User:Alisha, Deepa, Pamiz/Sandbox 1

From Proteopedia

proteopedia linkproteopedia link

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

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 the 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.[CITATION??] 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

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 (Figure 1); 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. It is a pro-drug that is protonated twice in the acidic environment of the parietal cell to form the active inhibitor, sulfenamide which forms disulfide bonds with Cys 813 and Cys 892 on the α subunit of the H+/K+-ATPase.3 Targeting this enzyme using PPIs is the most effective therapeutic control agent of gastric acid secretion.3 Esomeprazole is an α,β-heterodimeric enzyme, where the catalytic site is present in the α subunit (Figure 2).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

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.5 The enzyme catalyzes this reaction by changing conformation states between E1 and E2 (Scheme 1).6 H+/K+-ATPase pumps are normally inactive and inside vesicles.9 These vesicles are activated through a signaling pathway

Esomeprazole Mechanism

Esomeprazole is protonated twice within the acidic environment, and forms the active inhibitor—achiral sulfenamide at pKa of 1 (Scheme 2).11 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).12 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).14

Drug-Molecule Interaction

The interaction between Esomeprazole and H+/K+-ATPase has not yet been crystallized.15 Data obtained from the crystallized structure of a SCH28080-ATPase provides structural and binding site information.16 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.16 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.16 Using this information, the SCH28080-ATPase crystallized structure provides evidence of the two binding sites, Cys813 and Cys892.15,16 The binding pocket, as proposed using SCH28080 includes the following residues: Glu936, Lys791, Glu795, Cys813, Cys892, Phe126, and Glu822 (Figure 5). The negatively charged residues within the TM domains are important for K+ binding and are conserved in all P-type ATPases.16 The SCH28080 model shows that electrostatic and hydrophobic factors affect drug-enzyme interaction.16