Evidence for a Catalytic Strategy to Promote Nucleophile Activation in Metal-Dependent RNA-Cleaving Ribozymes and 8-17 DNAzyme

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 degrees gamma) catalysis, illustrates an additional role for divalent ions in ribozyme catalysis.