S

Enz-SH

Enz-SH

Figure 4 Mechanism of the acid activation of PPIs. The first step is protonation of the pyridine nitrogen in all the PPIs. This accounts for the accumulation in the parietal cell. The second protonation is the activation step. In all the PPIs, the activating protonation occurs at the nitrogen atom vicinal to the C-2 position of the imidazole ring. (In the particular case of tenatoprazole where X is N instead of C as in all other PPIs, the second protonation is spread throughout the imidazo-pyridine.) This second protonation results in a fraction of the species being present with an activated C-2 position and an unprotonated pyridine, which can then proceed to form the sulfenic acid via a transition state (A1). In solution, this proceeds to form the sulfenamide by dehydration. In the presence of thiols, the sulfenic acid reacts to form the disulfide, hence accelerating the reaction. Either the sulfenic acid or the sulfonamide can react with the luminally accessible cysteine residues of the gastric H + /K+ -ATPase, but it is likely, given the selectivity of cysteine labeling by pantoprazole and tenatoprazole (slowly activated compounds compared with omeprazole, lansoprazole, and tenatoprazole) that is the sulfenic acid formed in the vestibule of the enzyme that is responsible for the inhibition of activity.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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