20.500.12556/DiRROS-28694 Monovalent ions aid catalysis of two-metal-ion dependent RNA editors The cleavage and formation of phosphodiester bonds in nucleic acids is performed by diverse cellular machineries ranging from small protein enzymes to large complexes composed of proteins and/or RNA strands. While it has long been believed that these processes depend solely on a two-metal-ion mechanism, comparative structural analyses revealed that some complexes also contain highly conserved second-shell monovalent cations. The two-Mg2+-aided catalytic mechanism, in which both ions function as Lewis acids, with one metal activating the nucleophile (water or ribose hydroxyl) for the scissile phosphate group attack and the other stabilizing the leaving group, is well-established. In contrast, the function of monovalent ions has been largely overlooked, yielding divergent results across different catalytic settings. Nevertheless, recent evidence points to monovalent ions assisting catalysis beyond their roles in RNA folding and assembly. Here, building on recent computational studies on two-metal-ion dependent ribozymes, we showcase how divalent and monovalent ions finely tune the catalytic site arrangements and dynamics, affecting the kinetic and thermodynamic properties of RNA cleavage reactions. We discuss optimal catalytic mechanisms depending on nucleophile type and illuminate strategies adopted by second-shell monovalent ions to optimize catalytic geometries, which enable efficient proton transfer from nucleophile to the leaving group, a key event for effective catalysis. This review expands understanding of nucleic acid-processing machinery, providing key knowledge for potentially designing innovative gene-modulating tools and therapeutic strategies. two-metal-ion catalytic mechanism monovalent metal ion phosphodiester bond cleavage spliceosome ribonuclease biokemija RNK nukleinske kisline kataliza geni terapevtske strategije true false true Angleški jezik Slovenski jezik © 2026 The Authors. Published by Elsevier B.V. Neznano 2026-03-30 09:11:35 2026-03-30 09:24:44 2026-03-31 04:01:12 0000-00-00 00:00:00 2026 0 0 Nasl. z nasl. zaslona; Opis vira z dne 19. 3. 2026; str. 1-12 Vol. 557, [article no.] 217754 Jun. 2026 0000-00-00 Zaloznikova Objavljeno apc 0000-00-00 0000-00-00 2026-06-01 577 1873-3840 10.1016/j.ccr.2026.217754 272188931 https://www.sciencedirect.com/science/article/pii/S0010854526001906 1 b157112f-2c07-11f1-bbb2-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=42667 RAZ_Borisek_Jure_2026.pdf RAZ_Borisek_Jure_2026.pdf 1 FE2E94295CF90751A40D811B8DA70252 e9b5a606a6362e34b09961260b83d9eee2549538fc16a288f9dd882598bc1e65 67ff8f19-2c09-11f1-bbb2-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=42670 Kemijski inštitut 0 0 0