We can’t live without oxygen. Our cells rely on oxygen as the final acceptor of electrons in respiration, allowing us to extract far more energy from food than would be possible without oxygen.
But oxygen is also a dangerous compound. Reactive forms of oxygen, such as superoxide (oxygen with an extra electron), leak from the respiratory enzymes and wreak havoc on the cell. Almost 3 to 10% of the oxygen utilized by tissues is converted to its reactive intermediates. These superoxides can then cause mutations in DNA or attack enzymes that make amino acids and other essential molecules.
Oxidative stress may contribute to the development of many diseases and chronic conditions, including:
• age-related macular degeneration
• chronic obstructive pulmonary disease
• chronic fatigue syndrome
• heart disease
• insulin resistance
• neurodegenerative diseases (such as Parkinson’s, Alzheimer’s disease and ALS)
• rheumatoid arthritis
To combat this potential danger, most cells make superoxide dismutase, a protein that detoxifies superoxide. This protein is referred to as an enzyme, or as a protein that initiates or regulates a specific chemical or signaling action. Superoxide dismutase specifically neutralizes the superoxide radical, which is generated during normal aerobic processes.
As you might guess from its name, SOD dismutes superoxide. Dismutation is a term that refers to a special type of reaction, where two equal but opposite reactions occur on two separate molecules.
SOD takes two molecules of superoxide, strips the extra electron off of one, and places it on the other. So, one ends up with an electron less, forming normal oxygen, and the other ends up with an extra electron. The one with the extra electron then rapidly picks up two hydrogen ions to form hydrogen peroxide. Of course, hydrogen peroxide is also a dangerous compound, so the cell must use the enzyme.
Superoxide dismutation occurs according to the following formulae:
M3+ + O – → M2+ + O2
M2+ + O – + 2H+ → M3+ + H2O2
Types of SOD
Three unique and highly compartmentalized mammalian superoxide dismutases have been biochemically and molecularly characterized to date.
a) SOD1, or CuZn-SOD was the first enzyme to be characterized and is a copper and zinc-containing homodimer that is found almost exclusively in intracellular cytoplasmic spaces.
b) SOD2, or Mn-SOD exists as a tetramer and is initially synthesized containing a leader peptide, which targets this manganese-containing enzyme exclusively to the mitochondrial spaces.
c) SOD3, or EC-SOD is the most recently characterized SOD, exists as a copper and zinc-containing tetramer, and is synthesized containing a signal peptide that directs this enzyme exclusively to extracellular spaces.
SODs also play a critical role in inhibiting oxidative inactivation of nitric oxide, thereby preventing peroxynitrite formation and endothelial and mitochondrial dysfunction.
SOD1 is the major intracellular SOD (cytosolic Cu/ZnSOD). It exists as a 32kDa homodimer and is mainly localized in the cytosol with a smaller fraction in the intermembrane space of mitochondria.
It has also been reported that SOD1 is also localized in nuclei, lysosomes, and peroxisomes, using immunocytochemical methods, and shows widespread distribution in a variety of cells. The enzyme is sensitive to cyanide, which helps to distinguish it from SOD2, which is relatively resistant.
Like the other SODs, it is distinctive on account of the type of metal ion it binds, its structure and its location. SOD1 contains copper and zinc. It has a molecular mass of 32,000 daltons (where 1 dalton is the mass of a hydrogen atom). According to a 2002 review in Free Radical Biology and Medicine, mutations in the gene that codes for SOD1 have been linked to amyotrophic lateral sclerosis, better known as Lou Gherig’s Disease. In humans, the SOD1 gene is found on chromosome 21.
Superoxide dismutase 2, mitochondrial or SOD2, is an enzyme which in humans is encoded by the SOD2 gene.
Unlike SODs 1 and 3, SOD2 contains manganese, a transition metal. It consists of four identical subunits, each with a molecular mass of approximately 23,000 daltons. It is found in the mitochondria, the membrane-enveloped organelles that act as the powerhouse of the cell. The SOD2 gene is found on chromosome six in humans.
Mutations in this gene have been associated with idiopathic cardiomyopathy, sporadic motor neuron disease, glaucoma, neurological disorders, cancer and death. A common polymorphism associated with greater susceptibility to various patholiges is found in the mitochondrial leader targeting sequence (Val9Ala). Mice lacking SOD2 die shortly after birth, indicating that unchecked levels of superoxide are incompatible with mammalian life. However, mice 50% deficient in SOD2 have a normal lifespan and minimal phenotypic defects but do suffer increased DNA damage and increased incidence of cancer. In Drosophila melanogaster, over-expression of SOD2 has been shown to increase lifespan by 20%.
SOD3 is a homotetramer that consists of four identical subunits; its total molecular mass is 135,000 daltons. Like SOD1, SOD3 contains copper and zinc; unlike SODs 1 and 2, however, it is only expressed in specific cell types, and rather than being found in cells, it’s found in blood, lymph and cerebrospinal fluids instead.
The SOD3 gene is found on chromosome four. The product of this gene is thought to protect the brain, lungs, and other tissues from oxidative stress. It plays an important role in the metabolism of NO and in the pathology of such diseases as atherosclerosis, diabetes, and arthritis.
The protein is secreted into the extracellular space and forms a glycosylated homotetramer that is anchored to the extracellular matrix and cell surfaces through an interaction with heparan sulfate proteoglycan and collagen.
Recently, genetic variants in SOD3 have been associated with reduced lung function in adults and lung function decline in chronic obstructive pulmonary disease (COPD). Individual genetic differences influencing the development of lung structure and function may contribute to subsequent vulnerability to environmental stress and possibly the progression of chronic pulmonary diseases.
Superoxide dismutase can be found naturally in wheat grass, or in vegetables like broccoli and brussels sprouts. In addition, the body can synthesize superoxide dismutase on its own and adequate amounts of this enzyme can be produced if a person eats a relatively healthy diet and limits oxidative stress. For people with conditions that may be helped by extra levels of this enzyme, supplementation may be recommended.
However these supplements are somewhat controversial. This is because the enzyme is totally inactivated by stomach acid and therefore tablets need a special coating to survive the stomach acid and to be properly absorbed. Most medical professionals believe that oral supplementation is impossible, whereas others argue that specially coated capsules, or enteric capsules, are fully absorbable. Even if the enteric coated oral form passed through the digestive process unharmed, it is a plant based form which is a larger molecule and could not act in place of smaller forms found in the mitochondria and cytoplasm (SOD1 & SOD2).
SOD may also be injected. But since this form is derived from bovine sources, there were drawbacks associated with its use. The main problem was the nonhuman origin of the enzyme which gave rise to a variety of immunological problems and was taken off the market.
Researchers have pursued the concept of designing a synthetic, low-molecular-weight mimetics of the SOD enzymes, which could overcome the limitations associated with either the oral plant-based forms or the injectable bovine forms. In the process, the compound known as Tempol was discovered.