Copper-zinc superoxide dismutase mutants

CD spectroscopy has also provided valuable insight into the chemical stability and chemical denaturation of proteins. A recent study by Rumfeldt etal. examines the guanidinium-chloride induced denaturation of mutant copper-zinc superoxide dismutases (SODs). These mutant forms of the Cu, Zn-SOD enzyme are associated with toxic protein aggregation responsible for the pathology of amyotrophic lateral sclerosis. In this study, CD spectroscopy was used in conjunction with tryptophan fluorescence, enzyme activity, and sedimentation experiments to study the mechanism by which the mutated enzyme undergoes chemical denaturation. The authors found that the mutations in the enzyme structure increased the susceptibihty of the enzyme to form partially unfolded destabilized monomers, rather than the stable metaUated monomer intermediate or native metallated dimer. 

Goto JJ, Gralla EB, Valentine JS, Cabelli DE. (1998) Reactions of hydrogen peroxide with FALS mutant human copper-zinc superoxide dismutases studied by pulse radiolysis. J Biol Chem 273 30104-30109. 

These are (1) the copper-zinc superoxide dismutases, CuZnSOD, °° ° found in almost all eukaryotic cells and a very few prokaryotes, and (2) the manganese and iron superoxide dismutases, MnSOD and FeSOD, the former found in the mitochondria of eukaryotic cells, and both found in many prokaryotes. Recent studies of bacterial and yeast mutants that were engineered to contain no superoxide dismutases demonstrated that the cells were unusually sensitive... 

ALS occurs in sporadic and familial forms. The pathogenesis of neuronal degeneration in both sporadic and familial ALS may involve mutations in copper/zinc superoxide dismutase, mitochondrial dysfunction (alterations in respiratory complexes I and III), protein aggregation, and neuroinflammation (Aimer et al., 2001 Liu et al., 2002). Cytosolic Cu/Zn superoxide dismutase (SODl) is a ubiquitous small cytosolic metalloenzyme that catalyzes the conversion of superoxide anion to hydrogen peroxide. The mutant copper/zinc superoxide dismutase exhibits a toxic gain of function that adversely affects the function of neurons in the spinal cord, brain stem, and motor cortex. 

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