γ-(monophenyl)phosphono glutamate analogues as mechanism-based inhibitors of γ-glutamyl transpeptidase
γ-(monophenyl)phosphono glutamate analogues as mechanism-based inhibitors of γ-glutamyl transpeptidase
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DOI：
10.1016/j.bmc.2006.05.008
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发表时间：
2006-09-01
影响因子：
3.5
通讯作者：
Sakata, Kanzo
中科院分区：
文献类型：
--
作者：
Han, Liyou;Hiratake, Jun;Sakata, Kanzo
γ-谷氨酰转肽酶(GGT，EC 2.3.2.2)是细胞外谷胱甘肽的水解酶和转肽酶，在谷胱甘肽的动态平衡中起核心作用。本文报道了一系列具有不同吸电子对位基团的水解性稳定的单苯基谷氨酸膦类似物的合成和评价，作为大肠杆菌和人GGTS的机理和过渡态类似物。单苯基膦酸酯可能通过使酶的催化苏氨酸残基磷酸化而引起对大肠杆菌和人类酶的时间依赖和不可逆转的抑制。大肠杆菌GGT的失活速度高度依赖于酚的离基能力，吸电子基团显著加快了失活速度(Bronsted beta(Ig)=-1.4)，而人GGT的失活相当缓慢，几乎与离开基团的性质无关。与经典的GGT抑制剂Acivicin的抑制效力和图谱进行了比较，表明基于磷酸的谷氨酸类似物有望成为有效和选择性GGT抑制剂的候选者。(C)2006爱思唯尔有限公司。保留所有权利。
gamma-Glutamyl transpeptidase (GGT, EC 2.3.2.2) catalyzes the hydrolysis and transpeptidation of extracellular glutathione and plays a central role in glutathione homeostasis. We report here the synthesis and evaluation of a series of hydrolytically stable gamma-(monophenyl)phosphono glutamate analogues with varying electron-withdrawing para substituents on the leaving group phenols as mechanism-based and transition-state analogue inhibitors of Escherichia coli and human GGTs. The monophenyl phosphonates caused time-dependent and irreversible inhibition of both the E. coli and human enzymes probably by phosphonylating the catalytic Thr residue of the enzyme. The inactivation rate of E. coli GGT was highly dependent on the leaving group ability of phenols with electron-withdrawing groups substantially accelerating the rate (Bronsted beta(Ig), = - 1.4), whereas the inactivation of human GGT was rather slow and almost independent on the nature of the leaving group. The inhibition potency and profiles of the phosphonate analogues were compared to those of acivicin, a classical inhibitor of GGT, suggesting that the phosphonate-based glutamate analogues served as a promising candidate for potent and selective GGT inhibitors. (c) 2006 Elsevier Ltd. All rights reserved.