 Structure of a human Mn superoxide dismutase 2 tetramer[1] | |||||||||
| Identifiers | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| EC no. | 1.15.1.1 | ||||||||
| CAS no. | 9054-89-1 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDBPDBePDBsum | ||||||||
| Gene Ontology | AmiGO /QuickGO | ||||||||
| |||||||||
Superoxide dismutase (SOD,EC1.15.1.1) is anenzyme that alternately catalyzes thedismutation (or partitioning) of thesuperoxide (O−
2) anionradical into normal molecularoxygen (O2) andhydrogen peroxide (H
2O
2). Superoxide is produced as a by-product of oxygen metabolism and, if not regulated, causes many types ofcell damage.[2] Hydrogen peroxide is also damaging and is degraded by other enzymes such ascatalase. Thus, SOD is an importantantioxidant defense in nearly all living cells exposed to oxygen. One exception isLactobacillus plantarum and relatedlactobacilli, which use intracellular manganese to prevent damage from reactiveO−
2.[3][4]
SODs catalyze thedisproportionation of superoxide:
In this way,O−
2 is converted into two less damaging species.
The general form, applicable to all the different metal−coordinated forms of SOD, can be written as follows:
The reactions by which SOD−catalyzeddismutation ofsuperoxide for Cu,Zn SOD can be written as follows:
where M =Cu (n=1);Mn (n=2);Fe (n=2); Ni (n=2) only in prokaryotes.
In a series of such reactions, theoxidation state and the charge of the metalcation oscillates between n and n+1: +1 and +2 for Cu, or +2 and +3 for the other metals.
Irwin Fridovich andJoe McCord atDuke University discovered the enzymatic activity of superoxide dismutase in 1968.[5] SODs were previously known as a group ofmetalloproteins with unknown function; for example, CuZnSOD was known as erythrocuprein (or hemocuprein, or cytocuprein) or as the veterinary anti-inflammatory drug "Orgotein".[6] 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.[7]
There are three major families of superoxide dismutase, depending on the protein fold and the metalcofactor: the Cu/Zn type (which binds both copper andzinc), Fe and Mn types (which bind either iron ormanganese), and the Ni type (which bindsnickel).
 |  |  |
Protein family
| Protein domain
| Protein domain
| Protein family
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
In higher plants, SOD isozymes have been localized in different cell compartments. Mn-SOD is present in mitochondria andperoxisomes. Fe-SOD has been found mainly in chloroplasts but has also been detected in peroxisomes, and CuZn-SOD has been localized incytosol, chloroplasts, peroxisomes, andapoplast.[16][17]
There are three forms of superoxide dismutase present in humans, in all othermammals, and mostchordates.SOD1 is located in thecytoplasm,SOD2 in themitochondria, andSOD3 isextracellular. The first is adimer (consists of two units), whereas the others are tetramers (four subunits). SOD1 and SOD3 contain copper and zinc, whereas SOD2, the mitochondrial enzyme, hasmanganese in its reactive centre. Thegenes are located on chromosomes 21, 6, and 4, respectively (21q22.1, 6q25.3 and 4p15.3-p15.1).
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Inhigher plants, superoxide dismutase enzymes (SODs) act as antioxidants and protect cellular components from being oxidized byreactive oxygen species (ROS).[20] ROS can form as a result of drought, injury, herbicides and pesticides, ozone, plant metabolic activity, nutrient deficiencies, photoinhibition, temperature above and below ground, toxic metals, and UV or gamma rays.[21][22] To be specific, molecular O2 is reduced toO−
2 (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.[21] SODs catalyze the production of O2 andH
2O
2 from superoxide (O−
2), which results in less harmful reactants.
When acclimating to increased levels of oxidative stress, SOD concentrations typically increase with the degree of stress conditions. 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). They are thought to be the most ancient SOD metalloenzymes and are found within both prokaryotes and eukaryotes. 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. These are concentrated in thechloroplast,cytosol, and in some cases the extracellular space. Note that Cu-Zn SODs provide less protection than Fe SODs when localized in the chloroplast.[20][21][22]
Human white blood cells use enzymes such asNADPH oxidase to generate superoxide and other reactive oxygen species to kill bacteria. During infection, some bacteria (e.g.,Burkholderia pseudomallei) therefore produce superoxide dismutase to protect themselves from being killed.[23]
SOD out-competes damaging reactions of superoxide, thus protecting the cell from superoxide toxicity.The reaction of superoxide with non-radicals isspin-forbidden. In biological systems, this means that its main reactions are with itself (dismutation) or with another biological radical such asnitric oxide (NO) or with a transition-series metal. The superoxide anion radical (O−
2) spontaneously dismutes to O2 and hydrogen peroxide (H
2O
2) quite rapidly (~105 M−1s−1 at pH 7).[citation needed] SOD is necessary because superoxide reacts with sensitive and critical cellular targets. For example, it reacts with the NO radical, and makes toxicperoxynitrite.
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). In contrast, the reaction of superoxide with SOD is first order with respect to superoxide concentration. Moreover, superoxide dismutase has the largestkcat/KM (an approximation of catalytic efficiency) of any known enzyme (~7 billion M−1s−1),[24] 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 enzymeaconitase, can poison energy metabolism, and releases potentially toxic iron. Aconitase is one of several iron-sulfur-containing (de)hydratases in metabolic pathways shown to be inactivated by superoxide.[25]
Thephylogenetic relationships among superoxide dismutases (SODs) are one of many genetic components that have been used to help reconstruct an early timeline of events and predict the evolutionary descent of species, individuals, or genes from a common ancestor over time. Around the period of Earth's transition fromanaerobic toaerobic conditions about 2.4 billion years ago (bya), the evolution of SOD enzymes crucially allowed organisms to overcome the effects ofoxidative stress following the surge of molecular oxygen (O2) in the atmosphere (Miller 2012). However, evidence suggests that the origination ofreactive oxygen species (ROS) took place as early as 4.1 to 3.5 bya (Inupakutikaet al. 2016).[26] For the first aerobic organisms, survival depended largely on their ability to defend against ROS. For this reason, it is relevant to understand the environmental constraints that allowed such protective defense enzymes to evolve.
Atmospheric and oceanic compositions have drastically changed since the formation of early Earth. One significant event,the Great Oxidation Event (GOE), marked the period of time in which oxygen became a major component of Earth's atmosphere and surface ocean. However, the physical or biochemical drivers responsible for the transition from a reducing to oxidizing environment remains up for debate (Olejarzet al. 2021).[27] To date, the evolution ofcyanobacteria and cyanobacterial photosynthesis is commonly accepted as the primary driver of oxygen production, alongside several physical events behaving as proximal drivers of environmental state change (Kasting 2013; Inupakutikaet al. 2016).[28][29]
The atmospheric accumulation of highly reactive O2 likely exercised a strong selective pressure against anaerobic organisms, and led to the adaptive evolution of oxygen utilization in metabolism (Bodenet al. 2021).[30] The process ofoxidative phosphorylation and aerobic respiration permitted a 400-fold increase in energy extraction efficiency per mole glucose as compared to anaerobic respiration. Although the increased yield ofadenosine triphosphate (ATP), a common form of cellular energy currency, was metabolically beneficial, the tradeoff between efficiency and risk to the metabolic machinery grew more prominent. Behaving as the terminalelectron acceptor duringcellular respiration, the high rate of O2 electron flux is accompanied by an increased risk of ROS formation, which can induce irreversible damage to cellular organelles and their processes (Case 2017).[31] In response to the accumulation of the hazardous metabolic byproducts of aerobic respiration, biological systems evolved various strategies to counteractO2 toxicity.
During the transition from aerobic to anaerobic conditions, phylogenetic investigations suggest that SODs are ancient molecules, which were likely selected for before the GOE. While it is intuitively assumed that antioxidants emerged during the GOE to defend against O2 reactivity and toxicity caused by the accelerated oxygenation of the atmosphere,sequencing and phylogenetic analyses of antioxidant systems from ancient organisms suggests that antioxidant enzymes including SODs may have originated long before the surge of atmospheric and oceanic O2 (Wolfe-Simonet al. 2005; Inupakutikaet al. 2016).
The oxidizing capacity of O2 makes it a highly efficient final electron acceptor for several biological processes, producing more energy per mole substrate relative to other available electron acceptors during aerobic respiration (Bodenet al. 2021). On the other hand, its high reactivity also contributes to the uncontrolled removal of electrons, which underlies pathological cell damage through the propagation of highly reactive oxygen-containing molecules.
Superoxide (O2•−) is the most common reactive free-radical formed by the univalent reduction of O2. While they are known to exhibit beneficial roles in some cellular processes, superoxide free radicals also possess the ability to initiate a cascade of ROS and free-radical species formation in biological systems. As a consequence, the unrestrained and potentially lethal accumulation of ROS threatens to damage many biomolecules: lipids, proteins, DNA, and host cells. Additionally, oxidative stress in excess is understood to participate in the dysregulation of cellular processes and disease development (Zewenet al. 2018).[32]
To maintain a balance of intracellular superoxide, organisms have developed strategies to protect against overexposure. One such mechanism functions to catalyze the dismutation of superoxide radicals into hydrogen peroxide and oxygen, which is accomplished by SOD enzymes.
Studies examining the phylogenetic distribution of SODs support the proposal that the majorphysiological function of SOD is to act as a protective mechanism among oxygen-metabolizing organisms against the formation of superoxide free radicals (McCordet al. 1971).[33] Although the enzyme is functionally limited to the conversion of superoxide radicals into less toxic oxygen-containing molecules, methodological approaches utilizing phylogenetic and structural protein analysis suggest that three SODisoforms have evolved independently to combat superoxide accumulation. Each enzyme family is characterized by a distinct 3D structure, amino acid sequence, and with regard to the metal-bindingcofactor(s) used to support its structural stability andcatalytic activity (Case 2017): either manganese (MnSOD), nickel (NiSOD), or both copper and zinc (Miller 2012).[34] An additional family utilizing an iron cofactor (FeSOD) has also been identified, which is evolutionarily related to MnSOD (Wolfe-Simonet al. 2005). The evolution of metalliform diversity can likely be explained by changes in heavy metal bioavailability that took place during large compositional changes of the earth's early atmosphere and oceans.
SODs containing Fe (FeSOD), Mn (MnSOD), or may contain either (Fe/MnSOD) are believed to have been the earliest SOD isoforms among life on early earth. During this time, Fe and Mn would have been highly bioavailable. The differences between theoxidation and reduction potentials of each metal is thought to have been advantageous to organism survival, allowing them to exist in environments with varying O2 concentration and metal availability.
The most modern SOD family is believed to utilize both Cu and Zn ions (CuZnSOD). The absence of CuZnSODs fromarchaeal andprotist genomes coupled with the post-GOE increased bioavailability of Cu and Zn suggests that the development of this isoform took place at a later period in evolutionary time (Banciet al. 2005; Wilkinsonet al. 2006).[35][36]
The family of Ni-containing SODs (NiSOD) is less understood. Evidence suggests that these isoforms are largely distributed amongmarine bacteria andalgae (Wolfe-Simonet al. 2005; Dupontet al. 2008).[37][38] The evolution of NiSOD is currently predicted to have occurred around the time of the GOE when a decrease in aquatic bioavailability of Fe took place.
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.[39] Bydifferential scanning calorimetry (DSC), holo SOD1unfolds by a two-state mechanism: from dimer to two unfolded monomers.[39] In chemicaldenaturation experiments, holo SOD1 unfolds by a three-state mechanism with observation of a folded monomeric intermediate.[40]
Superoxide is one of the mainreactive 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 massiveoxidative stress.[41] Mice lacking SOD1 develop a wide range of pathologies, including hepatocellular carcinoma,[42] an acceleration of age-related muscle mass loss,[43] an earlier incidence of cataracts, and a reduced lifespan. Mice lacking SOD3 do not show any obvious defects and exhibit a normal lifespan, though they are more sensitive to hyperoxic injury.[44]Knockout mice of any SOD enzyme are more sensitive to the lethal effects of superoxide-generating compounds, such asparaquat anddiquat (herbicides).
Drosophila lacking SOD1 have a dramatically shortened lifespan, whereas flies lacking SOD2 die before birth. Depletion ofSOD1 andSOD2 in the nervous system and muscles ofDrosophila is associated with reduced lifespan.[45] The accumulation of neuronal and muscularROS appears to contribute to age-associated impairments. When overexpression of mitochondrial SOD2 is induced, the lifespan of adultDrosophila is extended.[46]
Amongblack garden ants (Lasius niger), the lifespan ofqueens is an order of magnitude greater than of workers despite no systematic nucleotide sequence difference between them.[47] TheSOD3 gene was found to be the most differentially over-expressed in the brains of queen vs worker ants. This finding raises the possibility of an important role of antioxidant function in modulating lifespan.[47]
SOD knockdowns in the wormC. elegans do not cause major physiological disruptions. However, the lifespan ofC. elegans can be extended by superoxide/catalase mimetics suggesting thatoxidative stress is a major determinant of the rate ofaging.[48]
Knockout or null mutations in SOD1 are highly detrimental to aerobic growth in the budding yeastSaccharomyces cerevisiae and result in a dramatic reduction in post-diauxic lifespan. In wild-typeS. cerevisiae,DNA damage rates increased 3-fold with age, but more than 5-fold in mutants deleted for either theSOD1 orSOD2 genes.[49]Reactive oxygen species levels increase with age in these mutant strains and show a similar pattern to the pattern ofDNA damage increase with age. Thus it appears that superoxide dismutase plays a substantial role in preserving genome integrity duringaging inS. cerevisiae.SOD2 knockout or null mutations cause growth inhibition on respiratory carbon sources in addition to decreased post-diauxic lifespan.
In the fission yeastSchizosaccharomyces pombe, deficiency of mitochondrial superoxide dismutaseSOD2 accelerates chronological aging.[50]
Several prokaryotic SOD null mutants have been generated, includingE. coli. The loss of periplasmic CuZnSOD causes loss of virulence and might be an attractive target for new antibiotics.
Mutations in the first SOD enzyme (SOD1) can cause familialamyotrophic lateral sclerosis (ALS, a form ofmotor neuron disease).[51][52][53][54] The most common mutation in the U.S. isA4V, while the most intensely studied isG93A. Inactivation of SOD1 causeshepatocellular carcinoma.[42] Diminished SOD3 activity has been linked to lung diseases such asacute respiratory distress syndrome (ARDS) orchronic obstructive pulmonary disease (COPD).[55][56][57] Superoxide dismutase is not expressed in neural crest cells in the developingfetus. Hence, high levels of free radicals can cause damage to them and induce dysraphic anomalies (neural tube defects).[citation needed]
Mutations inSOD1 can cause familial ALS (several pieces of evidence also show that wild-type SOD1, under conditions of cellular stress, is implicated in a significant fraction of sporadic ALS cases, which represent 90% of ALS patients.),[58] by a mechanism that is presently not understood, but not due to loss of enzymatic activity or a decrease in the conformational stability of the SOD1 protein. Overexpression of SOD1 has been linked to the neural disorders seen inDown syndrome.[59] In patients with thalassemia, SOD will increase as a form of compensation mechanism. However, in the chronic stage, SOD does not seem to be sufficient and tends to decrease due to the destruction of proteins from the massive reaction of oxidant-antioxidant.[60]
In mice, the extracellular superoxide dismutase (SOD3, ecSOD) contributes to the development ofhypertension.[61][62] Inactivation of SOD2 in mice causes perinatal lethality.[41]
Supplementary superoxide dimutase has been suggested as a treatment to preventbronchopulmonary dysplasia in infants who are bornpreterm, however, the effectiveness of his treatment is not clear.[63]
SOD has been used in experimental treatment of chronic inflammation ininflammatory bowel conditions.[64][65] SOD may amelioratecis-platinum-inducednephrotoxicity (rodent studies).[66] As "Orgotein" or "ontosein", a pharmacologically-active purified bovine liver SOD, it is also effective in the treatment of urinary tract inflammatory disease in man.[67] For a time, bovine liver SOD even had regulatory approval in several European countries for such use. This was cut short by concerns aboutprion disease.[citation needed]
AnSOD-mimetic agent,TEMPOL, is currently in clinical trials for radioprotection and to prevent radiation-induceddermatitis.[68] TEMPOL and similar SOD-mimetic nitroxides exhibit a multiplicity of actions in diseases involving oxidative stress.[69]
The synthesis of enzymes such as superoxide dismutase,L-ascorbate oxidase, and Delta 1DNA polymerase is initiated in plants with the activation ofgenes associated with stress conditions for plants.[70] The most common stress conditions can be injury, drought orsoil salinity. Limiting this process initiated by the conditions of strong soil salinity can be achieved by administering exogenousglutamine to plants. The decrease in the level of expression of genes responsible for the synthesis of superoxide dismutase increases with the increase in glutamine concentration.[70]
SOD may reduce free radical damage to skin—for example, to reduce fibrosis following radiation for breast cancer. Studies of this kind must be regarded as tentative, however, as there were not adequate controls in the study including a lack of randomization, double-blinding, or placebo.[71] Superoxide dismutase is known to reversefibrosis, possibly through de-differentiation ofmyofibroblasts back tofibroblasts.[72][further explanation needed]
SOD is commercially obtained from marinephytoplankton, bovine liver,horseradish,cantaloupe, and certain bacteria. For therapeutic purpose, SOD is usually injected locally. There is no evidence that ingestion of unprotected SOD or SOD-rich foods can have any physiological effects, as all ingested SOD isbroken down intoamino acids beforebeing absorbed. However, ingestion of SOD bound to wheat proteins could improve its therapeutic activity, at least in theory.[73]
| pyrazolones / pyrazolidines | |
|---|---|
| salicylates | |
| acetic acid derivatives and related substances | |
| oxicams | |
| propionic acid derivatives (profens) |
|
| n-arylanthranilic acids (fenamates) | |
| COX-2 inhibitors (coxibs) | |
| other | |
| NSAID combinations | |
Key:underline indicates initially developed first-in-class compound of specific group;#WHO-Essential Medicines;†withdrawn drugs;‡veterinary use. | |
Authority control databases: National |
|---|
