An unique catalytic strategy was recently reported for the glmS ribozyme [Bingaman et al., Nat. Chem. Biol.2017, 13, 439-445] that involves promotion of productive hydrogen bonding of the O2' nucleophile to facilitate its activation. We provide broad evidence of this strategy in the hammerhead, pistol, and VS ribozymes and 8-17 DNAzyme, enabled by a functionally important divalent metal ion that interacts with the scissile phosphate and disrupts nonproductive competitive hydrogen bonding with the O2' nucleophile. This strategy, designated tertiary gamma (3°γ) catalysis, illustrates an additional role for divalent ions in ribozyme catalysis.
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