Dissociative Transition State in Hepatitis Delta Virus Ribozyme Catalysis

Ribonucleases and small nucleolytic ribozymes are both able to catalyze RNA strand cleavage through 2′-O-transphosphorylation, provoking the question of whether protein and RNA enzymes facilitate mechanisms that pass through the same or distinct transition states. Here, we report the primary and sec...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2023-02, Vol.145 (5), p.2830-2839
Main Authors: Weissman, Benjamin, Ekesan, Şölen, Lin, Hsuan-Chun, Gardezi, Shahbaz, Li, Nan-Sheng, Giese, Timothy J., McCarthy, Erika, Harris, Michael E., York, Darrin M., Piccirilli, Joseph A.
Format: Article
Language:English
Subjects:
Catalysis
Catalytic Domain
Hepatitis Delta Virus - genetics
Hepatitis Delta Virus - metabolism
Kinetics
Nucleic Acid Conformation
RNA - chemistry
RNA, Catalytic - chemistry
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Summary:Ribonucleases and small nucleolytic ribozymes are both able to catalyze RNA strand cleavage through 2′-O-transphosphorylation, provoking the question of whether protein and RNA enzymes facilitate mechanisms that pass through the same or distinct transition states. Here, we report the primary and secondary 18O kinetic isotope effects for hepatitis delta virus ribozyme catalysis that reveal a dissociative, metaphosphate-like transition state in stark contrast to the late, associative transition states observed for reactions catalyzed by specific base, Zn2+ ions, or ribonuclease A. This new information provides evidence for a discrete ribozyme active site design that modulates the RNA cleavage pathway to pass through an altered transition state.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.2c10079