Huang T L, Shiotsuki T, Uematsu T, Borhan B, Li Q X, Hammock B D
College of Pharmacy, Xavier University of Louisiana, New Orleans 70125, USA.
Pharm Res. 1996 Oct;13(10):1495-500. doi: 10.1023/a:1016071311190.
Carboxylesterases are important in the detoxification of drugs, pesticides and other xenobiotics. This study was to evaluate a series of substrates and inhibitors for characterizing these enzymes.
A series of novel aliphatic esters and thioesters were used in spectral assays to monitor human, murine and porcine esterases. A series of transition state mimics were evaluated as selective esterase inhibitors.
Several alpha-alkyl thioacetothioates were found to be approximately 2 to 11-fold superior to commonly used substrates for monitoring carboxylesterase activity. Insertion of a heteroatom in the acid portion of these esters in the beta or gamma position relative to the carbonyl had a dramatic effect on enzyme activity with S or O substituents often improving the kCAT/K(M) ratio of the substrate and N decreasing it. Several alpha,alpha'-bis (2-oxo-3,3,3-trifluoropropylthio)alkanes proved to be potent selective transition state mimics of the esterase activity with IC50's from 10(-5) to 10(-9)M.
This library of substrates and inhibitors are useful research tools for characterizing the numerous isozymes of carboxylesterases present in mammalian tissues.
羧酸酯酶在药物、农药及其他外源性物质的解毒过程中发挥着重要作用。本研究旨在评估一系列用于表征这些酶的底物和抑制剂。
使用一系列新型脂肪族酯和硫酯进行光谱分析，以监测人、小鼠和猪的酯酶。评估了一系列过渡态类似物作为选择性酯酶抑制剂。
发现几种α-烷基硫代乙酰硫酯在监测羧酸酯酶活性方面比常用底物优越约2至11倍。在这些酯的酸部分中，相对于羰基在β或γ位插入杂原子对酶活性有显著影响，S或O取代基通常会提高底物的kCAT/K(M)比值，而N取代基则会降低该比值。几种α,α'-双(2-氧代-3,3,3-三氟丙基硫代)烷烃被证明是酯酶活性的有效选择性过渡态类似物，其IC50值在10(-5)至10(-9)M之间。
该底物和抑制剂文库是表征哺乳动物组织中存在的多种羧酸酯酶同工酶的有用研究工具。
