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ACS Chem Biol. 2019 Jun 21;14(6):1068-1076. doi: 10.1021/acschembio.9b00202. Epub 2019 Jun 7.

An Ontology for Facilitating Discussion of Catalytic Strategies of RNA-Cleaving Enzymes.

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Department of Chemistry, Center for RNA Molecular Biology, and Department of Biochemistry, Microbiology, and Molecular Biology , The Pennsylvania State University , University Park , Pennsylvania 16802 , United States.
Department of Chemistry , University of Florida , Gainesville , Florida 32611 , United States.
Department of Chemistry and Department of Biochemistry and Molecular Biology , The University of Chicago , Chicago , Illinois 60637 , United States.
Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine, Department of Chemistry and Chemical Biology , Rutgers University , Piscataway , New Jersey 08854-8087 , United States.


A predictive understanding of the mechanisms of RNA cleavage is important for the design of emerging technology built from biological and synthetic molecules that have promise for new biochemical and medicinal applications. Over the past 15 years, RNA cleavage reactions involving 2'-O-transphosphorylation have been discussed using a simplified framework introduced by Breaker that consists of four fundamental catalytic strategies (designated α, β, γ, and δ) that contribute to rate enhancement. As more detailed mechanistic data emerge, there is need for the framework to evolve and keep pace. We develop an ontology for discussion of strategies of enzymes that catalyze RNA cleavage via 2'-O-transphosphorylation that stratifies Breaker's framework into primary (1°), secondary (2°), and tertiary (3°) contributions to enable more precise interpretation of mechanism in the context of structure and bonding. Further, we point out instances where atomic-level changes give rise to changes in more than one catalytic contribution, a phenomenon we refer to as "functional blurring". We hope that this ontology will help clarify our conversations and pave the path forward toward a consensus view of these fundamental and fascinating mechanisms. The insight gained will deepen our understanding of RNA cleavage reactions catalyzed by natural protein and RNA enzymes, as well as aid in the design of new engineered DNA and synthetic enzymes.


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