The cells in exchange for the potassium

The proton pump (also called hydrogen-potassium adenosine triphosphatase) is an enzyme that plays an important role in the secretion of hydrochloric acid in the stomach. The proton pump consists of two subunits: the catalytic ?-subunit containing of 1033 amino acid residues and glycosylated ?-subunit containing 291 amino acid residues, as well as carbohydrate cytoplasmic fragments.
The proton pump (H+/K+ -ATPase) is present in large quantities in the parietal cells of the gastric mucosa. It transports the hydrogen ion H+ from the cytoplasm to the stomach through the apical membrane of the lining cells in exchange for the potassium ion K+ that the cytoplasm brings inside the cell. In this case, both cations are transported against the electrochemical gradient, and the hydrolysis of the ATP molecule serves as a source of energy for this transport. Simultaneously with protons of hydrogen, chlorine anions Cl- are entering the stomach lumen against the electrochemical gradient. K+ ions entering the cell leave the cell down the concentration gradient along with Cl- ions. H+ ions are formed in equivalent amounts with HCO3- with the dissociation of carbonic acid H2CO3 with the participation of carbonic anhydrase. HCO3 ions passively move into the blood down the concentration gradient through the basolateral membrane in exchange for Cl- ion. Thus, hydrochloric acid in the form of H+ and Cl- ions is released into the stomach lumen through the proton pump, whereas K+ ions entering back the lining cells.
The action of proton pump inhibitors (PPI) is based on the blocking of the proton pump, and these drugs are the most effective antiulcer medications. Once absorbed in the small intestine and got through the bloodstream into the gastric mucosa, PPIs accumulate in the secretory tubules of the lining cells. Here PPIs (at acidic pH) are activated and through the acid-dependent transformation are transformed into tetracyclic sulfenamide, which is covalently incorporated into the main cysteine groups of the proton pump. This prevents conformational transition of the proton pump and, thus blocks the production of hydrochloric acid by parietal cells of the stomach.

All proton pump inhibitors (omeprazole, pantoprazole, lansoprazole, rabeprazole and esomeprazole) are benzimidazole derivatives and have a very similar to its chemical structure. They differ in the structure of the radicals on the pyridine and benzimidazole rings.
Since PPIs reduce the production of acid in the stomach by blocking an enzyme H+/K+ ATPase, they are commonly used to treat patients with conditions caused by either an overproduction of acid or exacerbated by stomach acid: acid reflux (GERD), Zollinger-Ellison syndrome (overproduction of acid), ulcers caused by NSAIDs, erosive esophagitis, together with antibiotics to treat eradication of H. pylori.
Omeprazole was synthesized after an acid-activated prodrug Timoprazole was synthetized in 1975. So, in 1989 Omeprazole became the very first PPI drug introduced into clinical use. Omeprazole (Losec) was followed by lansoprazole (Prevacid), pantoprazole (Protonix) or rabeprazole (Aciphex) and more recently by the S-enantiomer of omeprazole (Nexium) (4).
PPIs are weak bases, which enables them to accumulate selectively in the acidic space of the secretory canaliculus of the stimulated parietal cell, where the pH is about 1.0. This acid space–dependent concentration of PPIs is the first important property that determines their therapeutic index, giving a concentration at the luminal surface of the pump that is about 1000-fold higher than in the blood. The second step is acid-dependent conversion from the accumulated prodrug to the activated species, which is a highly reactive thiophilic reagent. A second protonation of these compounds is required for their activation to the compounds that form disulfides with luminally accessible cysteines of the H,K-ATPase (4).
PPIs are used wisely to treat numerous conditions and they are generally well tolerated, however long-term use of PPIs has been linked to a number of safety concerns such as hypomagnesemia, vitamin B12 and iron deficiencies, osteoporosis, kidney disease, and even fractures (2).
Vitamin B12, produced in nature by certain bacteria, and archaea is essential for the body as it helps with energy metabolism, the nervous system support, and production of red blood cells, DNA and RNA. In the stomach in the presence of pepsin, vitamin B12 binds to R-proteins – transcobalamines I and III. This phase of transformation is necessary for the bonding of vitamin B12 and the internal factor of Castle in the duodenum for the subsequent absorption of vitamin B12 in the ileum. With achlorhydria, the transition of pepsinogen to pepsin is disrupted, which leads to impaired absorption and development of B12-deficiency and anemia (3).
The absorption of iron is also a pH-dependent process. Dietary iron is present in the form of insoluble poorly absorbed ferric iron Fe (III). In the body iron can be absorbed in the small intestine only after solubilization with hydrochloric acid and oxidation to the divalent Fe (II). Short-term hypochlorhydria and achlorhydria with a normal diet does not lead to iron deficiency in the body. However, prolonged acid-suppressive therapy with PPI increases the risk of iron deficiency due to iron malabsorption (3).
PPIs inhibit an acidic compartment of the lysosomes that play an essential role in the process of breaking down substances like nucleic acids and carbohydrates. Based on the results of the study conducted by Lui, prolonged use of PPIs significantly inhibits enzymatic activity of lysosomes. This is due to the fact that lysosomes also contain the same proton pump that is present in the stomach and produces acid. Blocking of lysosome proton pump function prevents the acidification of lysosomes, which leads to build-up of intracellular waste products that cannot be destroyed and eliminated. Accumulation of this build-up results in the cell aging and premature death. This can partly explain the increased incidence of vascular dementia, myocardial infarction and renal failure in patients who use PPI long-term (1).

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