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(2014) DJ-1 Is a Copper Chaperone Acting on SOD1 Activation.

(2009) Loss of Metal Ions, Disulfide Reduction and Mutations Related to Familial ALS Promote Formation of Amyloid-Like Aggregates from Superoxide Dismutase.

Manganese ions have been found to scavenge hydroxyl and superoxide radicals. The mechanism of binding of manganese ions to these reactive oxygen species is not known. Manganese is a crucial component of the metalloenzyme manganese superoxide dismutase (MnSOD). MnSOD is found in mitochondria and is the principal constituent of the mitochondrial oxidant defense system. Rats and mice fed manganese-deficient diets are found to have reduced MnSOD activity in heart muscle and nervous tissue. They also have mitochondrial abnormalities and pathological changes in these tissues. The pathological changes are thought to result from oxidative damage due to the decreased activity of MnSOD which normally would protect against this damage.

Levels of malondialdehyde (MDA) andsuperoxide dismutase (SOD) activity in the serum of rats.
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(2014) Superoxide Dismutases and Superoxide Reductases.

Levels of malondialdehyde (MDA) andsuperoxide dismutase (SOD) activity in the serum of rats.
Photo provided by Flickr

(2011) Structural Instability and Cu-Dependent Pro-Oxidant Activity Acquired by the Apo Form of Mutant SOD1 Associated with Amyotrophic Lateral Sclerosis.

(2010) Strategies for stabilizing superoxide dismutase (SOD1), the protein destabilized in the most common form of familial amyotrophic lateral sclerosis.

(2010) The structural biochemistry of the superoxide dismutases.

(2011) Direct Observation of Defects and Increased Ion Permeability of a Membrane Induced by Structurally Disordered Cu/Zn-Superoxide Dismutase Aggregates.

MDA content and SOD activity inculture supernatants of cardiomyocytes.
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(2015) The Disulfide Bond, but Not Zinc or Dimerization, Controls Initiation and Seeded Growth in Amyotrophic Lateral Sclerosis-linked Cu,Zn Superoxide Dismutase (SOD1) Fibrillation.

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(2006) Control of Superoxide Dismutase by Phosphorylation.


Superoxide Dismutases in Candida albicans: …

(2015) Glycoursodeoxycholic Acid Reduces Matrix Metalloproteinase-9 and Caspase-9 Activation in a Cellular Model of Superoxide Dismutase-1 Neurodegeneration.

Copper- and zinc-containing superoxide dismutase ..

The importance of the protein framework in controlling cofactor activity is a general question in biochemistry that is often difficult to examine quantitatively. WT SOD is an ultrastable protein that is sometimes purified as active protein with techniques as extreme as boiling and organic extraction (), and the extreme specificity of packing and interactions underlying this unusual stability that controls the metal ion cofactor accessibility and activity may make the protein more susceptible to the effects of mutation (). Furthermore, the copper ion is mobile for redox cycling during catalysis (), and thus, the active site must be finely tuned to discriminate among substrates, intermediates, and products that differ by only a single electron. The G93 site is on the opposite end of the β-barrel from the active site, ~19 Å from the copper ion, and ~24 Å from the zinc ion (). This mutation site is, therefore, particularly appropriate for testing of the idea that perturbation of the compact SOD framework can impact the metal ion sites, even for distant mutations. Strikingly, we do find that perturbations that decrease framework stability can, under the right circumstances, result in enhanced protein destabilization that accelerates aggregation ().

ferric reducing antioxidant potential and superoxide dismutase ..

However, copper loss may not be the only result of framework destabilization. Increased conformational flexibility in ALS mutants (such as seen in our ESR experiments) could result in several secondary consequences during conditions of dyshomeostasis (including metal loss), which would, thus, dictate and promote misfolding and aggregation in a mutant-specific fashion, leading to a similar phenotype (aggregation) but with distinct kinetics (). Our hypothesis, thus, also encompasses aspects of the oxidative damage hypothesis, which purports that reactive oxygen species within highly metabolic neurons put SOD at risk for oxidative damage; it was observed for hydrogen peroxide-mediated oxidative damage to active site histidine ligands, leading to copper ion release (). Furthermore, slightly destabilized mutant proteins may be more sensitive to the effects of oxidative modification, such as glutathionylation (), leading to their dissociation and misfolding. The destabilization hypothesis also predicts that loss of Zn () and ALS mutations introduced into covalently linked SOD dimers, such as those previously developed to increase serum half-life of SOD (), would increase disease in animal models of ALS. Placing our biophysical results in the context of SOD structural biochemistry, therefore, provides the basis for a unified mechanistic hypothesis that makes specific testable predictions for disease promotion and intervention.

Abstract Copper-zinc superoxide dismutase ..

Since the framework destabilization hypothesis was proposed (, ), much research has, nevertheless, been aimed at testing correlations between individual or collective ALS SOD mutations and the gain of toxic functions. However, rather than pointing to distinct gain-of-function activities, these results implicate a general loss of structure-based functional stability through direct mutation-induced destabilization of the protein framework and packing or indirect destabilization through loss of copper ions for some active site mutations. Subsequent effects of structural disintegrity point to loss of copper ions, loss of zinc ions, oxidative modifications, destabilization of the dimer interface, and misassembly leading to aggregation/filamentation. This test and extension of the framework destabilization hypothesis, which specifically links destabilization of the SOD fold and assembly with decreased copper ion binding, may explain why Cu, Zn SOD destabilizing mutants promote ALS, whereas mutations of the tetrameric α-β–fold Mn SOD evidently do not ().

COPPER-ZINC SUPEROXIDE DISMUTASE AND AMYOTROPHIC LATERAL SCLEROSIS

(2016) Concurrent Increases and Decreases in Local Stability and Conformational Heterogeneity in Cu, Zn Superoxide Dismutase Variants Revealed by Temperature-Dependence of Amide Chemical Shifts.

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