Potassium-competitive acid blockade: A new therapeutic strategy in acid-related diseases

Andersson, Kjell; Carlsson, Enar

doi:10.1016/j.pharmthera.2005.05.005

Cited by 167 publications

(152 citation statements)

References 101 publications

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“…These compounds provided very high affinity to the H,K-ATPase with excellent inhibition [2,24,55]. However, despite superior inhibition, developments of many APAs including SCH28080 were dropped because of toxicity.…”

Section: Acid Pump Antagonistsmentioning

confidence: 99%

The gastric HK-ATPase: structure, function, and inhibition

Shin

Munson

Vagin

et al. 2008

Pflugers Arch - Eur J Physiol

220

181

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The gastric H,K-ATPase, a member of the P 2 -type ATPase family, is the integral membrane protein responsible for gastric acid secretion. It is an α,β-heterodimeric enzyme that exchanges cytoplasmic hydronium with extracellular potassium. The catalytic α subunit has ten transmembrane segments with a cluster of intramembranal carboxylic amino acids located in the middle of the transmembrane segments TM4, TM5,TM6, and TM8. Comparison to the known structure of the SERCA pump, mutagenesis, and molecular modeling has identified these as constituents of the ion binding domain. The β subunit has one transmembrane segment with N terminus in cytoplasmic region. The extracellular domain of the β subunit contains six or seven Nlinked glycosylation sites. N-glycosylation is important for the enzyme assembly, maturation, and sorting. The enzyme pumps acid by a series of conformational changes from an E 1 (ion site in) to an E 2 (ion site out) configuration following binding of MgATP and phosphorylation. Several experimental observations support the hypothesis that expulsion of the proton at 160 mM (pH 0.8) results from movement of lysine 791 into the ion binding site in the E 2 P configuration. Potassium access from the lumen depends on activation of a K and Cl conductance via a KCNQ1/KCNE2 complex and Clic6. K movement through the luminal channel in E 2 P is proposed to displace the lysine along with dephosphorylation to return the enzyme to the E 1 configuration. This enzyme is inhibited by the unique proton pump inhibitor class of drug, allowing therapy of acid-related diseases.

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Section: Acid Pump Antagonistsmentioning

confidence: 99%

The gastric HK-ATPase: structure, function, and inhibition

Shin

Munson

Vagin

et al. 2008

Pflugers Arch - Eur J Physiol

220

181

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“…Therefore, the PDB 1wpg amide backbone was utilized as a starting template for improved homology modeling of the H,K ATPase E 2 P conformation. After constructing a model based on the PDB 1wpg backbone, however, the luminal vestibule required further expansion to explain access of the K + competitive naphthyridines to the empirically defined binding site for these specific inhibitors of the H,K ATPase (35). This was done by applying steered molecular dynamics to extract the inhibitor from the binding site to the extracytoplasmic space outside the entrance to the luminal vestibule.…”

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confidence: 99%

Analysis of the Gastric H,K ATPase for Ion Pathways and Inhibitor Binding Sites

2007

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New models of the gastric H,K ATPase in the E 1 K and E 2 P states are presented as the first structures of a K + counter-transport P 2 -type ATPase exhibiting ion entry and exit paths. Homology modeling was first used to generate a starting conformation from the srCa ATPase E 2 P form (PDB code 1wpg) that contains bound MgADP. Energy minimization of the model showed a conserved adenosine site but nonconserved polyphosphate contacts compared to the srCa ATPase. Molecular dynamics was then employed to expand the luminal entry sufficiently to allow access of the rigid K + competitive naphthyridine inhibitor, Byk99, to its binding site within the membrane domain. The new E 2 P model had increased separation between transmembrane segments M3 through M8, and addition of water in this space showed not only an inhibitor entry path to the luminal vestibule but also a channel leading to the ion binding site. Addition of K + to the hydrated channel with molecular dynamics modeling of ion movement identified a pathway for K + from the lumen to the ion binding site to give E 2 K. A K + exit path to the cytoplasm operating during the normal catalytic cycle is also proposed on the basis of an E 1 K homology model derived from the E 1 2Ca 2+ form of the srCa ATPase (PDB code 1su4). Autodock analyses of the new E 2 P model now correctly discriminate between high-and low-affinity K + competitive inhibitors. Finally, the expanded luminal vestibule of the E 2 P model explains high-affinity ouabain binding in a mutant of the H,K ATPase P 2 -type ATPases (ion pumps) catalyze active ion transport by coupling autophosphorylation and dephosphorylation to ion movement across lipid bilayers. The Na,K ATPases and the gastric H,K ATPase couple outward transport of sodium or protons to the inward transport of potassium. They are distinguished from the other members of this family by the presence of a glycosylated β subunit tightly bound to the larger catalytic (α) subunit and by the need for K + on their luminal surface for completion of the catalytic cycle. There is about 62% homology between their α subunits and about 35% homology between the gastric β subunit and the Na,K ATPase β 2 isoform (1). The α subunits contain the known binding sites for ATP, ions, and inhibitors. Several avenues of research have defined the biochemical features of the shared transport mechanism (2). Transport is achieved through a series of conformational transitions which alternatively bind the transported ions from the cytoplasm in the E 1 form or from the lumen after autophosphorylation from ATP to give the E 2 P conformer. Conversion to E 2 P is associated with export of the outbound cation with generation of luminal acid in the case of the H,K ATPase. For Na,K and H,K ATPases binding of potassium activates dephosphorylation to give a state with tightly bound ion (E 2 K occluded) in equilibrium with † Supported in part by the U.S. Veterans Administration and NIH Grants DK46917, DK53462, and DK58333. *Corresponding author. . kmunson@ucla.edu. ‡ David ...

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“…Gastric acid suppression can increase (digoxin) or decrease (ketoconazole and itraconazole) the absorption of other drugs, or reduce their solubility, which is considered a drug class effect. PPIs have been reported to reduce the bioavailability of drugs up to 50%, and they can alter drug metabolism by induction or inhibition of the cytochrome P 450 enzymes, particularly in patients taking medications with a narrow therapeutic window (diazepam, phenytoin and warfarin) (27,65). The PPIs with greater potential for drug-drug interactions are omeprazole, esomeprazole and lansoprazole; pantoprazole has a lower potential for drug interactions (66).…”

Section: Drug-drug Interactionsmentioning

confidence: 99%

Proton pump inhibitors in gastroesophageal reflux disease: a custom-tailored therapeutic regimen

Sobrino-Cossío

López-Alvarenga

Remes-Troche

et al. 2012

Rev. esp. enferm. dig.

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The Montreal Definition and Classification divides Gastroesophageal Reflux Disease (GERD) into esophageal symptomatic syndromes (and with mucosal damage) and extraesophageal syndromes (with acid established association and proposed association). In typical GERD symptoms, an 8-week treatment with PPIs is satisfactory in most cases (> 90%). Response rates to PPIs in GERD are highly variable, as they also rely on an appropriate clinical diagnosis of the disease; endoscopy differentiates the macroscopic GERD phenotype. The non-erosive variety (50-70% prevalence) has a different symptomatic response rate, as gastric acid is not the sole etiology of symptoms. The possible explanations of treatment failure include treatment adherence, PPI metabolism alterations and characteristics, and inadequate diagnosis. Refractory symptoms are related to gastric content neutralization by the chronic use of PPIs.Extraesophageal manifestations are associated with other pathophysiological mechanisms where an autonomic nervous system disturbance gives rise to symptoms. In these clinical entities, the relationship between symptoms and acid needs to be established in order to determine the use of PPIs, or consider other drugs. In other words, so as to "custom-tailor the best-fitting therapy" we need to answer the questions for whom, for what, how and for how long. Finally, PPI safety and tolerability are factors to be considered in elderly patients requiring chronic PPI use, who usually have chronic concomitant illnesses.

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Potassium-competitive acid blockade: A new therapeutic strategy in acid-related diseases

Cited by 167 publications

References 101 publications

The gastric HK-ATPase: structure, function, and inhibition

The gastric HK-ATPase: structure, function, and inhibition

Analysis of the Gastric H,K ATPase for Ion Pathways and Inhibitor Binding Sites

Proton pump inhibitors in gastroesophageal reflux disease: a custom-tailored therapeutic regimen

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