Nickel enzymes are critical for the survival of many different organisms; Urease and NiFe-hydrogenase are essential to acid viability in Helicobacter pylori , and Nickel dependent superoxide dismutases (NiSOD) provide defense against oxidative damage in Streptomyces species. The work herein focuses on understanding structure/function relationships in a metallochaperone involved in nickel trafficking and the unique role played by nickel in redox active enzymes. HypA is a metallochaperone in H. pylori that is able to sense both nickel loading and pH changes, which are critical to its proper function. XAS studies show that the structural zinc site is able to change ligand coordination (from a distorted tetrathiolate site to a tetrahedral site) upon Ni binding. Upon lowering the pH, the zinc site undergoes ligand substitution and forms a mixed N/S-donor site. Mutagenesis of the two conserved CxxC motifs, as well as two flanking histidine residues shows how changes at the zinc site are able to affect the nickel binding properties and conformation of HypA, and help sense fluctuations in pH. Superoxide dismutases rely on structural elements to adjust the redox potential of the active site to an optimum value, ~300 mV (vs NHE), to provide a source of protons for catalysis, and to control the access of anions to the active site. These aspects of the catalytic mechanism are examined herein for NiSOD and a series of mutants that affect a key tyrosine residue, Tyr9. Structural studies show that second sphere mutations do not affect the first coordination sphere of NiSOD. Kinetic investigations show that the mutant proteins have impaired but measurable activity. In the case of Y9F-NiSOD, the enzyme exhibits saturation behavior that is not observed in WT-NiSOD and suggests that release of peroxide is inhibited. The crystal structure of Y9F-NiSOD reveals an anion binding site that is occupied by either Cl- or Br- and is located close, but not within bonding distance of the nickel center. The structure of D3A-NiSOD reveals that in addition to affecting the interaction between subunits, this mutation repositions Tyr9 and leads to altered chemistry with peroxide. Proper positioning of second-sphere residues is critical in maintaining the optimal efficiency of NiSOD.