期刊
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
卷 1860, 期 1, 页码 97-107出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagen.2015.10.021
关键词
Proton pump inhibitors; Giardia lamblia; Triosephosphate isomerase; Structural perturbation; Sulfenamide
资金
- Consejo Nacional de Ciencia y Tecnologia [221583, 241343]
Background: Proton pump inhibitors (PPIs) are extensively used in clinical practice because of their effectiveness and safety. Omeprazole is one of the best-selling drugs worldwide and, with other PPIs, has been proposed to be potential drugs for the treatment of several diseases. We demonstrated that omeprazole shows cytotoxic effects in Giardia and concomitantly inactivates giardial triosephosphate isomerase (GlTIM). Therefore, we evaluated the efficiency of commercially available PPIs to inactivate this enzyme. Methods: We assayed the effect of PPIs on the GlTIM WT, single Cys mutants, and the human counterpart, following enzyme activity, thermal stability, exposure of hydrophobic regions, and susceptibility to limited proteolysis. Results: PPIs efficiently inactivated GlTIM: however, rabeprazole was the best inactivating drug and was nearly ten times more effective. The mechanism of inactivation by PPIs was through the modification of the Cys 222 residue. Moreover, there are important changes at the structural level, the thermal stability of inactivated-GlTIM was drastically diminished and the structural rigidity was lost, as observed by the exposure of hydrophobic regions and their susceptibility to limited proteolysis. Conclusions: Our results demonstrate that rabeprazole is the most potent PPI for GlTIM inactivation and that all PPIs tested have substantial abilities to alter GlTIM at the structural level, causing serious damage. General significance. This is the first report demonstrating the effectiveness of commercial PPIs on a glycolytic parasitic enzyme, with structural features well known. This study is a step forward in the use and understanding the implicated mechanisms of new antigiardiasic drugs safe in humans. (C) 2015 Elsevier B.V. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据