TY  - JOUR
AU  - Marker, Teresa
AU  - Steimbach, Raphael
AU  - Perez-Borrajero, Cecilia
AU  - Luzarowski, Marcin
AU  - Hartmann, Eric
AU  - Schleich, Sibylle
AU  - Pastor-Flores, Daniel
AU  - Espinet, Elisa
AU  - Trumpp, Andreas
AU  - Teleman, Aurelio
AU  - Gräter, Frauke
AU  - Simon, Bernd
AU  - Miller, Aubry
AU  - Dick, Tobias
TI  - Site-specific activation of the proton pump inhibitor rabeprazole by tetrathiolate zinc centres.
JO  - Nature chemistry
VL  - 17
IS  - 4
SN  - 1755-4330
CY  - London
PB  - Nature Publishing Group
M1  - DKFZ-2025-00403
SP  - 507-517
PY  - 2025
N1  - DKFZ-ZMBH Alliance / 2025 Apr;17(4):507-517 /#EA: A160#LA:A160#
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:39979415
DO  - DOI:10.1038/s41557-025-01745-8
UR  - https://inrepo02.dkfz.de/record/298993
ER  -