Superoxide dismutase discovery

Interest in superoxide dismutase has increased in recent years with the discovery that a mutation in the gene coding for SOD is linked to certain types of the neurodegenerative disease amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig s disease. Exactly how mutant forms of SOD are involved in ALS is a subject of intense research. 

In 1965 1967 a great interest has been attached to the possible role of free radicals in cancer after studies by Emanuel and his coworkers who reported the excessive production of free radicals in tumor cells (see, for example, Ref. [145]). On these grounds the authors suggested to apply antioxidant therapy for the treatment of cancer patients. Unfortunately, experimental proofs of overproduction of free radicals in cancer tissue turn out to be erroneous [146], A new interest in the role of free radicals in cancer development emerged after the discovery of superoxide and superoxide dismutases. 

The discovery of the superoxide dismutase activity of erythrocuprein has indeed opened a wide field. 

The general acceptance of free radicals in biological systems did not occur until the discovery (Mila) of superoxide dismutase (SOD), of which there are two enzymes, cytoplasmic CuZn-SOD and mitochondrial Mn-SOD. These enzymes catalyze the following reaction ... 

Andersen PM, Sims KB, Xin WW, Kiely R, O Neill G, Ravits J, Pioro E, Harati Y, Brower RD, Levine JS, Heinicke HU, Seltzer W, Boss M, Brown RH Jr. (2003) Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis a decade of discoveries, defects and disputes. Amyotroph Lateral Scler Other Motor Neuron Disord 4 62-73... 

The area next moved forward in 1969 following the discovery of superoxide dismutase (SOD) [9]. With the advent of methods to measure SOD activity and superoxide production great interest was shown in examining the relationship between pulmonary antioxidant defences, oxygen free radicals and tissue injury. 

Low-molecular-weight catalysts which mimic a natural enzymic function syn-Zymes) have potential utility for the treatment of diseases characterized by the overproduction of a potentially deleterious metabolic by-product or foreign gene product. The discovery and development of pentaaza macrocyclic ligand complexes of manganese(II) as functional mimics of superoxide dismutase (SOD) enzymes and their potential utility as human pharmaceutical agents is described. 

Since the discovery of superoxide dismutase (SOD) by McCord and Fridovich (Ml9), increasing numbers of papers have been published concerning the structural and functional aspects of this enzyme. Historically, a variety of SODs were reported as copper-containing proteins hemocuprein from bovine blood (M2), hepatocuprein from horse liver (M28), cerebrocuprein from human brain (P10), and ery throcupurein from human and beef erythrocytes (M9). Carrico and Deutsch (C2) gave the name cytocuprein to these proteins because the cupreins from various organs were found to be essentially identical. Cytocuprein was found to... 

Antioxidant enzymes do not always protect us. There was great excitement when it was found that victims of a hereditary form of the terrible neurological disease amyotrophic lateral sclerosis (ALS see also Chapter 30) carry a defective gene for Cu / Zn-superoxide dismutase (SOD Eq. 16-27). This discovery seemed to support the idea that superoxide anions in the brain were killing neurons. However, it now appears that in some cases of ALS the defective SOD is too active, producing an excess of H2O2, which damages neurons. 

Following discovery of the superoxide dismutase (SOD) enzymes by Keilin and Mann (i), and their ability to catalyze the dismutation of the superoxide radical anion (O2) in laboratory experiments (2), discussion has taken place over the intervening years as to whether such enzymes do catalyze O2 dismutation in vivo, and whether there is a need for a complex enzyme to accelerate a reaction that is already very fast. This is not the place to address these points, but the current feeling is that the answer to both questions is in the affirmative. 

Three decades elapsed between the first isolation of erythrocuprein and the discovery of a catalytic function for this protein. Attributable to the high interest in the biochemistry of reactive oxygen species, numerous enzymatic assays for superoxide dismutases were developed in the last years. Nevertheless, the original assay of McCord and Fridovich is still currently used for routine purposes The reactivity of super-... 

The first is biomedicine. The discovery of superoxide dismutase and nitrogen monoxide as messengers has led to an explosive growth in articles in which one-electron oxidations and reductions have been explored. Organic radicals play an important role in the treatment of cancers. The other is atmospheric chemistry where the modeling of reactions requires accurate reduction potentials (Stanbury 1989, Wardman 1989). 

SP 131 describes Pauling s 1933 discovery and verification of the superoxide free radical, which now, 67 years later—has become of much interest as an active agent in oxidative damage to tissues and in the aging process. The control of this substance in living organisms, by means of the superoxide dismutase enzyme that catalyzes its decomposition, is an example of a potential task of orthomolecular medicine (see below). 

Superoxide dismutase (SOD) was discovered in the 1960s by McCord and Fridovich in bovine erythrocytes where they described its functions as an enzyme which catalyzes the dismutation of superoxide radicals (Oj + O2 + 2H 02 + HjOj) (McCord and Fridovich 1969). Since the discovery of SOD, there are four isofoims of the enzyme which have been identified and they include Ni-SOD (cytoplasmic), Mn-SOD (mitochondrial), Cu/Zn-SOD (cytoplasmic), and EC-SOD (extracellular) (Mates and Sanchez-Jimenez 1999). The product of the dismutation of two superoxide anions carried out by SOD is the ROS, hydrogen peroxide, therefore biologically this enzyme is often coupled with antioxidants that remove hydrogen peroxide such as catalase and glutathione peroxidase. 

Although O2" is a stable anion radical, easily generated or even available commercially as the potassium salt, its chemical behavior has received significant attention only within the last several years. Chemical interest was spawned by the discovery of Fridovich and coworkers (] ) that superoxide dismutase, an enzyme present in all aerobic organisms studied, has as its function the dismutation of O2 into H2O2 and O2 (equation 1). Since... 

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