Omeprazole as a potent activator of human cytosolic aldehyde dehydrogenase ALDH1A1

• Published in: Biochimica et biophysica acta. General subjects Vol. 1864; no. 1; p. 129451
• Main Authors: Calleja, Luis Francisco, Belmont-Díaz, Javier Alejandro, Medina-Contreras, Oscar, Quezada, Héctor, Yoval-Sánchez, Belem, Campos-García, Jesús, Rodríguez-Zavala, José Salud
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.01.2020
• Subjects: 4-HNE; aldehyde dehydrogenase; aldehydes; ALDH activator; ALDH1A1; binding sites; drugs; Escherichia coli; etiology; gastric acid; human diseases; humans; hydrogen peroxide; Lipid aldehydes; lipids; mass spectrometry; Omeprazole; Oxidative stress; pathogenesis; stomach; temperature; therapeutics; Oxidative stress; Alda-1; Alda-89; MDA; Omeprazole; ALDH activator; ALDH3A1; ALDHs; 4-HNE; ALDH2; Lipid aldehydes; ALDH1A1; GdnHCl; p-NPA
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2019.129451

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. 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. 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. 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. •ALDHs detoxify lipid aldehydes implicated in the etiology of different human diseases.•Omeprazole was a potent ALDH1A1 activator, increasing the activity 4–6-fold.•The presence of omeprazole protected ALDH1A1 from inactivation by lipid aldehydes.•Treatment with omeprazole protected bacterial cells from the oxidative stress promoted by H2O2.•Omeprazole may be used in therapeutic strategies to avoid oxidative stress effects.