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Proton Pump


Introduction of Proton Pump

The proton pump is present in the biofilm and is a membrane protein that actively transports H+ against the electrochemical potential difference (ΔμH+) of H on both sides of the membrane. In a narrow sense, it refers to the decomposition of ATP to transport H+, or the synthesis of ATP by the energy of H. H+-. ATPase is present in mitochondria and chloroplasts and is the main means of obtaining energy in living organisms. Broadly, it also includes bacteriorhodopsin which directly converts light energy into transporting proton energy, and cytochrome c oxidase and NADH-NADP transhydrogenase which transport protons by electron transfer energy. Reversible ATPase is capable of transporting H+ by reverse concentration driven by external energy. There are three enzyme complexes in the mitochondrial inner membrane respiratory chain with proton pump function, which can transport H+ from the inner cavity to the outer cavity. They are cytochrome c oxidase, coenzyme QH2-cytochrome c reductase, and NADH-coenzyme Q reductase. Proton pumps are common on the plasma membrane of bacteria, and some are accompanied by components of the respiratory chain. The bacteriorhodopsin on the halophilic membrane is driven by light, and H+ can be transported into the bacteria to concentrate.

The family member of Proton Pump family and their structures respectively

Electron transfer results in a conformational change of the complex. Proton transfer is the result of changes in the pK value of the amino acid side chain. The conformational change causes a change in the pK value of the amino acid side chain, with the result that the side chain acting as a proton pump is exposed and alternately exposed to the inside or outside of the inner mitochondrial membrane, thereby causing proton shift. This system is the mechanism of the proton pump. There are three types of proton pumps: P-type, V-type, and F-type. The P-type proton pump has a cell membrane of eukaryotes and is characterized by transporting H+. The process involves phosphorylation and dephosphorylation of carrier proteins using ATP to phosphorylate themselves, undergoing conformational changes to transfer protons or other ions, such as H+ pumps on plant cell membranes, Na+-K+ pumps for animal cells, Ca2+ ion pumps, and H+- K+ ATPase (located in the epidermal cells of the stomach, secreting gastric acid). The V-type proton pump is located on the membrane of the vesicle (the lysosomal membrane of the animal cell, the endocytic body of the animal cell, the vesicle membrane of the Golgi apparatus, and the vacuolar membrane of the plant). It has the characteristics of hydrolyzing ATP to generate energy but does not undergo autophosphorylation. However, it keeps the pH stable in the cytoplasmic matrix and organelle. The F-type proton pump locates on the mitochondrial membrane and plant endometrium, and it is a tubular structure composed of many subunits. H+ moves along a concentration gradient, and the released energy is coupled with ATP synthesis, so it is also called ATP synthase. The F-type proton pump is located on the plasma membrane, mitochondrial inner membrane and chloroplast thylakoid membrane. The F-type proton pump can not only convert ADP into ATP by proton dynamic potential, but also transfer the proton by energy released by hydrolysis of ATP.

The mechanism of proton pump and their clinical application

Lindberg P et al. found that the drug that inhibits H+-K+-ATPase has three structures: pyridine ring, SO group and benzimidazole ring. Most of the proton pump inhibitors that have been marketed are benzimidazoles, which are weakly basic compounds with low activity. They can be quickly absorbed into the bloodstream and transported to the gastric mucosal cells in the intestinal tract. They are ionized with H+ and lose lipophilicity. In turn, the membrane permeability is lost, the drug concentration is rapidly increased, and it is converted into a biologically active sulfenamide compound, which is dehydrated and coupled with a thiol group on the cysteine residue of the H+-K+-ATPase α subunit. The action forms a covalent disulfide bond, thereby inhibiting the activity of the H+-K+-ATPase and exerting the acid suppression function of the proton pump. At present, the drugs applied clinically enhance the function of inhibiting gastric acid by differently modifying the pyridine ring or the benzimidazole ring. Proton pump inhibitors can be used for the treatment of gastroesophageal reflux disease. Gastroesophageal reflux disease refers to clinical syndromes characterized by heartburn and acid reflux, which are mainly caused by heart and duodenal contents, including non-erosive reflux disease, erosive esophagitis and Barrett's esophagus. Studies have shown that after taking a proton pump inhibitor, the patient's acid reflux and heartburn symptoms can be significantly relieved. Proton pump inhibitors commonly used in the treatment of gastroesophageal reflux disease are esomeprazole, omeprazole, lansoprazole and rabeprazole. Proton pump inhibitors are used to treat peptic ulcers, which are mainly gastric ulcers and duodenal ulcers. Duodenal ulcers are more common than gastric ulcers, mainly young and middle-aged people, and gastric ulcers occur in middle-aged and elderly people. Men have a higher proportion of peptic ulcers than women. The cure rate of duodenal ulcer and gastric ulcer with conventional doses of proton pump inhibitors can reach more than 90%, and the onset is fast, and the treatment time is short. Proton pumps can be used to eradicate Helicobacter pylori, which can cause chronic gastritis and gastrointestinal ulcers. With a single antibacterial drug, the cure rate is generally <20%, and it is easy to produce drug resistance. To effectively promote ulcer healing and reduce its recurrence and malignant transformation, the current first-line treatment for the eradication of Helicobacter pylori is a triple therapy with two antibacterial drugs plus a proton pump inhibitor. In Europe, all proton pump inhibitors can be used in the triple therapy of eradication of Helicobacter pylori for 7 days. The US Food and Drug Administration recommends omeprazole, esomeprazole, and lansoprazole for 10 to 14 days in triple therapy and 7 days for rabeprazole. The treatment of triple therapy in China is generally 7 days. After relapse, the medication plan or course of treatment needs to be adjusted. The currently preferred triple therapy for eradication of Helicobacter pylori is omeprazole, clarithromycin and amoxicillin. Proton pumps are used to treat upper gastrointestinal bleeding. There are many common causes of causing upper gastrointestinal bleeding, such as esophageal, gastric and duodenal ulcers, acute gastric mucosal damage, esophageal varices and gastric cancer. Proton pump inhibitors can rapidly inhibit gastric acid secretion, increase the pH value in the stomach, and achieve the purpose of hemostasis, which is helpful for the prevention and treatment of upper gastrointestinal bleeding, especially peptic ulcer combined with bleeding. Omeprazole is the first choice for the treatment of upper gastrointestinal bleeding. Proton pump can also be used to treat Zhuo-Ai syndrome. Zhuo-Ai syndrome is a rare disease. The main pathophysiological basis is that gastrinoma causes a large amount of gastric acid secretion, damages the gastric and duodenal mucosa, and causes erosion and ulceration. Clinical studies have shown that proton pump inhibitors such as omeprazole, iansoprazole and rabeprazole can be used for the treatment of this disease. When the dose is 2 to 3 times of the conventional dose, it can effectively reduce gastric acid secretion to <10 mmol/h, to achieve the purpose of controlling symptoms and curing ulcers. Barrett's esophagus and its associated disease are associated with gastroesophageal reflux. Studies have shown that taking proton pump inhibitors can reduce Barrett's esophageal dysplasia, partially or completely restore the esophageal mucosa, and reduce the incidence of esophageal adenocarcinoma. At present, endoscopic microwave coagulation combined with rabeprazole is being used in the treatment of Barrett's esophagus and related diseases. Proton pumps have also made some progress in the clinical application of pediatrics. Because children's physiology is very different from that of adults, there are still controversies about whether the use of proton pump inhibitors in the treatment of children with gastroesophageal reflux disease, peptic ulcer with Helicobacter pylori. Clinically, the first-generation proton pump inhibitor omeprazole enteric-coated capsule is used to treat children with gastroesophageal reflux disease, peptic ulcer with Helicobacter pylori, 0.6 ~ 0.8 mg/kg, treatment for 2 to 4 weeks. Second-generation and third-generation proton pump inhibitors such as esomeprazole magnesium enteric-coated tablets, pantoprazole enteric-coated tablets, rabeprazole enteric-coated capsules, and lansoprazole enteric-coated capsules have not been associated with pediatric drugs, and its safety and effectiveness have yet to be further evaluated.

Reference:

  1. Wei C, Pohorille A. M2 proton channel: toward a model of a primitive proton pump. Origins of Life & Evolution of the Biosphere the Journal of the International Society for the Study of the Origin of Life. 2015, 45(1-2):241.
  2. Lin K, Chen X, Li Z, et al. Proton pump inhibitors as also inhibitors of atrial fibrillation. European Journal of Pharmacology. 2013, 718(1–3):435-440.
  3. Vogt A, Guo Y, Tsunoda S P, et al. Conversion of a light-driven proton pump into a light-gated ion channel. Scientific Reports. 2015, 5(403-408):16450.
  4. Siegbahn P E, Blomberg M R. Mutations in the D-channel of cytochrome c oxidase causes leakage of the proton pump. Febs Letters. 2014, 588(4):545-548.

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