Superoxide dismutases (SOD) are a group of metalloenzymes (containing Fe, Mn, or Cu and Zn) that catalyze the disproportionation of superoxide free radical (O2•–) to form hydrogen peroxide and dioxygen as shown below (Eq. 1) .
These enzymes have been considered the defense system against the cytotoxic superoxide free radical. Moreover, mutants of Cu,Zn-SOD have recently been found to associate with the Gehrig's disease (familial amytrophic lateral sclerosis) . Cu,Zn-SOD is a prototypical dinuclear metalloprotein that has been subjected to extensive mechanistic and spectroscopic studies. The structure of the enzyme from bovine erythrocytes (dimer with MW = 32,000 Da) has been determined at 2.0 Å resolution by the use of X-ray crystallography which revealed a distorted square pyramidal Cu2+ and a distorted tetrahedral Zn2+ in the active site . The Cu2+ site is responsible of the catalysis and is coordinated by four His residues (His-44, His-46, His-61, and His-118) and a water molecule, and the Zn2+ site is bound to the protein through His-61, His-69, His-78, and Asp-81 (Figure 1). The two metal ions are 6.3 Å away from each other and bridged by the imidazolate of the His-61 residue. The positively charged Arg-141 located in the active site channel about 5 Å away from the Cu has been proposed to play a key role in the catalysis by providing an electric gradient to attract the negatively charged O2•– substrate. Studies focusing on this residue by means of chemical modification  and inhibitor (phosphate) binding  also indicate the significance of this residue in Cu,Zn-SOD catalysis.
 Valentine, J. S., and Pantoliano, M. W. 1981, in Copper Proteins, Spiro, T. G., (Ed.), Wiley: NY, Vol. 3, Chapter 8.
 (a) Radunovic, A., Shaw, C. E., Akman-Demir, G., Idrisoglu, H., and Leigh, P. N. 1997, "CuZnSOD-associated amyotrophic lateral sclerosis" Ann. Neurol., 42, 273-274. (b) Hart, P. J., Liu, H., Pellegrini, M., Nersissian, A. M., Gralla, E. B., Valentine, J. S., and Eisenberg, D. 1998, "Subunit asymmetry in the three-dimensional structure of a human CuZnSOD mutant found in familial amyotrophic lateral sclerosis" Protein Sci., 7, 545-555
 Tainer, J. A., Getzoff, E. D., Beem, K. M., Richardson, J. S., and Richardson, D. C. 1982, "Determination and analysis of the 2 Å-structure of copper, zinc superoxide dismutase" J. Mol. Biol., 160, 181-217
 Mota de Freitas, D., Ming, L.-J., Ramasamy, R., and Valentine, J. S. 1990, "35Cl and 1H NMR Study of Anion Binding to Reduced Bovine Copper-Zinc Superoxide Dismutase" Inorg. Chem., 29, 3512-3518.
 (a) Mota de Freitas, D., and Valentine, J. S. 1984, "Phosphate is an inhibitor of copper-zinc superoxide dismutase" Biochemistry, 23, 2079-2082. (b) Mota de Freitas, D., Luchinat, C., Banci, L., Bertini, I., and Valentine, J. S. 1987, "31P NMR study of the interaction of inorganic phosphate with bovine copper-zinc superoxide dismutase" Inorg. Chem., 26, 2788-2791.
 (a) Ming, L.-J., and Valentine, J. S. 1987, "Preparation and characterization of Cu2Ni2 and Ag2Ni2 superoxide dismutase, two new metal-substituted derivatives" J. Am. Chem. Soc., 109, 4426-4428. (b) Ming, L.-J., Banci, L., Luchinat, C., Bertini, I., and Valentine, J. S. 1988, "Characterization of copper-nickel and silver-nickel bovine superoxide dismutase by 1H NMR spectroscopy" Inorg Chem., 27, 4458-4463.
 Ming, L.-J., and Valentine, J. S. 1990, "NMR studies of nickel(II)-substituted derivatives of bovine copper-zinc superoxide dismutase with nickel(II) bound in the copper site" J. Am. Chem. Soc., 112, 6374-6383.
 Bertini, I., Luchinat, C., Ming, L.-J., Piccioli, M., Sola, M., and Valentine, J. S. 1992, "Two-dimensional 1H NMR studies of the paramagnetic metalloenzyme copper-nickel superoxide dismutase" Inorg. Chem., 31, 4433-4435.
 Bertini, I., Lanini, G., Luchinat, C., Messori, L., Monnanni, R., Scozzafava, A. 1985, "Investigation of Cu2Co2SOD and its anion derivatives. 1H NMR and electronic spectra" J. Am. Chem. Soc., 107, 4391-4396.