<p>An unique catalytic strategy was recently reported for the <em>glm</em>S ribozyme [Bingaman et al., <cite>Nat. Chem. Biol.</cite> <span class="NLM_year">2017</span>, <em>13</em>, 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.</p>
