SCH28080 prevents omeprazole inhibition of the gastric H+/K+-ATPase

Hersey, S. J.; Steiner, László; Mendlein, John; Rabon, E.; Sachs, George

doi:10.1016/0167-4838(88)90296-8

Cited by 32 publications

(28 citation statements)

References 18 publications

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“…In fact, omeprazole inhibition of gastric proton pump was partly prevented by SCH 28080 in the gastric microsomal preparation (43). On the other hand, as reported in the present study, the side chain of Tyr 801 is not involved in the interaction with omeprazole.…”

Section: Discussionsupporting

confidence: 64%

“…The C815T mutant showed a 5-fold higher K i value for SCH 28080 in the NH 4 ϩ -stimulated ATPase activity (22). SCH 28080 was reported to prevent the irreversible inhibition of acid transport by omeprazole (43). Therefore, the binding site of SCH 28080 seems to be partially overlapped with that of omeprazole.…”

Section: Construction Of M5 Mutants Of the Gastric Proton Pumpmentioning

confidence: 86%

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The Cavity Structure for Docking the K+-competitive Inhibitors in the Gastric Proton Pump

Asano¹,

Yoshida

Yashiro

et al. 2004

Journal of Biological Chemistry

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2-Methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine-3-acetonitrile (SCH 28080) is a reversible inhibitor specific for the gastric proton pump. The inhibition pattern is competitive with K ؉ . Here we studied the binding sites of this inhibitor on the putative three-dimensional structure of the gastric proton pump ␣-subunit that was constructed by homology modeling based on the structure of sarcoplasmic reticulum Ca 2؉ pump. Alanine and serine mutants of Tyr 801 located in the fifth transmembrane segment of the gastric proton pump ␣-subunit retained the 86 Rb transport and K ؉ -dependent ATPase (K ؉ -ATPase) activities. These mutants showed 60 -80-times lower sensitivity to SCH 28080 than the wild type in the 86 Rb transport activity. The K ؉ -ATPase activities of these mutants were not completely inhibited by SCH 28080. The sensitivity to SCH 28080 was dependent on the bulkiness of the side chain at this position. Therefore, the side chain of Tyr 801 is important for the interaction with this inhibitor. In the three-dimensional structure of the E 2 form (conformation with high affinity for K ؉ ) of the gastric proton pump, Tyr 801 faces a cavity surrounded by the first, fourth, fifth, sixth, and eighth transmembrane segments and fifth/sixth, seventh/eighth, and ninth/tenth loops. SCH 28080 can dock in this cavity. However, SCH 28080 cannot dock in the same location in the E 1 form (conformation with high affinity for proton) of the gastric proton pump due to the drastic rearrangement of the transmembrane helices between the E 1 and E 2 forms. These results support the idea that this cavity is the binding pocket of SCH 28080.The gastric H ϩ ,K ϩ -ATPase is a proton pump that is responsible for gastric acid secretion (1). This pump consists of two kinds of subunits, the ␣-and ␤-subunits. The ␣-subunit is the catalytic subunit containing 10 transmembrane segments. The ATP binding site (2, 3) and the cation binding sites are located on this subunit (4 -10). The ␤-subunit is the non-catalytic glycoprotein containing a single transmembrane segment and is involved in stabilization as well as targeting of the ␣-subunit to the plasma membrane (11). This pump belongs to the family of type II P-type ATPases, which include sarcoplasmic reticulum (SR) 1 Ca 2ϩ -ATPase (Ca 2ϩ pump) and Na ϩ ,K ϩ -ATPase (Na ϩ pump) (12).At present, inhibitors specific for the gastric proton pump are classified into two groups. Irreversible inhibitors such as omeprazole, rabeprazole, and lansoprazole, termed the proton pump inhibitors, are the first group. They are activated in acidic lumens, modify the cysteine residues located on the luminal side of the proton pump, and inhibit its pump activity. They are clinically used for controlling hyperacidity. The second classified group of specific proton pump inhibitors are the reversible inhibitors such as SCH 28080 (13) and 3-amino-5-methyl-2-(2-methyl-3-thienyl)imidazo[1,2-a]thieno[3,2-c]pyridine (SPI-447) (Fig. 1) (14), which are described as acid pump antagonists (APAs). They bind to the E 2 or E 2...

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Section: Discussionsupporting

confidence: 64%

Section: Construction Of M5 Mutants Of the Gastric Proton Pumpmentioning

confidence: 86%

The Cavity Structure for Docking the K+-competitive Inhibitors in the Gastric Proton Pump

Asano¹,

Yoshida

Yashiro

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

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“…Evidence was presented that the inhibitor binding site for omeprazole and SCH28080 overlap, since the inhibition of omeprazole under acid-transporting conditions could be prevented by the prior addition of SCH28080 (15). There is also evidence that the inhibition of the H,K-ATPase by the benzimidazole, rabeprazole, has a K ϩ -sensitive component.…”

Section: Table I Expression and Kinetic Parameters Of Wild Type And Mmentioning

confidence: 93%

“…SCH28080 prevented inhibition of acid transport by the benzimidazole, omeprazole (15), suggesting that SCH28080 and omeprazole binding sites overlap. Therefore, mutations of the benzimidazole-labeled cysteines were selected as targets for finding residues that are involved in the binding site of SCH28080.…”

mentioning

confidence: 99%

Comparison of Covalent with Reversible Inhibitor Binding Sites of the Gastric H,K-ATPase by Site-directed Mutagenesis

Lambrecht

Munson

Vagin

et al. 2000

Journal of Biological Chemistry

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“…The first issue was to generate a structure with sufficient space to allow inhibitor entry, that is, a water channel. This was aided by the knowledge of the omeprazole binding site at cysteine 813 and that omeprazole binding and SCH28080 inhibitions were mutually exclusive, 47 thus allowing a general location of the pathway for SCH28080. This hydrated entry is shown in Figure 21, where there is now room for rapid entry and exit of the K competitive inhibitors between TM4 and TM5 the TM5/TM6 loop and TM6.…”

Section: Apasmentioning

confidence: 99%

The Gastric H,K ATPase as a Drug Target

Sachs¹,

Shin²,

Vagin³

et al. 2007

Journal of Clinical Gastroenterology

139

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The recent progress in therapy if acid disease has relied heavily on the performance of drugs targeted against the H,K ATPase of the stomach and the H2 receptor antagonists. It has become apparent in the last decade that the proton pump is the target that has the likelihood of being the most sustainable area of therapeutic application in the regulation of acid suppression. The process of activation of acid secretion requires a change in location of the ATPase from cytoplasmic tubules into the microvilli of the secretory canaliculus of the parietal cell. Stimulation of the resting parietal cell, with involvement of F-actin and ezrin does not use significant numbers of SNARE proteins, because their message is depleted in the pure parietal cell transcriptome. The cell morphology and gene expression suggest a tubule fusion-eversion event. As the active H,K ATPase requires efflux of KCl for activity we have, using the transcriptome derived from 99% pure parietal cells and immunocytochemistry, provided evidence that the KCl pathway is mediated by a KCQ1/KCNE2 complex for supplying K + and CLIC6 for supplying the accompanying Cl − . The pump has been modeled on the basis of the structures of different conformations of the sr Ca ATPase related to the catalytic cycle. These models use the effects of site directed mutations and identification of the binding domain of the K competitive acid pump antagonists or the defined site of binding for the covalent class of proton pump inhibitors. The pump undergoes conformational changes associated with phosphorylation to allow the ion binding site to change exposure from cytoplasmic to luminal exposure. We have been able to postulate that the very low gastric pH is achieved by lysine 791 motion extruding the hydronium ion bound to carboxylates in the middle of the membrane domain. These models also allow description of the K + entry to form the K + liganded form of the enzyme and the reformation of the ion site inward conformation thus relating the catalytic cycle of the pump to conformational models. The mechanism of action of the proton pump inhibitor class of drug is discussed along with the cysteines covalently bound with these inhibitors. The review concludes with a discussion of the mechanism of action and binding regions of a possible new class of drug for acid control, the K + competitive acid pump antagonists.Keywords the H; K ATPase; acid secretion; acid pump antagonist; proton pump inhibitor Acid secretion by the human stomach results in a median diurnal pH of 1.4. At the turn of the 19th century, it was recognized that acid secretion is involved in peptic ulcer disease Reprints: Dr George Sachs, DSc, MD, Membrane Biology, Bldg 113, Rm 324, 11301 Wilshire Blvd., Los Angeles, CA 90073 (gsachs@ucla.edu). Until the introduction of cimetidine, a histamine-2 receptor blocker, 3 there was no therapy that was effective in suppressing acid secretion acceptable to patients. The introduction of this medication and other histamine-2 receptor antagonists revolutionized the t...

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SCH28080 prevents omeprazole inhibition of the gastric H+/K+-ATPase

Cited by 32 publications

References 18 publications

The Cavity Structure for Docking the K+-competitive Inhibitors in the Gastric Proton Pump

The Cavity Structure for Docking the K+-competitive Inhibitors in the Gastric Proton Pump

Comparison of Covalent with Reversible Inhibitor Binding Sites of the Gastric H,K-ATPase by Site-directed Mutagenesis

The Gastric H,K ATPase as a Drug Target

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