Site-specific activation of the proton pump inhibitor rabeprazole by tetrathiolate zinc centres
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.
Authors
- Daniel Pastor‐Flores (ORCID: https://orcid.org/0000-0003-4803-6072)
- Bernd Simon (ORCID: https://orcid.org/0000-0003-0164-5516)
- Aubry K. Miller (ORCID: https://orcid.org/0000-0002-1761-4143)
- Raphael R. Steimbach (ORCID: https://orcid.org/0000-0002-5509-3959)
- Sibylle Schleich
- Elisa Espinet (ORCID: https://orcid.org/0000-0002-0690-9878)
- Aurelio A. Teleman (ORCID: https://orcid.org/0000-0002-4237-9368)
- Cecilia Perez-Borrajero (ORCID: https://orcid.org/0000-0002-3167-7159)
- Frauke Gräter (ORCID: https://orcid.org/0000-0003-2891-3381)
- Marcin Luzarowski (ORCID: https://orcid.org/0000-0002-2115-0468)
- Teresa Marker (ORCID: https://orcid.org/0009-0004-1232-7526)
- Eric Hartmann (ORCID: https://orcid.org/0000-0002-3825-5469)
- Andreas Trumpp (ORCID: https://orcid.org/0000-0002-6212-3466)
- Tobias P. Dick (ORCID: https://orcid.org/0000-0003-1367-973X)
Institutions
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- L.A.C. (Switzerland) (CH)
- Max Planck Institute for Polymer Research (DE)
- Institut de Biologie Intégrative de la Cellule (FR)
- DKFZ-ZMBH Alliance (DE)
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (DE)
- European Molecular Biology Laboratory (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Heidelberg Institute for Theoretical Studies (DE)
- UConn Health (US)
Publication Details
- Journal
- Nature Chemistry
- Published
- 2025-02-20
- DOI
- https://doi.org/10.1038/s41557-025-01745-8
- Citations
- 11
- Primary Topic
- Adenosine and Purinergic Signaling
- Type
- article
- Field-Weighted Citation Impact
- 12.29
Funders
- Deutsches Krebsforschungszentrum
- European Commission
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung