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The aggregation of proteins rich in copper, zinc superoxide dismutase (SOD1) has facilitated pathogenesis of amyotrophic lateral sclerosis (ALS). This process is found to be triggered by the presence of double stranded DNA forms by electrostatic reactions between the two molecules.

Various methods like the measurement of amide hydrogen exchange kinetics, for analyzing the local environments are used to examine the conformational structural mobility in the human manganese superoxide dismutase (MnSOD), which consists of dimeric and tetrameric interfaces. The analysis reveals that the residues at such dimeric interfaces exhibit less conformational mobility and freedom, as compared to the residues at the tetrameric interfaces.

Density-functional calculations indicate that the second sphere of coordination around the metal centers of manganese and iron superoxide dismutases (MnSODs and FeSODs) plays an important role in the binding of O2(sup -). Results show that superoxide oxidation by Mn- or Fe- containing superoxide dismutases is facilitated by a cooperative effect between superoxide binding, protonation of the OH(sup -) bound to the metal and electron transfer from the superoxide molecule to the oxidized metal.

Dinuclear copper(II) complexes with N-substituted ligands as superoxide dismutase (SOD) mimics are investigated. The new N-(thiazol-2-yl)toluenesulfonamide (Htz-tol) and N-(thiazol-2-yl)toluenesulfonamide (Htz-tol) and N-(thiazol-2-yl)naphthalene-sulfonamide (Htz-naf) ligands are prepared and structurally characterized.

A study was conducted to show that the coordination of [Zn.sup.2+] to the ALS-associated enzyme Cu/Zn superoxide dismutase (SOD1) is directly controlled by the protein's folding pathway. The relatively rapid equilibration of metals in and out of the SOD1 structure shed light on the exceptionally long lifetime of holoSOD1 which is compatible with cellular turnover.

Manganese superoxide dismutase (MnSOD) from Saccharomyces cerevisiae (ScMnSOD) was purified to study the mechanism of product inhibition and determine its common feature between ScMnSOD and eukaryotic MnSODs. The findings for the optical and electron paramagnetic resonance spectra of ScMnSOD isolated in the [Mn.sup.2+] oxidation state could be used to demonstrate the origin of product inhibition by comparing human MnSOD with ScMnSOD.

The structures of the pathogenic human copper-zinc superoxide dismutase (SOD1) variants D124V and H80R, both of which demonstrate compromised zinc-binding sites are presented. The findings provide support to the view that immature mutant SOD1 species contribute to toxicity in SOD1-linked inherited form of the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS).

The covalent modification observed in human copper-zinc superoxide dismutase (SOD1) was characterized to ascertain it as a novel heptasulfane bridge connecting the two Cys111 residues in the SOD1 homodimer. The modification might provide SOD1 with a toxic gain of function due to the catalytic ability of polysulfanes and polysulfides to catalyze the generation of reaction oxygen and sulfur species.

The characteristics, as well as the structural and biophysical properties of His46Arg (H46R) and His48Gln (H48Q), two pathogenic superoxide dismutase (SOD1) mutations are discussed. These variants are shown to exhibit an ablated copper-binding site and are also able to form stable heterocomplexes with copper chaperone for SOD1.

The semisynthesis and spectroscopic characterization of a series of derivatives with the sequences 243-CACA, 243-CAUA, 243-UACA, and 243-UAUA in the D1 double mutant (C22AC25A) background produced by expressed protein ligation of Sec-containing tetrapeptides to an hCCS-243 truncation is described. The data indicated the involvement of Cys residues in D2 of hCCS formation, stability, and redox potential of the D3 cluster and their significance to the SOD1 thiol/disulfide oxidase activity.d

NMR spectroscopy is used to understand the structure of the SodCII-encoded monomeric Cu, Zn superoxide dismutase from Salmonella enterica. The results provide insight into the functional differences between monomeric and dimeric bacterial Cu, Zn superoxide dismutases and the convergent evolution toward a dimeric structure in prokaryotic and eukaryotic class of enzymes.

The pulse radiolysis technique is employed to study the mechanism of the catalytic action of Mn(II)-pentaazamacrocycle compounds as superoxide dismutase mimetics. The structure and pH of the system are shown to highly affect the initial rate of reaction.

The properties of two site-specific mutants of human manganese superoxide dismutase (MnSOD) in which Glu162 is replaced with Asp (E162D) and Ala (E162A) are examined. The results have shown that Glu162 at the tetrameric interface in human MnSOD has supported stability and efficient catalysis and has an important role in regulating product inhibition.

The effects of the substrate analogues azide and fluoride on the manganese (II) zero-field interactions of different manganese-containing superoxide dimutases (SOD) were measured using the high-field electron parametric resonance spectroscopy. For both azide and fluoride, the extent of binding was no more that 50%, implying either that a second binding site was present or that binding was self-limiting.

The novel SOD fold and Ni active site is identified by the 1.30 armstrong resolution crystal structure of nickel superoxide dismutase (NiSOD). The nine-residue Ni-hook structural motif (His-Cys-X-X-Pro-Cys-Gly-X-Tyr) provides almost all interactions critical for metal binding and catalysis.