The metal-activated hydroxide ion is a critical nucleophile in metalloenzymes that catalyze hydrolysis or hydration reactions. The most common metal used is zinc; occasionally, other transition metals such as manganese are required. Human carbonic anhydrase II and rat liver arginase serve as well-studied paradigms of zinc and manganese metalloenzymes, respectively. Comparative structure-function relationships between these two metalloenzymes highlight parallels in the chemistry of metal-activated hydroxide: () the protein environment of metal-bound hydroxide modulates its reactivity; () a hydrogen bond with metal-bound hydroxide holds it in the proper orientation for catalysis; () nonmetal substrate-binding sites are implicated in both enzyme mechanisms; and () regeneration of metal-bound hydroxide ion from a metal-bound water molecule requires proton transfer to bulk solvent mediated by a histidine proton shuttle residue. Interestingly, the electrostatics of catalysis differ between the two enzymes, in that the first step of catalysis requires formation of a negatively charged transition state in the carbonic anhydrase II mechanism, whereas a neutral transition state is approached in the arginase mechanism. This electrostatic feature may contribute to the differences in the chemistry, the metal binding sites, and the metal specificity between these two enzymes.


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  • Article Type: Review Article
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