Health
Zinc-carrying proteins can activate PPI in the absence of stomach acid
Acid reducing agents from the proton pump inhibitors (PPIs) group are bestselling drugs that prevent and alleviate stomach problems. PPIs are activated in acid-producing cells in the stomach, where they block acid production. Researchers at the German Cancer Research Center (DKFZ) have made the surprising discovery that zinc-carrying proteins found in all cells can also activate PPIs without the presence of stomach acid. The results can be key to understanding the side effects of PPI.
Excessive stomach acid can cause chronic complaints such as heartburn as well as gastritis and stomach ulcers. Doctors usually prescribe proton pump inhibitors (PPIs) for treatment. Examples include the drug pantoprazole, omeprazole, and rabeprazole. PPI binds and blocks gastric parietal enzymes known as proton pumps, effectively reduces the production of stomach acid.
PPI is a prodrug. In other words, they are employed as inactive precursors. Their activation to actual active substances is triggered by protons. The presence of many protons is a characteristic of acids. The proton pump in the intestinal wall supplies protons to oxidize gastric juices. PPI is locally activated due to particularly high concentrations of protons in the immediate vicinity of the proton pump. Proton-dependent activation ensures that, at least according to current doctrine, PPIs attack and paralyze the proton pump almost exclusively.
Short-term use of PPIs is usually very well tolerated, and harmless and long-term use poses health risks. Research suggests that the risk of heart attack, stroke, dementia and susceptibility to infection may increase. This raises the question of whether PPI is also activated outside the stomach and affects other proteins, i.e., is it irrelevant to the environment at high proton concentrations.
A team of researchers led by DKFZ biochemist Tobiasdick and chemist Aubrey Miller are considering the question. They used a method called Click Chemistry, a strategy for labeling Nobel Prize-winning molecules three years ago. They used it to track rabeprazole, a typical representative of PPI, in human cells in culture dishes, far from the acidic environment.
Along the way, the team made some amazing observations. PPIs were activated inside the pH neutrality of the cell and bound to dozens of proteins there. Further analysis showed that these are zinc binding proteins. “This hypothesized that protein-bound zinc could lead to PPI activation independent of the presence of protons,” biologist Teresa Marker said in the publication's first publication. I will explain that he is the author.
In the course of further investigation, the researchers were able to demonstrate that protein-bound zinc actually forms a chemical bond with PPI, leading to the activation of PPI. Activated PPIs are highly reactive and are combined in situ with zinc-carrying proteins. This destroys the structure and function of the attacked protein.
From a chemical perspective, this result makes sense because zinc mimics the effect of protons and can act like an acid. ”
Aubrey Miller, DKFZ chemist
Among the zinc-carrying proteins most affected by PPI, some play a role in the immune system. However, further research is needed to determine whether newly discovered activation mechanisms are associated with known or suspected side effects of PPI. “These results open up a new perspective to better understand the side effects of PPI,” summed up by Tobias Dick.
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Journal Reference:
Hartman, E. , et al. (2025). Site-specific activation of the proton pump inhibitor rabeprazole by zinc tetrathioate centers. Natural Chemistry. doi.org/10.1038/S41557-025-01745-8.
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