Regulation of CuZnSOD and Its Redox Signaling Potential: Implications for Amyotrophic Lateral Sclerosis

Abstract

Significance: Molecular oxygen is a Janus-faced electron acceptor for biological systems, serving as a reductant for respiration, or as the genesis for oxygen-derived free radicals that damage macromolecules. Superoxide is well known to perturb nonheme iron proteins, including Fe/S proteins such as aconitase and succinate dehydrogenase, as well as other enzymes containing labile iron such as the prolyl hydroxylase domain-containing family of enzymes; whereas hydrogen peroxide is more specific for two-electron reactions with thiols on glutathione, glutaredoxin, thioredoxin, and the peroxiredoxins. Recent Advances: Over the past two decades, familial cases of amyotrophic lateral sclerosis (ALS) have been shown to have an association with commonly altered superoxide dismutase 1 (SOD1) activity, expression, and protein structure. This has led to speculation that an altered redox balance may have a role in creating the ALS phenotype. Critical Issues: While SOD1 alterations in familial ALS are manifold, they generally create perturbations in the flux of electrons. The nexus of SOD1 between one-and two-electron signaling processes places it at a key signaling regulatory checkpoint for governing cellular responses to physiological and environmental cues. Future Directions: The manner in which ALS-associated mutations adjust SOD1's role in controlling the flow of electrons between one-and two-electron signaling processes remains obscure. Here, we discuss the ways in which SOD1 mutations influence the form and function of copper zinc SOD, the consequences of these alterations on free radical biology, and how these alterations might influence cell signaling during the onset of ALS. Antioxid. Redox Signal. 20, 1590Signal. 20, -1598

Metallothionein and Superoxide Dismutase—Antioxidative Protein Status in Fullerene-Doxorubicin Delivery to MCF-7 Human Breast Cancer Cells

“…Lysine 123 acetylation is a reversible PTM that regulates the interaction, subcellular localization, folding and activity of many proteins [ 48 ]. Specific conditions, such as H 2 O 2 and superoxide concentration, appear to favor SOD activity [ 49 ]. The maturation of SOD1 into a fully active enzyme requires several steps, including the insertion of Cu and Zn and oxidation of a critical disulfide that is essential for SOD activity [ 50 ].…”

The rational design of specific SOD1 inhibitors via copper coordination and their application in ROS signaling research

“… 14 – 27 Indeed, SOD1 is essential for H 2 O 2 -mediated oxidation and inactivation of protein tyrosine phosphatases (PTPs) in growth factor signaling, 30 and can integrate signals from oxygen and glucose to repress respiration with its normal enzymatic activity. 31 Both too high and too low SOD1 activities can lead to aberrant cellular ROS signaling that is linked to inflammation, amyotrophic lateral sclerosis (ALS), malignant cell proliferation, tumorigenesis and angiogenesis, 32 – 35 which makes the enzyme a key target for drug design for cancer and ALS therapy. 36 , 37 Moreover, controlling the intracellular SOD1 activity is essential to address the long-standing problem that intracellular ROS levels can't be directly regulated without external stimulation in the research and regulation of ROS signaling.…”

Superoxide Dismutase (SOD) Genes and Aging in Drosophila

“…Various possible mechanisms have been proposed for the toxicity of mutant Cu/ZnSOD, including misfolding and aggregation , disruptions of intracellular transport, disruptions of metal homeostasis (Lovejoy and Guillemin 2014), and disruptions of mitochondrial function (Hitchler and Domann 2014;Muyderman and Chen 2014). Transgenic Drosophila have been used in several studies to examine the effect of expression of human Cu/ZnSOD, including transgenes bearing human disease mutations.…”