The mechanism of action of the antisecretory agent omeprazole

Lindberg, Per; Nordberg, Peter; Alminger, Tomas; Brändström, Arne; Wallmark, Björn

doi:10.1021/jm00158a001

Cited by 294 publications

(86 citation statements)

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“…The labeling with omeprazole followed by thermolysin digestion of the labeled TM5/TM6 peptide showed indeed that labeling was at cysteine 813. Given the cationic nature and bulk of the omeprazole sulfenamide (11,12,23,24,30), Cys-813 is probably exposed at the extracytoplasmic surface. Fig.…”

Section: Discussionmentioning

confidence: 99%

“…This pK a and the membrane permeability of the unprotonated form result in their selective accumulation in the acidic space of the secretory canaliculus of the active parietal cell or in the acid transporting gastric-derived vesicles studied here. Following accumulation, the compounds undergo an acid-catalyzed rearrangement to a cationic sulfenamide in the extracytoplasmic space (11,12). This cationic sulfenamide is relatively membrane impermeant and is able to react with thiol groups within the catalytic subunit of the H,K-ATPase to form relatively stable disulfides (13,24,30).…”

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confidence: 99%

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Sites of Reaction of the Gastric H,K-ATPase with Extracytoplasmic Thiol Reagents

Besancon

Simon²,

Sachs

et al. 1997

Journal of Biological Chemistry

244

178

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The vesicular gastric H,K-ATPase catalyzes an electroneutral H for K exchange allowing acidification of the intravesicular space. There is a total of 28 cysteines present in the ␣ subunit of the gastric H,K-ATPase, of which 10 are found in the predicted transmembrane segments and their connecting loop, and 9 are present in the ␤ subunit, of which 6 are disulfide-linked. To determine which of these was accessible to extracytoplasmic attack, the enzyme was inhibited by four different sub- , under acid transporting conditions. All of these compounds are weak bases that accumulate in the acidic space generated by the pump and undergo an acid catalyzed rearrangement to a cationic sulfenamide, which forms disulfides with accessible cysteines. The relative rates of acid activation of these compounds corresponded to the relative rates of inhibition of ATPase activity and acid transport. Fragmentation of the enzyme by trypsin followed by SDS-polyacrylamide gel electrophoresis showed that omeprazole bound covalently to one of the two cysteines in the domains containing the fifth and sixth transmembrane segments and their extracytoplasmic loop and to cysteine 892 in the loop between the seventh and eighth transmembrane segments, but inhibition correlated with the reaction with cysteines in the fifth and sixth domain. Lansoprazole bound to the cysteines in these two domains as well as to cysteine 321 toward the extracytoplasmic end of the third transmembrane segments. Pantoprazole bound only to either cysteine 813 or 822 in the fifth and sixth transmembrane region. The inhibition of Rabeprazole correlated also with its binding to this part of the protein, but this compound continued to bind after full inhibition, eventually binding also to cysteines 321 and 892. No binding was found to any of the cysteines in the seventh to tenth transmembrane segments. Thermolysin digestion of the isolated omeprazole-labeled fifth and sixth transmembrane pair showed that cysteine 813 was the site of labeling. It is concluded that binding of these sided reagents to cysteine 813 in the loop between transmembrane (TM)5 and TM6 is sufficient for inhibition of ATPase activity and acid transport by the gastric acid pump. Of the 10 cysteines present in the membrane and extracytoplasmic domain, only three are exposed sufficiently to allow reactivity with these cationic thiol reagents. The binding to cysteine 813 defines the location of the extracytoplasmic loop between TM5 and TM6 and places the carboxylic acids 820 and 824 conserved between the gastric H,K-and the Na,K-ATPases in TM6, consistent with their assumed role in cation binding.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Sites of Reaction of the Gastric H,K-ATPase with Extracytoplasmic Thiol Reagents

Besancon

Simon²,

Sachs

et al. 1997

Journal of Biological Chemistry

244

178

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“…Some marketed drugs like omeprazole consist of modified imidazole as a core unit [68]. Nikoofar et al [69] synthesized ZnO-nanorods.…”

Section: Synthesis Of Imidazolesmentioning

confidence: 99%

Recent developments on nano-ZnO catalyzed synthesis of bioactive heterocycles

Banerjee

2017

J Nanostruct Chem

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Last decade has seen tremendous applications of nano-ZnO as a mild, cheap, efficient, commercially available, environmentally benign, non-toxic, reusable, heterogeneous catalyst for the various organic transformations. The present review summarizes the applications of nano-ZnO as an efficient heterogeneous catalyst for the synthesis of diverse biologically relevant heterocycles reported so far. Graphical abstract Nano

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“…Omeprazole (Figure 1), a substituted benzimidazole, is a potent inhibitor of gastric acid secretion widely used against acid-related diseases such as peptic ulcer disease and gastroesophageal reflux disease. 11 Omeprazole contains a tricoordinated sulfur atom in a pyramidal structure and therefore can exist in two different optically active forms, (S)-and (R)-omeprazole. Omeprazole was first approved as a racemic mixture, but the (S) isomer was recently introduced on the market.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective analysis of omeprazole in pharmaceutical formulations by chiral high-performance liquid chromatography and capillary electrophoresis

Bonato¹,

Paias²

2004

J. Braz. Chem. Soc.

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Foram desenvolvidos dois métodos sensíveis e simples baseados em cromatografia líquida de alta eficiência e eletroforese capilar (EC) para a análise enantiosseletiva de omeprazol em formulações. O omeprazol racêmico e (S)-omeprazol foram extraídos de comprimidos disponíveis comercialmente usando metanol:NaOH 2,5 mol L -1 (90:10, v/v). A separação quiral do omeprazol por HPLC foi obtida empregando a coluna CHIRALPAK AD, fase móvel composta por hexano:etanol (40:60, v/v) e detecção em 302 nm. A resolução dos enantiômeros do omeprazol por EC foi obtida empregando β-ciclodextrina sulfatada (3% em tampão fosfato, 20 mmol L -1 , pH 4.0) e detecção em 202 nm.We developed two sensitive and simple assay procedures based on high-performance liquid chromatography and capillary electrophoresis (CE) for the enantioselective analysis of omeprazole in pharmaceutical formulations. Rac-omeprazole and (S)-omeprazole were extracted from commercially available tablets using methanol:NaOH 2.5 mol L -1 (90:10, v/v). Chiral HPLC separation of omeprazole was obtained on a CHIRALPAK AD column using hexane:ethanol (40:60, v/v) as the mobile phase and detection at 302 nm. The resolution of omeprazole enantiomers by CE was carried out using 3% sulfated β-cyclodextrin in 20 mmol L -1 phosphate buffer, pH 4.0 and detection at 202 nm.

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The mechanism of action of the antisecretory agent omeprazole

Cited by 294 publications

References 0 publications

Sites of Reaction of the Gastric H,K-ATPase with Extracytoplasmic Thiol Reagents

Sites of Reaction of the Gastric H,K-ATPase with Extracytoplasmic Thiol Reagents

Recent developments on nano-ZnO catalyzed synthesis of bioactive heterocycles

Enantioselective analysis of omeprazole in pharmaceutical formulations by chiral high-performance liquid chromatography and capillary electrophoresis

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