Omeprazole as a potent activator of human cytosolic aldehyde dehydrogenase ALDH1A1
| Autor: | Jesús Campos-García, Oscar Medina-Contreras, Belem Yoval-Sánchez, José S. Rodríguez-Zavala, Héctor Quezada, Javier A. Belmont-Díaz, Luis Francisco Calleja |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Biophysics Aldehyde dehydrogenase Oxidative phosphorylation medicine.disease_cause Biochemistry Aldehyde Dehydrogenase 1 Family 03 medical and health sciences 0302 clinical medicine In vivo medicine Escherichia coli Humans Molecular Biology Omeprazole chemistry.chemical_classification Aldehydes Binding Sites biology Retinal Dehydrogenase Hydrogen Peroxide ALDH1A1 Molecular Docking Simulation Kinetics Oxidative Stress 030104 developmental biology Enzyme chemistry Docking (molecular) 030220 oncology & carcinogenesis biology.protein Lipid Peroxidation Oxidative stress medicine.drug Protein Binding |
| Zdroj: | Biochimica et biophysica acta. General subjects. 1864(1) |
| ISSN: | 1872-8006 |
| Popis: | Background Accumulation of lipid aldehydes plays a key role in the etiology of human diseases where high levels of oxidative stress are generated. In this regard, activation of aldehyde dehydrogenases (ALDHs) prevents oxidative tissue damage during ischemia-reperfusion processes. Although omeprazole is used to reduce stomach gastric acid production, in the present work this drug is described as the most potent activator of human ALDH1A1 reported yet. Methods Docking analysis was performed to predict the interactions of omeprazole with the enzyme. Recombinant human ALDH1A1 was used to assess the effect of omeprazole on the kinetic properties. Temperature treatment and mass spectrometry were conducted to address the nature of binding of the activator to the enzyme. Finally, the effect of omeprazole was evaluated in an in vivo model of oxidative stress, using E. coli cells expressing the human ALDH1A1. Results Omeprazole interacted with the aldehyde binding site, increasing 4–6 fold the activity of human ALDH1A1, modified the kinetic properties, altering the order of binding of substrates and release of products, and protected the enzyme from inactivation by lipid aldehydes. Furthermore, omeprazole protected E. coli cells over-expressing ALDH1A1 from the effects of oxidative stress generated by H2O2 exposure, reducing the levels of lipid aldehydes and preserving ALDH activity. Conclusion Omeprazole can be repositioned as a potent activator of human ALDH1A1 and may be proposed for its use in therapeutic strategies, to attenuate the damage generated during oxidative stress events occurring in different human pathologies. |
| Databáze: | OpenAIRE |
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