Zinc-carrying proteins may activate PPIs in the absence of gastric acid

Sour reduced medicines from the Proton pump inhibitors group (PPIs) are best -selling medicines that prevent and relieve stomach problems. PPIs are activated in the acid -producing cells of the stomach, where they block the production of acid. Researchers from the German Cancer Research Center (DKFZ) made the surprising discovery that zinc-bearing proteins, which are found in all cells, can also activate PPIs with the presence of stomach acid. The result can be a key to understand the side effects of PPIs.

Excessive stomach acid can not only cause heartburn, but also chronic complaints such as gastritis or even a stomach ulcer. Doctors usually prescribe a proton pump inhibitor (PPI) for treatment. Examples are the drugs pantoprazole, omeprazole and rabeprazole. PPIs bind and block an enzyme in the stomach -parietal cells known as the proton pump, reducing the production of stomach acid.

PPIs are prodrugs, which means that they are taken as inactive precursors. Their activation for the actual active substance is activated by protons. The presence of many protons is the characteristic of an acid. The proton pump in the intestinal wall supplies the protons for acidification of the stomach fluid. Since there is a particularly high concentration of protons in the immediate vicinity of the proton pump, the PPIs are activated locally. Proton-dependent activation ensures that PPIs attack and paralyze almost exclusively, at least according to the current doctrine.

Although it is usually very well tolerated in the short term use of PPIs and is considered harmless, long -term use is health risks. Studies have suggested the possibility of an increased risk of heart attacks, strokes, dementia and sensitivity to infections. This raises the question of whether PPIs are also activated outside the stomach and influence other proteins, ie independently of an environment with a high proton concentration.

A team of researchers led by biochemist Tobias Dick and chemist Aubry Miller, both at the DKFZ, investigated this question. They used a method that is known as Click Chemistry, a strategy for labeling molecules that received the Nobel Prize three years ago. They used it to follow Rabeprazole, a typical representative of PPIs, in human cells in the breeding dish, far from an sour environment.

In the process the team made a surprising observation: the PPI was activated in the pH-neutral interior of the cells and bound to dozens of proteins there. Further analysis showed that these were zinc -binding proteins. “This has led us to assume that protein -bound zinc can lead to the activation of PPIs, regardless of the presence of protons,” explains biologist Teresa Marker, first author of the publication.

In the course of further research, the researchers were able to demonstrate that protein -bound zinc in fact forms a chemical bond with the PPI, which then leads to the activation of the PPI. The activated PPI is very reactive and combines on site with the zinc-bearing protein. This in turn disrupts the structure and function of the attacked protein.

From a chemical point of view, this result makes sense, because zinc can imitate the effect of protons and behave like an acid. “

AUBRY MILLER, Chemist of the DKFZ

Among the zinc-bearing proteins that were most affected by the PPI, some play a role in the immune system. However, further studies are needed to determine whether the newly discovered activation mechanism is associated with the well -known or suspected side effects of PPIs. “These results open new perspectives for a better understanding of the side effects of PPIs,” summarizes Tobias Dick.