Department of Cell Biology, University of Oklahoma Health Sciences Centre, Oklahoma City, OK 73104, USA.
J Enzyme Inhib Med Chem. 2012 Aug;27(4):476-89. doi: 10.3109/14756366.2011.597748. Epub 2011 Aug 24.
A novel class of inhibitors of the enzyme γ-glutamyl transpeptidase (GGT) were evaluated. The analog OU749 was shown previously to be an uncompetitive inhibitor of the GGT transpeptidation reaction. The data in this study show that it is an equally potent uncompetitive inhibitor of the hydrolysis reaction, the primary reaction catalyzed by GGT in vivo. A series of structural analogs of OU749 were evaluated. For many of the analogs, the potency of the inhibition differed between the hydrolysis and transpeptidation reactions, providing insight into the malleability of the active site of the enzyme. Analogs with electron withdrawing groups on the benzosulfonamide ring, accelerated the hydrolysis reaction, but inhibited the transpeptidation reaction by competing with a dipeptide acceptor. Several of the OU749 analogs inhibited the transpeptidation reaction by slow onset kinetics, similar to acivicin. Further development of inhibitors of the GGT hydrolysis reaction is necessary to provide new therapeutic compounds.
研究了一类新型的γ-谷氨酰转肽酶（GGT）抑制剂。先前的研究表明，OU749 类似物是 GGT 转肽反应的非竞争性抑制剂。本研究中的数据表明，它也是一种同样有效的非竞争性水解反应抑制剂，是 GGT 在体内催化的主要反应。对 OU749 的一系列结构类似物进行了评估。对于许多类似物，水解和转肽反应的抑制效力不同，这为酶的活性位点的可变性提供了深入了解。苯磺酰胺环上带有吸电子基团的类似物加速了水解反应，但通过与二肽受体竞争，抑制了转肽反应。OU749 的几种类似物通过缓慢起始动力学抑制转肽反应，类似于 acivicin。需要进一步开发 GGT 水解反应抑制剂，以提供新的治疗化合物。
