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.

中文翻译：

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奥美拉唑是人胞质醛脱氢酶ALDH1A1的有效活化剂。

背景

脂质醛的积累在产生高水平氧化应激的人类疾病的病因中起着关键作用。在这方面，醛脱氢酶（ALDHs）的激活可防止缺血再灌注过程中氧化性组织损伤。尽管奥美拉唑用于减少胃酸的产生，但在目前的研究中，该药物被描述为迄今报道的最有效的人类ALDH1A1激活剂。

方法

进行对接分析以预测奥美拉唑与酶的相互作用。重组人ALDH1A1用于评估奥美拉唑对动力学性质的影响。进行温度处理和质谱分析以解决活化剂与酶结合的性质。最后，使用表达人ALDH1A1的大肠杆菌细胞，在氧化应激的体内模型中评估了奥美拉唑的作用。

结果

奥美拉唑与醛结合位点相互作用，使人ALDH1A1的活性增加4-6倍，改变了动力学特性，改变了底物结合和产物释放的顺序，并保护了酶免于脂醛的灭活。此外，奥美拉唑保护过表达ALDH1A1的大肠杆菌细胞免受H ₂ O ₂暴露产生的氧化应激的影响，从而降低脂质醛的水平并保持ALDH活性。

结论

奥美拉唑可以重新定位为人ALDH1A1的有效活化剂，并可能被建议用于治疗策略，以减轻在不同人类病理学中发生的氧化应激事件期间产生的损害。