The disulfide binding of the inhibitor takes place in the luminal sector of the H/K ATPase were 2 mol of inhibitor is bound per 1 mol of active site H/K ATPase.
All PPIs react with cysteine 813 in the loop between TM5 and TM6 on the H/K ATPase, fixing the enzyme in the E2 configuration. Omeprazole reacts with cysteine 813 and 892. Rabeprazole binds to cysteine 813 and both 892 and 321. Lansoprazole reacts with cysteine 813 and cysteine 321, whereas pantoprazole and tenatoprazole react with cysteine 813 and 822.
Reaction with cysteine 822 confers a rather special property to the covalently inhibited enzyme, namely irreversibility to reducing agents. The likely first step is binding of the prodrug protonated on the pyridine of the compound with cysteine 813. Then the second proton is added with acid transport by the H/K ATPase, and the compound is activated. Recent data suggest the hydrated sulfenic acid to be the reactive species forming directly from the mono-protonated benzimidazole bound on the surface of the pump.