neuritic plaques in Alzheimer's disease (AD). The substrate generally used to study the AAA activity of cholinesterases is N-(2-nitrophenyl)acetamide. However, use of this substrate requires high concentrations of enzyme and substrate, and prolonged periods of incubation at elevated temperature. As a consequence, difficulties in performing kinetic analysis of AAA activity associated with cholinesterases have hampered understanding this activity. Because of its potential biological importance, we sought to develop a more efficient and specific substrate for use in studying the AAA activity associated with BuChE, and for exploring the catalytic site for this hydrolysis. Here, we describe the structure-activity relationships for hydrolysis of anilides by cholinesterases. These studies led to a substrate, N-(2-nitrophenyl)trifluoroacetamide, that was hydrolyzed several orders of magnitude faster than N-(2-nitrophenyl)acetamide by cholinesterases. Also, larger N-(2-nitrophenyl)alkylamides were found to be more rapidly hydrolyzed by BuChE than N-(2-nitrophenyl)acetamide and, in addition, were more specific for hydrolysis by BuChE. Thus, N-(2-nitrophenyl)alkylamides with six to eight carbon atoms in the acyl group represent suitable specific substrates to investigate further the function of the AAA activity of BuChE. Based on the substrate structure-activity relationships and kinetic studies, the hydrolysis of anilides and esters of choline appears to utilize the same catalytic site in BuChE.
机译：胆碱酯酶除具有众所周知的酯酶作用外，还表现出芳基酰化酶（AAA）活性，从而可催化某些芳香胺的酰胺水解。这种催化的生物学功能是未知的。此外，还不知道酯酶催化位点是否参与胆碱酯酶的AAA活性。据推测，AAA活性，尤其是丁酰胆碱酯酶（BuChE）的AAA活性可能在神经系统的发育和病理过程例如在阿尔茨海默氏病（AD）中神经斑的形成中很重要。通常用于研究胆碱酯酶的AAA活性的底物是N-（2-硝基苯基）乙酰胺。但是，使用这种底物需要高浓度的酶和底物，并需要长时间在高温下孵育。结果，在进行与胆碱酯酶相关的AAA活性的动力学分析方面的困难阻碍了对该活性的理解。由于其潜在的生物学重要性，我们寻求开发一种更有效和特异性的底物，用于研究与BuChE相关的AAA活性，并探索这种水解的催化位点。在这里，我们描述了胆碱酯酶水解酸酐的结构-活性关系。这些研究导致了底物N-（2-硝基苯基）三氟乙酰胺，其被胆碱酯酶的水解速度比N-（2-硝基苯基）乙酰胺快了几个数量级。同样，发现较大的N-（2-硝基苯基）烷基酰胺比N-（2-硝基苯基）乙酰胺更能被BuChE水解，此外，它们对于BuChE的水解更具有特异性。因此，在酰基中具有六个至八个碳原子的N-（2-硝基苯基）烷基酰胺代表合适的特定底物，以进一步研究BuChE的AAA活性的功能。基于底物的结构-活性关系和动力学研究，苯胺的酸酐和酯的水解似乎利用了BuChE中相同的催化位点。

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