Summary: Nickel-containing superoxide dismutase
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Superoxide dismutase Edit Wikipedia article
Structure of a human Mn superoxide dismutase 2 tetramer.
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
||This article may be too technical for most readers to understand. (August 2014)|
Superoxide dismutases (SOD, EC 188.8.131.52) are enzymes that catalyze the dismutation of superoxide (O2−) into oxygen and hydrogen peroxide. Thus, they are an important antioxidant defense in nearly all cells exposed to oxygen. One anomaly is Lactobacillus plantarum and related lactobacilli, which use a different mechanism.
- M(n+1)+-SOD + O2− → Mn+-SOD + O2
- Mn+-SOD + O2− + 2H+ → M(n+1)+-SOD + H2O2.
In this reaction the oxidation state of the metal cation oscillates between n and n+1.
Irwin Fridovich and Joe McCord discovered the activity of superoxide dismutase. SODs were previously known as a group of metalloproteins with unknown function; for example, CuZnSOD was known as erythrocuprein and as the veterinary anti-inflammatory drug "Orgotein". 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.
Several common forms of SOD exist: they are proteins cofactored with copper and zinc, or manganese, iron, or nickel. Thus, there are three major families of superoxide dismutase, depending on the metal cofactor: Cu/Zn (which binds both copper and zinc), Fe and Mn types (which bind either iron or manganese), and the Ni type, which binds nickel.
- Copper and zinc – most commonly used by eukaryotes. 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 the bovine erythrocytes: The Cu-Zn enzyme is a homodimer of molecular weight 32,500. The bovine Cu-Zn protein was the first SOD structure to be solved, in 1975. It is an 8-stranded "Greek key" beta-barrel, with the active site held between the barrel and two surface loops. 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.
- Iron or manganese – used by prokaryotes and protists, and in mitochondria
- Iron – E. coli and many other bacteria also contain a form of the enzyme with iron (Fe-SOD); some bacteria contain Fe-SOD, others Mn-SOD, and some contain both. (For the E. coli Fe-SOD). Fe-SOD can be found in the plastids of plants. 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.
- Manganese – Chicken liver (and nearly all other) mitochondria, and many bacteria (such as E. coli), contain a form with manganese (Mn-SOD): For example, the Mn-SOD found in human mitochondria. The ligands of the manganese ions are 3 histidine side-chains, an aspartate side-chain and a water molecule or hydroxy ligand, depending on the Mn oxidation state (respectively II and III).
- Nickel – prokaryotic. This has a hexameric 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. Mn-SOD is present in mitochondria and peroxisomes. 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. The first is a dimer (consists of two units), whereas the others are tetramers (four subunits). 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). 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. To be specific, molecular O2 is reduced to O2− (an 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.
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 the chloroplast, cytosol, and in some cases the extracellular space. Note that Cu-Zn SODs provide less protection than Fe SODs when localized in the chloroplast.
Human white blood cells 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.
Simply stated, SOD out-competes damaging reactions of superoxide, thus protecting the cell from superoxide toxicity. 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. For example, it reacts with the NO radical, and makes toxic peroxynitrite. 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 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". 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. Aconitase is one of several iron-sulfur-containing (de)hydratases in metabolic pathways shown to be inactivated by superoxide.
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 SOD1 develop a wide range of pathologies, including hepatocellular carcinoma, an acceleration of age-related muscle mass loss, 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. Knockout mice of any SOD enzyme are more sensitive to the lethal effects of superoxide-generating drugs, such as paraquat and diquat.
Drosophila lacking SOD1 have a dramatically shortened lifespan, whereas flies lacking SOD2 die before birth. SOD knockdowns in C. elegans do not cause major physiological disruptions. Knockout or null mutations in SOD1 are highly detrimental to aerobic growth in the yeast Sacchormyces cerevisiae and result in a dramatic reduction in post-diauxic lifespan. SOD2 knockout or null mutations cause growth inhibition on respiratory carbon sources in addition to decreased post-diauxic lifespan.
Several prokaryotic SOD null mutants have been generated, including E. Coli. The loss of periplasmic CuZnSOD causes loss of virulence and might be an attractive target for new antibiotics.
Role in disease
Mutations in the first SOD enzyme (SOD1) can cause familial amyotrophic lateral sclerosis (ALS, a form of motor neuron disease). The most common mutation in the U.S. is A4V, while the most intensely studied is G93A. The other two isoforms of SOD have not been linked to any human diseases, however, in mice inactivation of SOD2 causes perinatal lethality and inactivation of SOD1 causes hepatocellular carcinoma. Mutations in SOD1 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.), 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 in Down syndrome.
In mice, the extracellular superoxide dismutase (SOD3, ecSOD) contributes to the development of hypertension. Diminished SOD3 activity has been linked to lung diseases such as Acute Respiratory Distress Syndrome (ARDS) or Chronic obstructive pulmonary disease (COPD).
Superoxide dismutase is also not expressed in neural crest cells in the developing fetus. Hence, high levels of free radicals can cause damage to them and induce dysraphic anomalies (neural tube defects).
SOD has powerful antinflammatory activity. For example, SOD is a highly effective experimental treatment of colonic inflammation in colitis. Treatment with SOD decreases reactive oxygen species generation and oxidative stress and, thus, inhibits endothelial activation and indicate that modulation of factors that govern adhesion molecule expression and leukocyte-endothelial interactions. Therefore, such antioxidants may be important new therapies for the treatment of inflammatory bowel disease.
Likewise, SOD has multiple pharmacological activities. E.g., it ameliorates cis-platinum-induced nephrotoxicity in rodents. 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. For a time, bovine liver SOD even had regulatory approval in several European countries for such use. This was truncated by concerns about prion disease.
An SOD-mimetic agent, TEMPOL, is currently in clinical trials for radioprotection and to prevent radiation-induced hair-loss. TEMPOL and similar SOD-mimetic nitroxides exhibit a multiplicity of actions in diseases involving oxidative stress. For a review, see Wilcox.
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. Superoxide dismutase is known to reverse fibrosis, perhaps through reversion of myofibroblasts back to fibroblasts.[further explanation needed]
SOD is commercially obtained from bovine liver, though it is also found in yeast, spinach, and chicken liver.
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- Online 'Mendelian Inheritance in Man' (OMIM) 105400 (ALS)
- The ALS Online Database
- A short but substantive overview of SOD and its literature.
- Damage-Based Theories of Aging Includes a discussion of the roles of SOD1 and SOD2 in aging.
- Physicians' Comm. For Responsible Med.
- SOD and Oxidative Stress Pathway Image
- Historical information on SOD research"The evolution of Free Radical Biology & Medicine: A 20-year history" and "Free Radical Biology & Medicine The last 20 years: The most highly cited papers"
- JM McCord discusses the discovery of SOD
Nickel-containing superoxide dismutase Provide feedback
Nickel containing superoxide dismutase (NiSOD) is a metalloenzyme containing a hexameric assembly of right-handed 4-helix bundles of up-down-up-down topology with an N-terminal His-Cys-X-X-Pro-Cys-Gly-X-Tyr motif that chelates the active site Ni ions. NiSOD catalyses the disproportionation of superoxide to peroxide and molecular oxygen through alternate oxidation and reduction of Ni, protecting cells from the toxic products of aerobic metabolism .
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR014123
This entry represents nickel-dependent superoxide dismutase (NiSOD) (EC), a SOD enzyme that uses nickel, rather than iron, manganese, copper, or zinc. All SOD enzymes catalyse the dismutation of toxic superoxide radical anions to oxygen and hydrogen peroxide in order to protect cells from oxidative damage. The catalytic cycle of NiSOD consists of two half-reactions, each initiated by the successive approach of substrate to the metal centre. The first (reductive) phase involves Ni(III) reduction to Ni(II), and the second (oxidative) phase involves the metal reoxidation back to its resting state [PUBMED:16756300]. NiSOD has a novel SOD fold and assembly, consisting of a hexameric assembly of 4-helix bundles of up-and-down topology, which contains a 9-residue nickel-hook structural motif that is critical for metal binding and catalysis [PUBMED:15209499]. A gene for a required protease (NiSOD maturation protease; INTERPRO) is adjacent to the NiSOD gene.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||antioxidant activity (GO:0016209)|
|superoxide dismutase activity (GO:0004784)|
|nickel cation binding (GO:0016151)|
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- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- Pfam viewer
- an HTML-based viewer that uses DAS to retrieve alignment fragments on request
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
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Note: You can also download the data file for the tree.
Curation and family details
|Author:||Mistry J, Sammut SJ|
|Number in seed:||25|
|Number in full:||144|
|Average length of the domain:||126.20 aa|
|Average identity of full alignment:||43 %|
|Average coverage of the sequence by the domain:||79.80 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||6|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
How the sunburst is generated
Colouring and labels
Anomalies in the taxonomy tree
Missing taxonomic levels
Unmapped species names
Too many species/sequences
The tree shows the occurrence of this domain across different species. More...
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Sod_Ni domain has been found. There are 81 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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