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	Ulcers caused by the bacterium ''Helicobacter pylori'' can be treated using Esomeprazole in conjunction with proper antibiotics [1]. Gastric acid is released through the H+/K+-ATPase pump, which is the final step in acid release [2]. Esomeprazole is a specific, irreversible inhibitor of the pump [2].		Ulcers caused by the bacterium ''Helicobacter pylori'' can be treated using Esomeprazole in conjunction with proper antibiotics [1]. Gastric acid is released through the H+/K+-ATPase pump, which is the final step in acid release [2]. Esomeprazole is a specific, irreversible inhibitor of the pump [2].
-	[[Image:PPI gif.gif]] [6]	+	[[Image:PPI gif.gif]] '''Function of PPIs'''[6]
	== H+/K+-ATPase ==		== H+/K+-ATPase ==

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Revision as of 20:39, 6 December 2013

Contents 1 Introduction 2 H+/K+-ATPase 3 Conformational Change and Signaling Pathway of H+/K+-ATPase 4 Esomeprazole Mechanism 5 Drug-Molecule Interaction 6 Esomeprazole Resistance 7 References

Introduction

Esomeprazole is the (S) enantiomer of Omeprazole. Esomperazole is a Proton Pump Inhibitor (PPI) that binds to H+/K+-ATPase and inhibits the secretion of gastric acid from parietal cells into the lumen of the stomach. Esomeprazole’s commercial brand name, Nexium, is used to treat Gastro-esophageal Reflux Disease (GERD), peptic and gastric ulcers, and Zollinger-Ellison syndrome [1].

Ulcers caused by the bacterium Helicobacter pylori can be treated using Esomeprazole in conjunction with proper antibiotics [1]. Gastric acid is released through the H+/K+-ATPase pump, which is the final step in acid release [2]. Esomeprazole is a specific, irreversible inhibitor of the pump [2].

                                          Function of PPIs[6]

H+/K+-ATPase

The H+/K+-ATPase pump is part of the P-type ATPase family located within the cytoplasmic membrane of resting parietal cells; powered through ATP hydrolysis, the ATPase is translocated to the canalicular membrane and begins to pump cytoplasmic H+ into the canalicular space, in exchange for extracellular K+ ions. H+/K+-ATPase is an α,β-heterodimeric enzyme, where the catalytic site is present in the α subunit [7]. Transmembrane segments TM4, TM5, TM6, and TM8, are located in the α subunit and contain the ion binding region of the enzyme [7]. Binding of ions and ATP to these domains will induce movements in the membrane domain that catalyze ion displacement [7]. Targeting this enzyme using PPIs is the most effective therapeutic control agent of gastric acid secretion [8].

                                      [9]       [10]

Conformational Change and Signaling Pathway of H+/K+-ATPase

Inorganic Pi produced from the hydrolysis of ATP drives a conformational change in the enzyme and allows release of H+ into the highly acidic environment [11]. The enzyme catalyzes this reaction by changing conformation states between E1 and E2 [12]. H+/K+-ATPase pumps are normally inactive and inside vesicles [13]. These vesicles are activated through a signaling pathway.

H+/K+-ATPase signal pathway (acetylcholine, histamine, and gastrin) activates the pump in order to move the vesicles toward the lumen [13]. These signals bind to their corresponding receptors and activate the cAMP and Ca2+ dependent pathways [13]. Increased levels of intracellular Ca2+ and cAMP will promote the translocation of vesicles to the canalicular membrane, activating the H+/K+-ATPase [13]. Histamine binds to Histamine H2, and sends a signal through a G protein which activates adenylate cyclase, and catalyzes the conversion of ATP to cAMP [13].Gastrin will stimulate the release of histamine by binding to CCK2 [13]. Acetylcholine binds to Muscarinic M3 and releases Ca2+ from the endoplasmic reticulum [13].

                                      [14]

Esomeprazole Mechanism

Esomeprazole is protonated twice within the acidic environment, and forms the active inhibitor—achiral sulfenamide at pKa of 1.0 [15]. The mechanism by which Esomeprazole is converted is as follows: the pyridine ring is first protonated (1), which alters the configuration of the enzyme to the E2 form. Esomeprazole accumulates in the stimulated secretory canaliculus of the parietal cell. As H+ is being transported by the ATPase, the second H+ is added onto the benzimidazole moiety (2) [7]. The bis-protonated forms are in equilibrium with the unprotonated pyridine and protonated benzimidazole rings [7].The protonated benzimidazole ring reacts with the unprotonated pyridine moiety enabling intramolecular rearrangement, resulting in a tetracyclic sulfenic acid (3) [7]. The sulfenic acid is dehydrated to form an active sulfenamide; both are thiophilic agents that are permanently cationic and membrane impermeable (4) [16]. Sulfenamide can form disulfide bonds with Cys813 residues located between TM5 and TM6 loops and a Cys892 located between the TM7 and TM8 loops on the α subunit of the H+/K+-ATPase(5) [17].

Drug-Molecule Interaction

spinqualitylabelsall models H+/K+-ATPase Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

The interaction between Esomeprazole and H+/K+-ATPase has not yet been crystallized [18]. Data obtained from the crystallized structure of a SCH28080-ATPase provides structural and binding site information [19]. SCH28080 is a competitive K+ inhibitor that interacts with the enzyme’s Phe126 residue and prevents disulfide bond formation between Omeprazole and Cys813, suggesting mutually exclusive inhibitions and an overlapping binding site [19]. The crystallized structure of SCH28080-ATPase shows the same luminal-open (E2) conformation as Esomeprazole, and is the first and only crystallized evidence of PPI-ATPase binding site and conformational change [19]. Using this information, the SCH28080-ATPase crystallized structure provides evidence of the two binding sites, Cys813 and Cys892 [18,19]. Cys 813 and Cys 892 residues are within the . Here are the at the binding pocket of Esomeprazole.

Esomeprazole Resistance

Resistance to treatment with PPIs, including Esomeprazole, has been speculated among Barrett’s Esophagus (BE) patients who did not indicate any symptomatic improvement after being placed on a standard PPI drug dose [20]. No contributory mutations causing PPI resistance have been found [20]. It is speculated that the high acid exposure in BE patients may be due to “reflux diathesis” rather than resistance to gastric acid secretion [21]. Other possible reasons for PPI failure include Helicobacter pylori infection, rapid metabolism, and bioavailability; reasons of clinical significance include delayed gastric emptying and visceral hypersensitivity [20]. More studies need to be conducted to understand the mechanisms underlying the development of resistance to PPIs [20].

References