Inhibition of Escherichia coli tryptophan indole-lyase by tryptophan homologues
Inhibition of Escherichia coli tryptophan indole-lyase by tryptophan homologues
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DOI：
10.1016/j.abb.2014.07.027
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发表时间：
2014-10-15
影响因子：
3.9
通讯作者：
Phillips, Robert S.
中科院分区：
文献类型：
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作者：
Do, Quang T.;Nguyen, Giang T.;Phillips, Robert S.
我们设计、合成并评估了同型色氨酸类似物作为大肠杆菌色氨酸吲哚裂解酶（色氨酸酶，TIL， E.C. 4.1.99.1）可能的机制抑制剂。由于类醌结构是TIL反应机制中的中间体，我们预计生理底物L-Trp的同源性将提供类似于β消除过渡态的类似物，并可能抑制TIL。我们的研究结果表明，l -同型色氨酸（1a）是一种中等竞争性TIL抑制剂，K-i = 67 μ M，而l -双色氨酸（1b）表现出更强的抑制作用，K-i = 4.7 μ M。预稳态动力学表明，1a可以形成外部醛二胺和类醌，但1b只能形成外部醛二胺，这表明抑制机制存在差异。这些结果表明，强抑制并不需要形成类醌络合物。此外，色氨酸类似物被评价为鼠伤寒沙门菌色氨酸合酶抑制剂。我们的研究结果表明，化合物1b对TIL的选择性至少是Trp合成酶的25倍。我们报道，化合物1b与之前报道的最有效的抑制剂相当，同时对TIL具有高选择性。因此，1b是开发新型抗菌药物的潜在先导。(C) 2014爱思唯尔公司版权所有。
We have designed, synthesized and evaluated homotryptophan analogues as possible mechanism-based inhibitors for Escherichia colt tryptophan indole-lyase (tryptophanase, TIL, E.C. 4.1.99.1). As a quinonoid structure is an intermediate in the reaction mechanism of TIL, we anticipated that homologation of the physiological substrate, L-Trp would provide analogues resembling the transition state for beta-elimination, and potentially inhibit TIL. Our results demonstrate that L-homotryptophan (1a) is a moderate competitive inhibitor of TIL, with K-i = 67 mu M, whereas L-bishomotryptophan (1b) displays more potent inhibition, with K-i = 4.7 mu M. Pre-steady-state kinetics indicated the formation of an external aldimine and quinonoid with 1a, but only the formation of an external aldimine for 1b, suggesting differences in the inhibition mechanism. These results demonstrate that formation of a quinonoid complex is not required for strong inhibition. In addition, the Trp analogues were evaluated as inhibitors of Salmonella typhimurium Trp synthase. Our results indicate that compound 1b is at least 25-fold more selective toward TIL than Trp synthase. We report that compound 1b is comparable to the most potent inhibitor previously reported, while displaying high selectivity for TIL. Thus, 1b is a potential lead for the development of novel antibacterials. (C) 2014 Elsevier Inc. All rights reserved.