Superoxide dismutase (SOD, ) is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that alternately catalyzes the
dismutation
In chemistry, disproportionation, sometimes called dismutation, is a redox reaction in which one compound of intermediate oxidation state converts to two compounds, one of higher and one of lower oxidation states. More generally, the term can b ...
(or partitioning) of the
superoxide
In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of t ...
()
radical
Radical may refer to:
Politics and ideology Politics
*Radical politics, the political intent of fundamental societal change
*Radicalism (historical), the Radical Movement that began in late 18th century Britain and spread to continental Europe and ...
into ordinary molecular
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
(O
2) and
hydrogen peroxide
Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3% ...
(). Superoxide is produced as a by-product of oxygen metabolism and, if not regulated, causes many types of cell damage. Hydrogen peroxide is also damaging and is degraded by other enzymes such as
catalase
Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting t ...
. Thus, SOD is an important
antioxidant
Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubricant ...
defense in nearly all living cells exposed to oxygen. One exception is ''
Lactobacillus plantarum
''Lactiplantibacillus plantarum'' (formerly ''Lactobacillus arabinosus'' and ''Lactobacillus plantarum'') is a widespread member of the genus ''Lactiplantibacillus'' and commonly found in many fermented food products as well as anaerobic plant ma ...
'' and related
lactobacilli
The ''Lactobacillaceae'' are a family of lactic acid bacteria. It is the only family in the lactic acid bacteria which includes homofermentative and heterofermentative organisms; in the ''Lactobacillaceae,'' the pathway used for hexose fermentati ...
, which use a different mechanism to prevent damage from reactive .
Chemical reaction
SODs catalyze the
disproportionation
In chemistry, disproportionation, sometimes called dismutation, is a redox reaction in which one compound of intermediate oxidation state converts to two compounds, one of higher and one of lower oxidation states. More generally, the term can b ...
of superoxide:
: 2 HO
2 → O
2 + H
2O
2
In this way, is converted into two less damaging species.
The pathway by which SOD-catalyzed
dismutation
In chemistry, disproportionation, sometimes called dismutation, is a redox reaction in which one compound of intermediate oxidation state converts to two compounds, one of higher and one of lower oxidation states. More generally, the term can b ...
of
superoxide
In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of t ...
may be written, for Cu,Zn SOD, with the following reactions:
* Cu
2+-SOD + → Cu
+-SOD + O
2 (reduction of copper; oxidation of superoxide)
* Cu
+-SOD + + 2H
+ → Cu
2+-SOD + H
2O
2 (oxidation of copper; reduction of superoxide)
The general form, applicable to all the different metal-coordinated forms of SOD, can be written as follows:
* M
(n+1)+-SOD + → M
n+-SOD + O
2
* M
n+-SOD + + 2H
+ → M
(n+1)+-SOD +
where M =
Cu (n=1);
Mn (n=2);
Fe (n=2); Ni (n=2) only in prokaryotes.
In a series of such reactions, the
oxidation state
In chemistry, the oxidation state, or oxidation number, is the hypothetical charge of an atom if all of its bonds to different atoms were fully ionic. It describes the degree of oxidation (loss of electrons) of an atom in a chemical compound. C ...
and the charge of the metal
cation
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
oscillates between n and n+1: +1 and +2 for Cu, or +2 and +3 for the other metals .
Types
General
Irwin Fridovich
Irwin Fridovich (August 2, 1929 – November 2, 2019) was an American biochemist who, together with his graduate student Joe M. McCord, discovered the enzymatic activity of copper-zinc superoxide dismutase (SOD),—to protect organisms from the ...
and
Joe McCord at
Duke University
Duke University is a private research university in Durham, North Carolina. Founded by Methodists and Quakers in the present-day city of Trinity in 1838, the school moved to Durham in 1892. In 1924, tobacco and electric power industrialist James ...
discovered the enzymatic activity of superoxide dismutase in 1968.
SODs were previously known as a group of
metalloprotein
Metalloprotein is a generic term for a protein that contains a metal ion Cofactor (biochemistry), cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins (out of ~20,000) contain zinc-bi ...
s with unknown function; for example, CuZnSOD was known as erythrocuprein (or hemocuprein, or cytocuprein) or 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.
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
Copper is a chemical element with the symbol Cu (from la, cuprum) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkis ...
and
zinc
Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
), Fe and Mn types (which bind either
iron
Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in f ...
or
manganese
Manganese is a chemical element with the symbol Mn and atomic number 25. It is a hard, brittle, silvery metal, often found in minerals in combination with iron. Manganese is a transition metal with a multifaceted array of industrial alloy use ...
), and the Ni type (which binds
nickel
Nickel is a chemical element with symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel is a hard and ductile transition metal. Pure nickel is chemically reactive but large pieces are slow to ...
).
* Copper and zinc – most commonly used by
eukaryote
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s, including humans. The
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
s of virtually all
eukaryotic
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
cells contain an SOD enzyme with
copper
Copper is a chemical element with the symbol Cu (from la, cuprum) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkis ...
and
zinc
Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
(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.
[.] 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
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the de ...
and one
aspartate side-chains; one histidine is bound between the two metals.
*
![Iron Superoxide Dismutase Active Site](https://upload.wikimedia.org/wikipedia/commons/2/2a/Iron_Superoxide_Dismutase_Active_Site.png)
Iron or manganese – used by
prokaryote
A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Connec ...
s and
protist
A protist () is any eukaryotic organism (that is, an organism whose cells contain a cell nucleus) that is not an animal, plant, or fungus. While it is likely that protists share a common ancestor (the last eukaryotic common ancestor), the exc ...
s, and in
mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
and
chloroplast
A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant and algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, and stores it in ...
s
** Iron – Many bacteria contain a form of the enzyme with
iron
Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in f ...
(Fe-SOD); some bacteria contain Fe-SOD, others Mn-SOD, and some (such as ''
E. coli'') contain both. Fe-SOD can also be found in the
chloroplasts
A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant cell, plant and algae, algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, ...
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. They are usually dimers, but occasionally tetramers.
** Manganese – Nearly all
mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
, and many
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
, contain a form with
manganese
Manganese is a chemical element with the symbol Mn and atomic number 25. It is a hard, brittle, silvery metal, often found in minerals in combination with iron. Manganese is a transition metal with a multifaceted array of industrial alloy use ...
(Mn-SOD): For example, the Mn-SOD found in human mitochondria. The ligands of the manganese ions are 3
histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the de ...
side-chains, an
aspartate side-chain and a water molecule or
hydroxy ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
, depending on the Mn oxidation state (respectively II and III).
[; ]
* Nickel –
prokaryotic
A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Connec ...
. 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. Mn-SOD is present in mitochondria and
peroxisome
A peroxisome () is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen pero ...
s. Fe-SOD has been found mainly in chloroplasts but has also been detected in peroxisomes, and CuZn-SOD has been localized in
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
, chloroplasts, peroxisomes, and
apoplast
Inside a plant, the apoplast can mean the space outside of cell membranes, where material can diffuse freely; that is, the extracellular spaces.
''Apoplast '' can also refer especially to the continuum of cell walls of adjacent cells; fluid and ...
.
Human
Three forms of superoxide dismutase are present in humans, in all other
mammals
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
, and most
chordates
A chordate () is an animal of the phylum Chordata (). All chordates possess, at some point during their larval or adult stages, five synapomorphies, or primary physical characteristics, that distinguish them from all the other taxa. These five ...
.
SOD1
Superoxide dismutase u-Zn'' also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the ''SOD1'' gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, fam ...
is located in the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
,
SOD2
Superoxide dismutase 2, mitochondrial (SOD2), also known as manganese-dependent superoxide dismutase (MnSOD), is an enzyme which in humans is encoded by the ''SOD2'' gene on chromosome 6. A related pseudogene has been identified on chromosome 1 ...
in the
mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
, and
SOD3
Extracellular superoxide dismutase u-Zn'' is an enzyme that in humans is encoded by the ''SOD3'' gene.
This gene encodes a member of the superoxide dismutase (SOD) protein family. SODs are antioxidant enzymes that catalyze the dismutation of ...
is
extracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
. The first is a
dimer
Dimer may refer to:
* Dimer (chemistry), a chemical structure formed from two similar sub-units
** Protein dimer, a protein quaternary structure
** d-dimer
* Dimer model, an item in statistical mechanics, based on ''domino tiling''
* Julius 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
Manganese is a chemical element with the symbol Mn and atomic number 25. It is a hard, brittle, silvery metal, often found in minerals in combination with iron. Manganese is a transition metal with a multifaceted array of industrial alloy use ...
in its reactive centre. The
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
s are located on chromosomes 21, 6, and 4, respectively (21q22.1, 6q25.3 and 4p15.3-p15.1).
Plants
In
higher plants
Vascular plants (), also called tracheophytes () or collectively Tracheophyta (), form a large group of land plants ( accepted known species) that have lignified tissues (the xylem) for conducting water and minerals throughout the plant. They ...
, superoxide dismutase enzymes (SODs) act as antioxidants and protect cellular components from being oxidized by
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
(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 O
2 is reduced to (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 O
2 and from superoxide (), 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
A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant and algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, and stores it in ...
,
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
, and in some cases the extracellular space. Note that Cu-Zn SODs provide less protection than Fe SODs when localized in the chloroplast.
Bacteria
Human white blood cells use enzymes such as
NADPH oxidase
NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase) is a membrane-bound enzyme complex that faces the extracellular space. It can be found in the plasma membrane as well as in the membranes of phagosomes used by neutrophil white ...
to generate superoxide and other reactive oxygen species to kill bacteria. During infection, some bacteria (e.g., ''
Burkholderia pseudomallei
''Burkholderia pseudomallei'' (also known as ''Pseudomonas pseudomallei'') is a Gram-negative, bipolar, aerobic, motile rod-shaped bacterium. It is a soil-dwelling bacterium endemic in tropical and subtropical regions worldwide, particularly in T ...
'') therefore produce superoxide dismutase to protect themselves from being killed.
Biochemistry
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
Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
(NO) or with a transition-series metal. The superoxide anion radical () spontaneously dismutes to O
2 and hydrogen peroxide () quite rapidly (~10
5 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
Peroxynitrite (sometimes called peroxonitrite) is an ion with the formula ONOO−. It is a structural isomer of nitrate,
Preparation
Peroxynitrite can be prepared by the reaction of superoxide with nitric oxide:
:
It is prepared by the react ...
.
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 largest ''k''
cat/''K''
M (an approximation of catalytic efficiency) of any known enzyme (~7 x 10
9 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. Aconitase is one of several iron-sulfur-containing (de)hydratases in metabolic pathways shown to be inactivated by superoxide.
Stability and folding mechanism
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.
In chemical
denaturation experiments, holo SOD1 unfolds by a three-state mechanism with observation of a folded monomeric intermediate.
Physiology
Superoxide is one of the main
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
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
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
.
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 compounds, such as
paraquat and
diquat (
herbicide
Herbicides (, ), also commonly known as weedkillers, are substances used to control undesired plants, also known as weeds.EPA. February 201Pesticides Industry. Sales and Usage 2006 and 2007: Market Estimates. Summary in press releasMain page fo ...
s).
''
Drosophila
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
'' lacking SOD1 have a dramatically shortened lifespan, whereas flies lacking SOD2 die before birth. Depletion of
SOD1
Superoxide dismutase u-Zn'' also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the ''SOD1'' gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, fam ...
and
SOD2
Superoxide dismutase 2, mitochondrial (SOD2), also known as manganese-dependent superoxide dismutase (MnSOD), is an enzyme which in humans is encoded by the ''SOD2'' gene on chromosome 6. A related pseudogene has been identified on chromosome 1 ...
in the nervous system and muscles of ''
Drosophila
''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
'' is associated with reduced lifespan.
The accumulation of neuronal and muscular
ROS appears to contribute to age-associated impairments. When overexpression of mitochondrial SOD2 is induced, the lifespan of adult ''Drosophila'' is extended.
Among
black garden ant
The black garden ant (''Lasius niger''), also known as the common black ant, is a formicine ant, the type species of the subgenus ''Lasius'', which is found across Europe and in some parts of North America, South America, Asia and Australasia. ...
s (''Lasius niger''), the lifespan of
queens
Queens is a borough of New York City, coextensive with Queens County, in the U.S. state of New York. Located on Long Island, it is the largest New York City borough by area. It is bordered by the borough of Brooklyn at the western tip of Long ...
is an order of magnitude greater than of workers despite no systematic nucleotide sequence difference between them.
The ''
SOD3
Extracellular superoxide dismutase u-Zn'' is an enzyme that in humans is encoded by the ''SOD3'' gene.
This gene encodes a member of the superoxide dismutase (SOD) protein family. SODs are antioxidant enzymes that catalyze the dismutation of ...
'' 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.
[
SOD knockdowns in the worm '']C. elegans
''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (r ...
'' do not cause major physiological disruptions. However, the lifespan of ''C. elegans'' can be extended by superoxide/catalase
Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting t ...
mimetics suggesting that oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
is a major determinant of the rate of aging
Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...
.
Knockout or null mutations in SOD1 are highly detrimental to aerobic growth in the budding yeast ''Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...
'' and result in a dramatic reduction in post-diauxic lifespan. In wild-type ''S. cerevisiae'', DNA damage
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
rates increased 3-fold with age, but more than 5-fold in mutants deleted for either the ''SOD1
Superoxide dismutase u-Zn'' also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the ''SOD1'' gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, fam ...
'' or ''SOD2
Superoxide dismutase 2, mitochondrial (SOD2), also known as manganese-dependent superoxide dismutase (MnSOD), is an enzyme which in humans is encoded by the ''SOD2'' gene on chromosome 6. A related pseudogene has been identified on chromosome 1 ...
'' genes. Reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
levels increase with age in these mutant strains and show a similar pattern to the pattern of DNA damage
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
increase with age. Thus it appears that superoxide dismutase plays a substantial role in preserving genome integrity during aging
Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...
in ''S. cerevisiae''.
SOD2 knockout or null mutations cause growth inhibition on respiratory carbon sources in addition to decreased post-diauxic lifespan.
In the fission yeast ''Schizosaccharomyces pombe
''Schizosaccharomyces pombe'', also called "fission yeast", is a species of yeast used in traditional brewing and as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically meas ...
'', deficiency of mitochondrial superoxide dismutase SOD2
Superoxide dismutase 2, mitochondrial (SOD2), also known as manganese-dependent superoxide dismutase (MnSOD), is an enzyme which in humans is encoded by the ''SOD2'' gene on chromosome 6. A related pseudogene has been identified on chromosome 1 ...
accelerates chronological aging.
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
Superoxide dismutase u-Zn'' also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the ''SOD1'' gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, fam ...
) can cause familial amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
(ALS, a form of motor neuron disease
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
). The most common mutation in the U.S. is A4V, while the most intensely studied is G93A
Superoxide dismutase u-Zn'' also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the ''SOD1'' gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, fami ...
. The other two isoforms of SOD have not been linked to many human diseases, however, in mice inactivation of SOD2 causes perinatal lethality and inactivation of SOD1 causes hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.
It occurs in t ...
. Mutations in SOD1
Superoxide dismutase u-Zn'' also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the ''SOD1'' gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, fam ...
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
Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...
. 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.
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
A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal deve ...
. Hence, high levels of free radicals can cause damage to them and induce dysraphic anomalies (neural tube defects).
Pharmacological activity
SOD has powerful antiinflammatory activity. For example, SOD is a highly effective experimental treatment of chronic inflammation in colitis
Colitis is swelling or inflammation of the large intestine ( colon). Colitis may be acute and self-limited or long-term. It broadly fits into the category of digestive diseases.
In a medical context, the label ''colitis'' (without qualification ...
. Treatment with SOD decreases reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
generation and oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
and, thus, inhibits endothelial activation. Therefore, such antioxidants may be important new therapies for the treatment of inflammatory bowel disease
Inflammatory bowel disease (IBD) is a group of inflammation, inflammatory conditions of the colon (anatomy), colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine a ...
.
Likewise, SOD has multiple pharmacological activities. E.g., it ameliorates cis-platinum-induced nephrotoxicity Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxin ...
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 cut short by concerns about prion disease
Prions are misfolded proteins that have the ability to transmit their misfolded shape onto normal variants of the same protein. They characterize several fatal and transmissible neurodegenerative diseases in humans and many other animals. It i ...
.
An SOD-mimetic agent, TEMPOL
4-Hydroxy-TEMPO or TEMPOL, formally 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl, is a heterocyclic compound. Like the related TEMPO, it is used as a catalyst and chemical oxidant by virtue of being a stable aminoxyl radical. Its major appeal ove ...
, is currently in clinical trials for radioprotection and to prevent radiation-induced dermatitis
Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved can v ...
. TEMPOL and similar SOD-mimetic nitroxides exhibit a multiplicity of actions in diseases involving oxidative stress.
Cosmetic uses
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
Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
, possibly through de- differentiation of myofibroblasts
A myofibroblast is a cell phenotype that was first described as being in a state between a fibroblast and a smooth muscle cell.
Structure
Myofibroblasts are contractile web-like fusiform cells that are identifiable by their expression of α-sm ...
back to fibroblasts
A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...
.
Commercial sources
SOD is commercially obtained from marine phytoplankton
Phytoplankton () are the autotrophic (self-feeding) components of the plankton community and a key part of ocean and freshwater ecosystems. The name comes from the Greek words (), meaning 'plant', and (), meaning 'wanderer' or 'drifter'.
Ph ...
, bovine liver, horseradish
Horseradish (''Armoracia rusticana'', syn. ''Cochlearia armoracia'') is a perennial plant of the family Brassicaceae (which also includes mustard, wasabi, broccoli, cabbage, and radish). It is a root vegetable, cultivated and used worldwide ...
, cantaloupe
The cantaloupe, rockmelon (Australia and New Zealand, although cantaloupe is used in some states of Australia), sweet melon, or spanspek (Southern Africa) is a melon that is a variety of the muskmelon species (''Cucumis melo'') from the fami ...
, 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 is broken down into amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s before being absorbed. However, ingestion of SOD bound to wheat proteins could improve its therapeutic activity, at least in theory.
See also
* Catalase
Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting t ...
* Glutathione peroxidase
Glutathione peroxidase (GPx) () is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid h ...
* Jiaogulan
''Gynostemma pentaphyllum'', also called jiaogulan (, Pinyin: jiǎogǔlán, literally "twisting blue plant"), is a dioecious, herbaceous climbing vine of the family Cucurbitaceae ( cucumber or gourd family) widely distributed in South and Eas ...
* NADPH oxidase
NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase) is a membrane-bound enzyme complex that faces the extracellular space. It can be found in the plasma membrane as well as in the membranes of phagosomes used by neutrophil white ...
, an enzyme which ''produces'' superoxide
* Peroxidase
Peroxidases or peroxide reductases ( EC numberbr>1.11.1.x are a large group of enzymes which play a role in various biological processes. They are named after the fact that they commonly break up peroxides.
Functionality
Peroxidases typically ca ...
References
External links
* (ALS)
The ALS Online Database
Includes a discussion of the roles of SOD1 and SOD2 in aging.
Physicians' Comm. For Responsible Med.
PDBe-KB
provides an overview of all the structure information available in the PDB for Human Superoxide dismutase u-Zn
PDBe-KB
provides an overview of all the structure information available in the PDB for Human Superoxide dismutase n mitochondrial
PDBe-KB
provides an overview of all the structure information available in the PDB for Human Extracellular superoxide dismutase u-Zn
{{Authority control
Antioxidants
Metalloproteins
Oxidoreductases
EC 1.15.1
Copper enzymes
Aging-related enzymes
Iron enzymes
Zinc enzymes
Nickel enzymes
Manganese enzymes