Marker Teresa, Steimbach Raphael R, Perez-Borrajero Cecilia, Luzarowski Marcin, Hartmann Eric, Schleich Sibylle, Pastor-Flores Daniel, Espinet Elisa, Trumpp Andreas, Teleman Aurelio A, Gräter Frauke, Simon Bernd, Miller Aubry K, Dick Tobias P
Division of Redox Regulation, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany.
Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
Nat Chem. 2025 Apr;17(4):507-517. doi: 10.1038/s41557-025-01745-8. Epub 2025 Feb 20.
Proton pump inhibitors have become top-selling drugs worldwide. Serendipitously discovered as prodrugs that are activated by protonation in acidic environments, proton pump inhibitors inhibit stomach acid secretion by covalently modifying the gastric proton pump. Despite their widespread use, alternative activation mechanisms and potential target proteins in non-acidic environments remain poorly understood. Employing a chemoproteomic approach, we found that the proton pump inhibitor rabeprazole selectively forms covalent conjugates with zinc-binding proteins. Focusing on DENR, a protein with a C4 zinc cluster (that is, zinc coordinated by four cysteines), we show that rabeprazole is activated by the zinc ion and subsequently conjugated to zinc-coordinating cysteines. Our results suggest that drug binding, activation and conjugation take place rapidly within the zinc coordination sphere. Finally, we provide evidence that other proton pump inhibitors can be activated in the same way. We conclude that zinc acts as a Lewis acid, obviating the need for low pH, to promote the activation and conjugation of proton pump inhibitors in non-acidic environments.
质子泵抑制剂已成为全球畅销药物。质子泵抑制剂最初是偶然发现的前体药物，在酸性环境中通过质子化被激活，通过共价修饰胃质子泵来抑制胃酸分泌。尽管它们被广泛使用，但在非酸性环境中的替代激活机制和潜在靶蛋白仍知之甚少。采用化学蛋白质组学方法，我们发现质子泵抑制剂雷贝拉唑与锌结合蛋白选择性地形成共价缀合物。聚焦于具有C4锌簇（即由四个半胱氨酸配位锌）的蛋白质DENR，我们表明雷贝拉唑被锌离子激活，随后与锌配位半胱氨酸缀合。我们的结果表明，药物结合、激活和缀合在锌配位球内迅速发生。最后，我们提供证据表明其他质子泵抑制剂也可以以同样的方式被激活。我们得出结论，锌作为路易斯酸，无需低pH值，即可促进非酸性环境中质子泵抑制剂的激活和缀合。
