1. Instituto Nacional de Pediatría
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Título :	Proton pump inhibitors drastically modify triosephosphate isomerase from Giardia lamblia at functional and structural levels, providing molecular leads in the design of new antigiardiasic drugs
Creador:	García Torres, Itzhel
Nivel de acceso:	Open access
Palabras clave :	Diseño de Drogas Estabilidad de Enzimas Giardia lamblia - efectos de drogas Giardia lamblia - enzimología Humanos Interacciones Hidrofóbicas e Hidrofílicas Espectrometría de Masas Inhibidores de la Bomba de Protones - farmacología Triosa-Fosfato -antagonistas & inhibidores Triosa-fosfato isomerasa - química Triosa-fosfato isomerasa - fisiología Drug Design Enzyme Stability Giardia lamblia - drug effects Giardia lamblia - enzymology Humans Hydrophobic and Hydrophilic Interactions Mass Spectrometry Proton Pump Inhibitors - pharmacology Triose-Phosphate Isomerase - antagonists & inhibitors Triose-Phosphate Isomerase - chemistry Triose-Phosphate Isomerase - physiology Giardia lamblia; Inhibidores de la bomba de protones; Perturbaciones estructurales; Sulfenamide; Trioso isomerasa Giardia lamblia; Proton pump inhibitors; Structural perturbation; Sulfenamide; Triosephosphate isomerase
Descripción :	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 GITIM 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. © 2015 Elsevier B.V.
Colaborador(es) u otros Autores:	De La Mora-De La Mora José Ignacio Marcial-Quino J Gómez-Manzo Saúl Vanoye-Carlo America Navarrete-Vázquez G Colín-Lozano B Gutiérrez-Castrellón P Sierra-Palacios E López-Velázquez G Enríquez-Flores Sergio
Fecha de publicación :	2016
Tipo de publicación:	Artículo
Formato:	pdf
Identificador del Recurso :	10.1016/j.bbagen.2015.10.021
Fuente:	Biochimica et Biophysica Acta - General Subjects 1860(1):97 - 107
URI :	http://repositorio.pediatria.gob.mx:8180/handle/20.500.12103/2743
Idioma:	eng
Aparece en las colecciones:	Artículos

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