Category Archives: SOD



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Class of enzymes Superoxide dismutase (SOD, EC is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide (O2−) radical into ordinary molecular oxygen (O2) and hydrogen peroxide (H2O2). Superoxide is produced as a by-product of oxygen metabolism and, if not regulated, causes many types of cell damage.

Thus, SOD is an important antioxidant defense in nearly all living cells exposed to oxygen. One exception is and related lactobacilli, which use a different mechanism to prevent damage from reactive O2−. SODs catalyze the disproportionation of superoxide: 2 HO2 → O2 + H2O2 In this way, O2− is converted into two less damaging species.

where M = Cu (n=1) ; Mn (n=2) ; Fe (n=2) ; Ni (n=2). In a series of such reactions, the oxidation state and the charge of the metal cation oscillates between n and n+1: +1 and +2 for Cu, or +2 and +3 for the other metals . Irwin Fridovich and Joe McCord at Duke University discovered the enzymatic activity of superoxide dismutase in 1968.

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Likewise, Brewer (1967) identified a protein that later became known as superoxide dismutase as an indophenol oxidase by protein analysis of starch gels using the phenazine-tetrazolium technique. There are three major families of superoxide dismutase, depending on the protein fold and the metal cofactor: the Cu/Zn type (which binds both copper and zinc), Fe and Mn types (which bind either iron or manganese), and the Ni type (which binds nickel).

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The cytosols of virtually all eukaryotic cells contain an SOD enzyme with copper and zinc (Cu-Zn-SOD). For example, Cu-Zn-SOD available commercially is normally purified from bovine red blood cells. The bovine Cu-Zn enzyme is a homodimer of molecular weight 32,500. It was the first SOD whose atomic-detail crystal structure was solved, in 1975.

The two subunits are tightly joined back-to-back, mostly by hydrophobic and some electrostatic interactions. The ligands of the copper and zinc are six histidine and one aspartate side-chains; one histidine is bound between the two metals. Active site for iron superoxide dismutaseIron or manganese – used by prokaryotes and protists, and in mitochondria and chloroplasts Iron – Many bacteria contain a form of the enzyme with iron (Fe-SOD); some bacteria contain Fe-SOD, others Mn-SOD, and some (such as ) contain both.

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The 3D structures of the homologous Mn and Fe superoxide dismutases have the same arrangement of alpha-helices, and their active sites contain the same type and arrangement of amino acid side-chains. They are usually dimers, but occasionally tetramers. Manganese – Nearly all mitochondria, and many bacteria, contain a form with manganese (Mn-SOD): For example, the Mn-SOD found in human mitochondria.

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Nickel – prokaryotic. This has a hexameric (6-copy) structure built from right-handed 4-helix bundles, each containing N-terminal hooks that chelate a Ni ion. The Ni-hook contains the motif His-Cys-X-X-Pro-Cys-Gly-X-Tyr; it provides most of the interactions critical for metal binding and catalysis and is, therefore, a likely diagnostic of NiSODs. In higher plants, SOD isozymes have been localized in different cell compartments.

Fe-SOD has been found mainly in chloroplasts but has also been detected in peroxisomes, and CuZn-SOD has been localized in cytosol, chloroplasts, peroxisomes, and apoplast. Three forms of superoxide dismutase are present in humans, in all other mammals, and most chordates. SOD1 is located in the cytoplasm, SOD2 in the mitochondria, and SOD3 is extracellular.

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SOD1 and SOD3 contain copper and zinc, whereas SOD2, the mitochondrial enzyme, has manganese in its reactive centre. The genes are located on chromosomes 21, 6, and 4, respectively (21q22.1, 6q25.3 and 4p15.3-p15.1). In higher plants, superoxide dismutase enzymes (SODs) act as antioxidants and protect cellular components from being oxidized by reactive oxygen species (ROS).

To be specific, molecular O2 is reduced to O2− (a ROS called superoxide) when it absorbs an excited electron released from compounds of the electron transport chain. Superoxide is known to denature enzymes, oxidize lipids, and fragment DNA. SODs catalyze the production of O2 and H2O2 from superoxide (O2−), which results in less harmful reactants.

The compartmentalization of different forms of SOD throughout the plant makes them counteract stress very effectively. There are three well-known and -studied classes of SOD metallic coenzymes that exist in plants. First, Fe SODs consist of two species, one homodimer (containing 1-2 g Fe) and one tetramer (containing 2-4 g Fe).

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Fe SODs are most abundantly localized inside plant chloroplasts, where they are indigenous. Second, Mn SODs consist of a homodimer and homotetramer species each containing a single Mn(III) atom per subunit. They are found predominantly in mitochondrion and peroxisomes. Third, Cu-Zn SODs have electrical properties very different from those of the other two classes.

Note that Cu-Zn SODs provide less protection than Fe SODs when localized in the chloroplast. Human white blood cells use enzymes such as NADPH oxidase to generate superoxide and other reactive oxygen species to kill bacteria. During infection, some bacteria (e.g., ) therefore produce superoxide dismutase to protect themselves from being killed.

The reaction of superoxide with non-radicals is spin-forbidden. In biological systems, this means that its main reactions are with itself (dismutation) or with another biological radical such as nitric oxide (NO) or with a transition-series metal. The superoxide anion radical (O2−) spontaneously dismutes to O2 and hydrogen peroxide (H2O2) quite rapidly (~105 M−1s−1 at pH 7).[] SOD is necessary because superoxide reacts with sensitive and critical cellular targets.

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Because the uncatalysed dismutation reaction for superoxide requires two superoxide molecules to react with each other, the dismutation rate is second-order with respect to initial superoxide concentration. Thus, the half-life of superoxide, although very short at high concentrations (e.g., 0.05 seconds at 0.1mM) is actually quite long at low concentrations (e.g., 14 hours at 0.1 nM).

Moreover, superoxide dismutase has the largest kcat/KM (an approximation of catalytic efficiency) of any known enzyme (~7 x 109 M−1s−1), this reaction being limited only by the frequency of collision between itself and superoxide. That is, the reaction rate is “diffusion-limited”. The high efficiency of superoxide dismutase seems necessary: even at the subnanomolar concentrations achieved by the high concentrations of SOD within cells, superoxide inactivates the citric acid cycle enzyme aconitase, can poison energy metabolism, and releases potentially toxic iron.

SOD1 is an extremely stable protein. In the holo form (both copper and zinc bound) the melting point is > 90 °C. In the apo form (no copper or zinc bound) the melting point is ~ 60 °C. By differential scanning calorimetry (DSC), holo SOD1 unfolds by a two-state mechanism: from dimer to two unfolded monomers.

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Superoxide is one of the main reactive oxygen species in the cell. As a consequence, SOD serves a key antioxidant role. The physiological importance of SODs is illustrated by the severe pathologies evident in mice genetically engineered to lack these enzymes. Mice lacking SOD2 die several days after birth, amid massive oxidative stress.

Mice lacking SOD3 do not show any obvious defects and exhibit a normal lifespan, though they are more sensitive to hyperoxic injury. Knockout mice of any SOD enzyme are more sensitive to the lethal effects of superoxide-generating compounds, such as paraquat and diquat (herbicides). lacking SOD1 have a dramatically shortened lifespan, whereas flies lacking SOD2 die before birth.

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The SODs represent the first enzymatic defense system against radical damage by oxygen: thus, this enzyme is essential for all aerobic organisms, but not for anaerobes. In support of this hypothesis, McCord believed that the existence of an aerobic organism depends mainly on its ability to produce SODs since its deficiency is responsible for oxygen sensitivity and allows survival only in an anaerobic environment.

In physiological conditions, the superoxide dismutases, together with the non-enzymatic ROS scavengers as vitamins E, A, and C maintain a steady state between oxidant and antioxidant systems (Russo et al., 2011). The dysregulation in redox homeostasis, determined by an imbalance between ROS production and scavenging capacity, determines considerable cellular damage as membrane lipoperoxidation, nucleic acid and structural alterations of proteins contributing to neurodegenerative and cardiovascular diseases.

In the last years, many data obtained in in vitro studies performed in many cellular lines, mainly neuroblastoma SK-N-BE cells, indicate that SOD1 is secreted and is able to activate, through muscarinic M1 receptor, cellular pathways involving ERK1/2 and AKT activation; these effects are associated with intracellular calcium increase that is further accentuated when these cells are stimulated with mutated SOD1G93A.

The intracellular cytosolic SOD1 localization has been a matter of debate; recent evidences, performed in transfected mouse neuroblastoma neuro2 cells, demonstrated that both wild type SOD1 (wt-SOD1) and SOD1 mutants are distributed into luminal structures of endoplasmic and Golgi apparatus (Urushitani et al., 2008). The first experimental evidence that some cellular lines could be able to secrete the Cu,Zn superoxide dismutase date back to many years ago when we, for the first time, showed the secretion of this protein by experiments performed in hepatocytes and fibroblasts (Mondola et al., 1996), neuroblastoma SK-N-BE cells (Mondola et al., 1998; Gomes et al., 2007; Polazzi et al., 2013) and in thymus derived epithelial cells (Cimini et al., 2002).

In addition, we demonstrated that in human neuroblastoma SK-N-BE cells, that show a greater sensitivity to glucose deprivation-induced cytotoxicity due to enhanced sensitivity to ROS (Shutt et al., 2010), SOD1 export takes place in normal conditions and is increased following oxidative stress (Mondola et al., 1996, 1998). Successively, we showed that SOD1 in human neuroblastoma SK-N-BE cells is exported through a microvesicular secretory pathway that is impaired by brefeldin-A (BFA), and by 2-deoxyglucose, and sodium azide, which reduces ATP intracellular pool (Mondola et al., 2003).

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Another important aspect was the discovery that besides the constitutive SOD1 export, the secretion of this enzyme is also induced. To this respect, we showed (Santillo et al., 2007) that SOD1 is actively released from rat brain synaptosomes as well as from rat pituitary GH3 cells that represent a good model to study the inducible SOD1 release since they possess all the neuronal protein machinery involved in synaptic vesicle exocytosis.

In addition, in the attempt to evaluate the possible role carried out by SOD1 export, we recently demonstrated, in SK-N-BE neuroblastoma cell line, that this enzyme is able, through the involvement of muscarinic M1 receptor, to activate ERK1/2 and AKT in a dose and time-dependent manner. This effect was remarkably reduced by M1 receptor silencing as well as by using M1 antagonist pirenzepine (Damiano et al., 2013).

However, FGF-1 and the 18 kDa isoform of FGF-2 have been shown to be secreted by an alternative pathway being directly translocated from the cytoplasm into the extracellular space. Analogously, also interleukin 1β (IL-1β) has been reported to be secreted by a vesicular non-classical export pathway. Soluble proteins classically contain N-terminal signal peptides that direct them to the translocation apparatus of the Endoplasmic Reticulum (ER) (Walter et al., 1984).

In addition, non-classical protein secretion is both energy and temperature dependent and can be stimulated or inhibited by various treatments (Cleves, 1997; Hughes, 1999). The list of proteins that could be exported from cells in the absence of a functional ERG system (unconventional secretory pathway), as IL-1β and galectin-1 (also referred to as L-14), is continually growing; for further data see the review of Nickel (2003).

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For this reason SOD1 secretion should bypass the canonical ERG secretory pathway. We previously demonstrated that BFA as well as 2-deoxyglucose and sodium azide (NaN3), impairs SOD1 export (Mondola et al., 2003). In our opinion, the treatment with BFA probably dysregulates not only the classical secretory ERG pathway but also the microvesicular membrane traffic of unconventional protein secretion or alternative protein export.

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Furthermore, these authors showed that SOD1A4V inhibits secretory protein transport from the ER to the Golgi apparatus. Amyotrophic lateral sclerosis (ALS) is an adult onset, neurodegenerative disease characterized by selective death of the upper and lower motor neurons of the brain and spinal cord. Symptoms include muscle atrophy, spasticity, paralysis and eventual death from respiratory failure within 3–5 years of diagnosis.

Clinical and pathological processes indicate that ER stress represents a key pathway involved in cell death. In the transgenic SOD1G93A ALS rat model unfolded protein response and ER stress-induced apoptosis has been observed (Atkin et al., 2006); an unfolded protein response, including induction of stress sensor kinases, chaperones, and apoptotic mediators, has been shown also in spinal cord motor neurons of human patients with the sporadic form of ALS (sALS) that is not restricted to SOD1 mutations (Atkin et al., 2008).

SOD1 and other proteins are misfolded in fALS and in sALS, but it is not clear how this triggers ER stress, fragmentation of the Golgi apparatus, disruption of axonal transport and apoptosis. Nearly 20% of fALS is caused by SOD1 gene mutations (Neumann et al., 2006). Indeed, the majority of SOD1 mutants maintain their enzymatic activity suggesting the occurrence of gain of toxic activity function rather than a simple loss of function (Strong et al., 2005; Dion et al., 2009).

(2005) demonstrated an impaired constitutive extracellular secretion of mutant SOD1 in NSC-34 cells that induces frequent cytoplasmic inclusions and protein insolubility. These data link the deficient secretion of mutant SOD1 with intracellular protein aggregates and toxicity in NSC-34 cells. In addition, these authors showed that in a transgenic rat model of ALS the chronic intraspinal infusion of exogenous human wt-SOD1 significantly delayed disease progression suggesting a novel extracellular role for SOD1 in ALS; therefore extracellular delivery of human wt-SOD1 could improve clinical disease in transgenic ALS rats supporting a novel extracellular role for mutant and wt-SOD1 in ALS pathogenesis and therapy, respectively.

In addition, in transgenic mice, carrying SOD1 mutations, toxic effects to motor neurons by microglia activation were observed (Urushitani et al., 2006; Zhao et al., 2010). The microglia cells can carry out an important role in ALS progression (Pramatarova et al., 2001) since microglia activation can be observed before neuron loss in transgenic mice expressing human SOD1 mutants (Alexianu et al., 2001).

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