Hydrogen potassium ATPase

Last updated
ATPase, H+/K+ exchanging, alpha polypeptide
Identifiers
SymbolATP4A
NCBI gene 495
HGNC 819
OMIM 137216
RefSeq NM_000704
UniProt P20648
Other data
EC number 7.2.2.19
Locus Chr. 19 q13.1
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Structures Swiss-model
Domains InterPro
ATPase, H+/K+ exchanging, beta polypeptide
Identifiers
SymbolATP4B
NCBI gene 496
HGNC 820
OMIM 137217
RefSeq NM_000705
UniProt P51164
Other data
EC number 7.2.2.19
Locus Chr. 13 q34
Search for
Structures Swiss-model
Domains InterPro

Gastric hydrogen potassium ATPase, also known as H+/K+ ATPase, is an enzyme which functions to acidify the stomach. [1] It is a member of the P-type ATPases, also known as E1-E2 ATPases due to its two states. [2]

Contents

Biological function and location

The gastric hydrogen potassium ATPase or H+/K+ ATPase is the proton pump of the stomach. It exchanges potassium from the intestinal lumen with cytoplasmic hydronium [2] and is the enzyme primarily responsible for the acidification of the stomach contents and the activation of the digestive enzyme pepsin [3] (see gastric acid).

The H+/K+ ATPase is found in parietal cells, which are highly specialized epithelial cells located in the inner cell lining of the stomach called the gastric mucosa. Parietal cells possess an extensive secretory membrane system and the H+/K+ ATPase is the major protein constituent of these membranes. A small amount of H+/K+ ATPase is also found in the renal medulla. [2]

Genes and protein structure

The H+/K+ ATPase is a heterodimeric protein, the product of 2 genes. The gene ATP4A [4] encodes the H+/K+ ATPase α subunit, and is a ~1000-amino acid protein that contains the catalytic sites of the enzyme and forms the pore through the cell membrane that allows the transport of ions. Hydronium ions bind to two active sites present in the α subunit. [5] The α subunit also has a phosphorylation site (Asp385). [6] The gene ATP4B [7] encodes the β subunit of the H+/K+ ATPase, which is a ~300-amino acid protein with a 36-amino acid N-terminal cytoplasmic domain, a single transmembrane domain, and a highly glycosylated extracellular domain.

Structure of the hydrogen potassium ATPase. The a subunit is shown in pink; the b subunit is shown in blue. Hydrogen potassium ATPase.jpg
Structure of the hydrogen potassium ATPase. The α subunit is shown in pink; the β subunit is shown in blue.

The H+/K+ ATPase β subunit stabilizes the H+/K+ ATPase α subunit and is required for function of the enzyme. The β subunit prevents the pump from running in reverse, [8] and it also appears to contain signals that direct the heterodimer to membrane destinations within the cell, although some of these signals are subordinate to signals found in H+/K+ ATPase α subunit.

The structure of H+/K+ ATPase has been determined for humans, dogs, hogs, rats, and rabbits and is 98% homologous across all species. [2]

Enzyme mechanism and activity

H+/K+ ATPase is a P2-type ATPase, a member of the eukaryotic class of P-type ATPases. [9] Like the Ca2+ and the Na+/K+ ATPases, the H+/K+ ATPase functions as an α, β protomer. [10] Unlike other eukaryotic ATPases, the H+/K+ ATPase is electroneutral, transporting one proton into the stomach lumen per potassium ion retrieved from the gastric lumen. [9] As an ion pump the H+/K+ ATPase is able to transport ions against a concentration gradient using energy derived from the hydrolysis of ATP. Like all P-type ATPases, a phosphate group is transferred from adenosine triphosphate (ATP) to the H+/K+ ATPase during the transport cycle. This phosphate transfer powers a conformational change in the enzyme that helps drive ion transport.[ citation needed ]

The hydrogen potassium ATPase is activated indirectly by gastrin that causes ECL cells to release histamine. [11] The histamine binds to H2 receptors on the parietal cell, activating a cAMP-dependent pathway which causes the enzyme to move from the cytoplasmic tubular membranes to deeply folded canaliculi of the stimulated parietal cell. [2] Once localized, the enzyme alternates between two conformations, E1 and E2, to transport ions across the membrane.

Mechanism of the H /K ATPase demonstrating how E1-E2 conformational change corresponds to ion release. See Shin et al. Gastric hydrogen potassium ATPase mechanism.svg
Mechanism of the H /K ATPase demonstrating how E1-E2 conformational change corresponds to ion release. See Shin et al.

The E1 conformation binds a phosphate from ATP and hydronium ion on the cytoplasmic side. The enzyme then changes to the E2 conformation, allowing hydronium to be released in the lumen. The E2 conformation binds potassium, and reverts to the E1 conformation to release phosphate and K+ into the cytoplasm where another ATP can be hydrolyzed to repeat the cycle. [2] The β subunit prevents the E2-P conformation from reverting to the E1-P conformation, making proton pumping unidirectional. [8] The number of ions transported per ATP varies from 2H+/2K+ to 1H+/1K+depending on the pH of the stomach. [12]

Disease relevance and inhibition

Inhibiting the hydrogen potassium pump to decrease stomach acidity has been the most common method of treating diseases including gastroesophageal reflux disease (GERD/GORD) and peptic ulcer disease (PUD). [13] Reducing acidity alleviates disease symptoms but does not treat the actual cause of GERD (abnormal relaxation of the esophageal sphincter) or PUD ( Helicobacter pylori and NSAIDs). [14]

Three drug classes have been used to inhibit H+/K+-ATPases. H2-receptor antagonists, like cimetidine (Tagamet), inhibit the signaling pathway that leads to activation of the ATPase. This type of inhibitor is effective in treating ulcers but does not prevent them from forming, and patients develop tolerance to them after about one week, leading to a 50% reduction in efficacy. [15] Proton pump inhibitors (PPIs) were later developed, starting with Timoprazole in 1975. [15] PPIs are acid-activated prodrugs that inhibit the hydrogen-potassium ATPase by binding covalently to active pumps. [16] Current PPIs like Omeprazole have a short half-life of approximately 90 minutes. [17] Acid pump antagonists (APAs) or potassium-competitive acid blockers (PCABs) are a third type of inhibitor that blocks acid secretion by binding to the K+ active site. [15] APAs provide faster inhibition than PPIs since they do not require acid activation. Revaprazan was the first APA used clinically in east Asia, and other APAs are being developed since they appear to provide better acid control in clinical trials. [17]

Inactivation of the proton pump can also lead to health problems. A study in mice by Krieg et al. [18] found that a mutation of the pump's α-subunit led to achlorhydria, resulting in problems with iron absorption, leading to iron deficiency and anemia. The use of PPIs has not been correlated with an elevated risk of anemia, so the H+/K+-ATPase is thought to aid iron absorption but is not necessarily required. [18]

Current association of dementia and PPIs have been documented in Germany and in research articles denoting how Benzimidazole derivatives, Astemizole (AST) and Lansoprazole (LNS) interact with anomalous aggregates of tau protein (neurofibrillary tangles). [19] [20] [21] Current theories include the non-selective blockade of sodium-potassium pumps in the brain causing osmotic imbalances or swelling in the cells. [auth opinion] Interaction of PPIs with other drug affecting the sodium-potassium pump, e.g., digoxin, warfarin etc., has been well documented. [22] Memory has been associated with astrocytes and the alpha3 subunit of adenosine receptor found in hydrogen/Sodium-potassium pumps may be a focal point in dementia. [23] [24] [25] Chronic use of PPIs may cause down regulation of alpha3 subunit increasing damage to astrocytes. [26] Osteopetrosis via TCIRG1 gene has a strong association with pre-senile dementia. [27] [28]

See also

Related Research Articles

<span class="mw-page-title-main">Proton-pump inhibitor</span> Class of drugs for reducing stomach acid

Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump.

A proton pump is an integral membrane protein pump that builds up a proton gradient across a biological membrane. Proton pumps catalyze the following reaction:

In cellular biology, active transport is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellular energy to achieve this movement. There are two types of active transport: primary active transport that uses adenosine triphosphate (ATP), and secondary active transport that uses an electrochemical gradient. This process is in contrast to passive transport, which allows molecules or ions to move down their concentration gradient, from an area of high concentration to an area of low concentration, without energy.

<span class="mw-page-title-main">ATPase</span> Dephosphorylation enzyme

ATPases (EC 3.6.1.3, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3-ATPase, adenosine triphosphatase) are a class of enzymes that catalyze the decomposition of ATP into ADP and a free phosphate ion or the inverse reaction. This dephosphorylation reaction releases energy, which the enzyme (in most cases) harnesses to drive other chemical reactions that would not otherwise occur. This process is widely used in all known forms of life.

<span class="mw-page-title-main">Urease</span> Multiprotein Nickel-containing complex which hydrolyses urea

Ureases, functionally, belong to the superfamily of amidohydrolases and phosphotriesterases. Ureases are found in numerous bacteria, fungi, algae, plants, and some invertebrates, as well as in soils, as a soil enzyme. They are nickel-containing metalloenzymes of high molecular weight.

<span class="mw-page-title-main">ATP synthase</span> Enzyme

ATP synthase is an enzyme that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). ATP synthase is a molecular machine. The overall reaction catalyzed by ATP synthase is:

<span class="mw-page-title-main">Sodium–potassium pump</span> Enzyme found in the membrane of all animal cells

The sodium–potassium pump is an enzyme found in the membrane of all animal cells. It performs several functions in cell physiology.

<span class="mw-page-title-main">Omeprazole</span> Medication to treat gastroesophageal reflux disease and other conditions

Omeprazole, sold under the brand names Prilosec and Losec, among others, is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent upper gastrointestinal bleeding in people who are at high risk. Omeprazole is a proton-pump inhibitor (PPI) and its effectiveness is similar to that of other PPIs. It can be taken by mouth or by injection into a vein. It is also available in the fixed-dose combination medication omeprazole/sodium bicarbonate as Zegerid and as Konvomep.

<span class="mw-page-title-main">Gastric acid</span> Digestive fluid formed in the stomach

Gastric acid, gastric juice, or stomach acid is a digestive fluid formed within the stomach lining. With a pH between 1 and 3, gastric acid plays a key role in digestion of proteins by activating digestive enzymes, which together break down the long chains of amino acids of proteins. Gastric acid is regulated in feedback systems to increase production when needed, such as after a meal. Other cells in the stomach produce bicarbonate, a base, to buffer the fluid, ensuring a regulated pH. These cells also produce mucus – a viscous barrier to prevent gastric acid from damaging the stomach. The pancreas further produces large amounts of bicarbonate and secretes bicarbonate through the pancreatic duct to the duodenum to neutralize gastric acid passing into the digestive tract.

<span class="mw-page-title-main">Pantoprazole</span> Stomach acid suppressing medication

Pantoprazole, sold under the brand name Protonix, among others, is a proton pump inhibitor used for the treatment of stomach ulcers, short-term treatment of erosive esophagitis due to gastroesophageal reflux disease (GERD), maintenance of healing of erosive esophagitis, and pathological hypersecretory conditions including Zollinger–Ellison syndrome. It may also be used along with other medications to eliminate Helicobacter pylori. Effectiveness is similar to other proton pump inhibitors (PPIs). It is available by mouth and by injection into a vein.

<span class="mw-page-title-main">Parietal cell</span> Epithelial cell in the stomach

Parietal cells (also known as oxyntic cells) are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor. These cells are located in the gastric glands found in the lining of the fundus and body regions of the stomach. They contain an extensive secretory network of canaliculi from which the HCl is secreted by active transport into the stomach. The enzyme hydrogen potassium ATPase (H+/K+ ATPase) is unique to the parietal cells and transports the H+ against a concentration gradient of about 3 million to 1, which is the steepest ion gradient formed in the human body. Parietal cells are primarily regulated via histamine, acetylcholine and gastrin signalling from both central and local modulators.

<span class="mw-page-title-main">Rabeprazole</span> Stomach acid suppressing medication

Rabeprazole, sold under the brand name Aciphex, among others, is a medication that decreases stomach acid. It is used to treat peptic ulcer disease, gastroesophageal reflux disease, and excess stomach acid production such as in Zollinger–Ellison syndrome. It may also be used in combination with other medications to treat Helicobacter pylori. Effectiveness is similar to other proton pump inhibitors (PPIs). It is taken by mouth.

<span class="mw-page-title-main">Achlorhydria</span> Medical condition

Achlorhydria and hypochlorhydria refer to states where the production of hydrochloric acid in gastric secretions of the stomach and other digestive organs is absent or low, respectively. It is associated with various other medical problems.

<span class="mw-page-title-main">Bafilomycin</span> Chemical compound

The bafilomycins are a family of macrolide antibiotics produced from a variety of Streptomycetes. Their chemical structure is defined by a 16-membered lactone ring scaffold. Bafilomycins exhibit a wide range of biological activity, including anti-tumor, anti-parasitic, immunosuppressant and anti-fungal activity. The most used bafilomycin is bafilomycin A1, a potent inhibitor of cellular autophagy. Bafilomycins have also been found to act as ionophores, transporting potassium K+ across biological membranes and leading to mitochondrial damage and cell death.

<span class="mw-page-title-main">P-type ATPase</span>

The P-type ATPases, also known as E1-E2 ATPases, are a large group of evolutionarily related ion and lipid pumps that are found in bacteria, archaea, and eukaryotes. P-type ATPases are α-helical bundle primary transporters named based upon their ability to catalyze auto- (or self-) phosphorylation (hence P) of a key conserved aspartate residue within the pump and their energy source, adenosine triphosphate (ATP). In addition, they all appear to interconvert between at least two different conformations, denoted by E1 and E2. P-type ATPases fall under the P-type ATPase (P-ATPase) Superfamily (TC# 3.A.3) which, as of early 2016, includes 20 different protein families.

<span class="mw-page-title-main">ATP6V1G2</span>

V-type proton ATPase subunit G 2 is an enzyme that in humans is encoded by the ATP6V1G2 gene.

In the field of enzymology, a proton ATPase is an enzyme that catalyzes the following chemical reaction:

Proton pump inhibitors (PPIs) block the gastric hydrogen potassium ATPase (H+/K+ ATPase) and inhibit gastric acid secretion. These drugs have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease (GERD) and peptic ulcer disease. PPIs also can bind to other types of proton pumps such as those that occur in cancer cells and are finding applications in the reduction of cancer cell acid efflux and reduction of chemotherapy drug resistance.

The P-type plasma membrane H+
-ATPase
is found in plants and fungi. For the gastric H+
/K+
ATPase, see Hydrogen potassium ATPase.

<span class="mw-page-title-main">Azeloprazole</span> Chemical compound

Azeloprazole is a drug under investigation for acid-related medical conditions responsive to suppressing the production of stomach acid. It is considered a member of the proton pump inhibitor class of medications.

References

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