Journal Article

DKFZ-2025-00403

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Site-specific activation of the proton pump inhibitor rabeprazole by tetrathiolate zinc centres.

Marker, T. (First author)DKFZ* ; Steimbach, R.DKFZ* ; Perez-Borrajero, C. ; Luzarowski, M. ; Hartmann, E. ; Schleich, S.DKFZ* ; Pastor-Flores, D.DKFZ* ; Espinet, E. ; Trumpp, A.DKFZ* ; Teleman, A.DKFZ* ; Gräter, F. ; Simon, B. ; Miller, A.DKFZ* ; Dick, T. (Last author)DKFZ*

2025
Nature Publishing Group London

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Please use a persistent id in citations: doi:10.1038/s41557-025-01745-8

Abstract: 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.

Note: DKFZ-ZMBH Alliance / 2025 Apr;17(4):507-517 /#EA: A160#LA:A160#

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Contributing Institute(s):

1. A160 Redoxregulation (A160)
2. AG Wirkstoffforschung (A390)
3. B140 Signal Transduction in Cancer (B140)
4. A010 Stammzellen und Krebs (A010)
5. DKTK HD zentral (HD01)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 20 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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