Superoxide Dismutase

J.A. Tainer, Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.

The discovery of superoxide dismutases (SODs), which convert superoxide radicals to molecular oxygen and hydrogen peroxide, has been termed the most important discovery of modern biology never to win a Nobel Prize. Here, we review the reasons this discovery has been underappreciated, as well as discuss the robust results supporting its premier biological importance and utility for current research. We highlight our understanding of the SOD function gained through structural biology analyses, which reveal important hydrogen-bonding schemes and metal-binding motifs. These structural features create remarkable enzymes that promote catalysis at faster than diffusion-limited rates by using electrostatic guidance. These architectures additionally alter the redox potential of the active site metal center to a range suitable for the superoxide disproportionation reaction and protect against inhibition of catalysis by molecules such as phosphate.

SOD structures may also control their enzymatic activity through product inhibition; manipulation of these product inhibition levels has the potential to generate therapeutic forms of SOD. Markedly, structural destabilization of the SOD architecture can lead to disease, as mutations in Cu, ZnSOD may result in familial amyotrophic lateral sclerosis, a relatively common, rapidly progressing and fatal neurodegenerative disorder. We describe our current understanding of how these Cu, ZnSOD mutations may lead to aggregation/fibril formation, as a detailed understanding of these mechanisms provides new avenues for the development of therapeutics against this so far untreatable neurodegenerative pathology.

Structural biochemistry studies have provided striking insights into the functions of the superoxide dismutases.

Medical Center, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Accumulated evidence has shown that reactive oxygen species (ROS) are important mediators of cell signaling events such as inflammatory reactions (superoxide) and the maintenance of vascular tone (nitric oxide). However, overproduction of ROS such as superoxide has been associated with the pathogenesis of a variety of diseases including cardiovascular diseases, neurological disorders, and pulmonary diseases. Antioxidant enzymes are, in part, responsible for maintaining low levels of these oxygen metabolites in tissues and may play key roles in controlling or preventing these conditions. One key antioxidant enzyme implicated in the regulation of ROS-mediated tissue damage is extracellular superoxide dismutase (EC-SOD). EC-SOD is found in the extracellular matrix of tissues and is ideally situated to prevent cell and tissue damage initiated by extracellularly produced ROS. In addition, EC-SOD is likely to play an important role in mediating nitric oxide-induced signaling events, since the reaction of superoxide and nitric oxide can interfere with nitric oxide signaling.

This review will discuss the regulation of EC-SOD and its role in a variety of oxidant-mediated diseases.

Institute of Space Medico-Engineering, Beijing, China.

In order to prolong the in vivo half-life of Superoxide Dismutase (SOD) to improve the blood compatibility and to treat tissue injuries caused by activated oxygen during ischemia and hypoxia, erythrocytes were used as SOD carrier. The entrapment of SOD into rabbit erythrocytes was successfully employed. It demonstrated in vitro experiment that SOD activity maintained a stable level in the first 8 hours, and these erythrocytes can be stored at 4 degrees C for one week without loss of activity. The SOD carrier erythrocytes might be useful in clinical and special environmental medicine.

Pediatric Critical Care, Department of Pediatrics, University of Colorado School of Medicine, 4200 E 9th Ave B131, Denver, CO 80262, USA.

The extracellular space is protected from oxidant stress by the antioxidant enzyme extracellular superoxide dismutase (EC-SOD), which is highly expressed in selected tissues including blood vessels, heart, lungs, kidney, and placenta. EC-SOD contains a unique heparin-binding domain at its carboxy-terminus that establishes localization to the extracellular matrix where the enzyme scavenges superoxide anion. The EC-SOD heparin-binding domain can be removed by proteolytic cleavage, releasing active enzyme into the extracellular fluid. In addition to protecting against extracellular oxidative damage, EC-SOD, by scavenging superoxide, preserves nitric oxide bioactivity and facilitates hypoxia-induced gene expression. Loss of EC-SOD activity contributes to the pathogenesis of a number of diseases involving tissues with high levels of constitutive extracellular superoxide dismutase expression.

A thorough understanding of the biological role of EC-SOD will be invaluable for developing novel therapies to prevent stress by extracellular oxidants.

By Dale Kiefer – Life Extension Magazine

For years, scientists have sought a way to boost one of the body’s most powerful natural antioxidant enzymes: superoxide dismutase (SOD). Present both inside and outside cell membranes, SOD is one of the body’s primary internal anti-oxidant defenses and plays a critical role in reducing the oxidative stress implicated in atherosclerosis and other life-threatening diseases. Studies have shown that SOD can play a critical role in reducing internal inflammation and lessening pain associated with conditions such as arthritis.

Department of Microbiology and Immunology, University of Michigan Medical School, West Medical Center Drive, Ann Arbor, MI, USA.

A bacterium can swim through a fluid environment or coordinate motion with a group of bacteria and swarm across a surface. The flagellar motor, which propels the bacterium, is fueled by proton motive force. In contrast to the physiology that governs swimming motility, much less is known about the energy sources required for multicellular swarming on surfaces. In this study, we used Proteus mirabilis as a model organism to study vigorous swarming behavior and genetic and biochemical approaches to define energy pathways and central metabolism that contribute to multicellular motility.

We found that swarming bacteria use a complete aerobic tricarboxylic acid (TCA) cycle but do not respire oxygen as the terminal electron acceptor, suggesting that multicellular cooperation during swarming reduces the amount of energy required by individual bacteria to achieve rapid motility.

U.S. National Library of Medicine, 8600 Rockville Pike, Bethesda, MD 20894

The SOD1 gene provides instructions for making an enzyme called superoxide dismutase, which is abundant in cells throughout the body. This enzyme attaches (binds) to molecules of copper and zinc to break down toxic, charged oxygen molecules called superoxide radicals. Superoxide radicals can damage cells if too many accumulate within cells. Superoxide radicals are byproducts of normal cell processes, particularly energy-producing reactions, and must be broken down regularly.

Department of Psychiatry and Behavioral Sciences, Box #3412, Duke University Medical Center, Durham, NC 27710, USA

Extracellular superoxide dismutase (EC-SOD) quenches free radicals and attenuates age-related cognitive decline: opportunities for novel drug development in aging.

Superoxide dismutase (SOD) is one of the most effective mechanisms in physiology for inactivating reactive oxygen species. Elevated SOD activity can be therapeutically useful by protecting against oxidative stress-induced neurotoxicity. Acutely increased extracellular-SOD (EC-SOD) activity protects against neurobehavioral impairment caused by acute ischemia. Chronically increased EC-SOD activity may also be therapeutically useful by protecting against chronic oxidative stress-induced neurobehavioral damage that accumulates during the aging process. We have found that mice with genetic overexpression of EC-SOD do not show the aging-induced decline in learning and memory that control, wild type mice show. From 14-22 months of age, the EC-SOD overexpressing mice have significantly better spatial learning working memory function than that of controls. This effect is specific to the aging period. Young adult EC-SOD overexpressing mice do not have better learning and memory function than controls. The beneficial effects of increased EC-SOD activity with aging may be achieved without risk of impairment during younger ages by chronically administering EC-SOD mimetics from mature adulthood into the aging period. Novel EC-SOD mimetics may be useful in attenuating aging-induced cognitive impairments and other aspects of physiological decline with aging.

Buck Institute, 8001 Redwood Boulevard, Novato, CA 94945, U.S.A.

To date, more than 40 genes have been identified in the nematode Caenorhabditis elegans, which, when mutated, lead to an increase in lifespan. Of those tested, all confer increased resistance to oxidative stress. In addition, the lifespan of C. elegans can also be extended by the administration of synthetic superoxide dismutase/catalase mimetics. These compounds also appear to confer resistance to oxidative damage, since they protect against paraquat treatment.

The protective effects of these compounds are apparent with treatment during either development or adulthood. These findings have demonstrated that pharmacological intervention in the aging process is possible and that these compounds can provide important information about the underlying mechanisms.

To date, such interventions have targeted known processes rather than screening compound libraries because of the limitations of assessing lifespan in nematodes.

However, we have recently developed a microplate-based assay that allows for a rapid and objective score of nematode survival at rates many times higher than previously possible. This system now provides the opportunity to perform high-throughput screens for compounds that affect nematode survival in the face of acute oxidative stress and will facilitate the identification of novel drugs that extend nematode lifespan.

Inserm UMR-S490, Université René Descartes, 45, rue des Saints Pères, 75270 Paris Cedex 06, France.

A number of theories have attempted to account for aging processes in various species. Following the << rate of living >> theory of Pearl, Harman suggested fifty years ago that the accumulation of oxidants could explain the alteration of physical and cognitive functions with aging. Oxygen metabolism leads to reactive species, including free radicals, which tend to oxidize surrounding molecules such as DNA, proteins, and lipids. As a consequence, various functions of cells and tissues can be altered, leading to DNA instability, protein denaturation, and accumulation of lipid byproducts.

Oxidative stress is an adaptive process that is triggered upon oxidant accumulation and which comprises the induction of protective and survival functions.

Experimental evidence suggests that the aging organism is in a state of oxidative stress, which supports the free radical theory. A number of other theories have been proposed; some of these are actually compatible with the free radical theory. Caloric restriction is among the best models to increase life span in many species.

While the relationship between caloric restriction and corrected metabolic rate is controversial, the decrease in ROS production by mitochondria appears to be experimentally supported. The ROS and mitochondrial theories of aging appear to be compatible. Genetic models of increased life span, particularly those affecting the Foxo pathway, are usually accompanied by increased resistance to oxidative insult. The free radical theory is not consistent with programmed senescence theories involving the cell division dependent decrease in telomere length; however, oxidants are known to alter telomere structure. An appealing view of the role of oxidative stress in aging is the trade-off principle which states that a phenotypic trait can be evolutionarily conserved because of its positive effects on development, growth, or fertility, and despite its negative effect on somatic functions and aging. It is likely that most cellular stresses which comprise adaptive and toxic functions follow such a rule.

Department of Biochemistry, University of Toronto, University Health Network, Toronto Medical Discovery Tower, Medical and Related Sciences (MaRS), 101 College Street, Toronto, ON, Canada, M5G 1L7.

Fourteen years after the discovery that mutations in Cu, Zn superoxide dismutase (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS), the mechanism by which mutant SOD1 exerts toxicity remains unknown. The two principal hypotheses are (a) oxidative damage stemming from aberrant SOD1 redox chemistry, and (b) misfolding of the mutant protein. Here we review the structure and function of wild-type SOD1, as well as the changes to the structure and function in mutant SOD1. The relative merits of the two hypotheses are compared and a common unifying principle is outlined. Lastly, the potential for therapies targeting SOD1 misfolding is discussed.

Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52240, USA.

Extracellular superoxide dismutase (SOD3) is a secreted enzyme that regulates levels of extracellular superoxide and protects the extracellular matrix from degradation by reactive species. The SOD3 protein contains a heparin-binding domain and resides in a microenvironment rich in other heparin-bound growth factors, raising the possibility that SOD3 may have some biological role independent of its catalytic activity. To begin to address this, we designed and created enzymatically inactive mutant constructs targeting either the copper coordinating (i.e. H96 and H98) or superoxide channeling (i.e. N180 and R186) amino acid residues of SOD3.

All constructs expressed equal quantities of immature intracellular SOD proteins, but only the N180A, R186A, and combination N180A/R186A mutants produced fully processed and secreted extracellular protein. Furthermore, while SOD activity was significantly inhibited in the single N180A and R186A mutants, the activity was completely abrogated in the N180A/R186A double mutant. Overall, the use of this novel tool may have broad-reaching impacts into various fields of biology and medicine and will aid in the delineation of cellular processes that are regulated by solely the SOD3 protein, its reactive oxygen species substrates, and products, or the combination of both.

Department of Pediatrics, Queen’s University, Kingston, Ontario, Canada.

We have previously provided evidence that two transition metal cations, Zn2+ and Cu2+, can alter the conformation of nerve growth factor (NGF), rendering it unable to bind to its receptors or to activate signal transduction pathways. In the present study, we have assessed the influence of Zn2+ and Cu2+ on NGF-mediated protection from an oxidative insult. Exposure of rat pheochromocytoma (PC12) cells to hydrogen peroxide resulted in an increase in cell death via apoptosis, which was inhibited by NGF. Zn2+ and Cu2+, when added to cultures at a concentration of 100 microM, prevented NGF-mediated survival-promoting effects. Neither of these ions had an effect on basal cell viability (in the absence of NGF) after an oxidative insult. These results demonstrate that Zn2+ and Cu2+ can selectively inhibit NGF-mediated resistance to oxidative stress, and have significant implications for neuronal function under both physiological and pathological (e.g. cerebral ischemia) conditions.

Department of Biology, University of California at San Diego, La Jolla 92093.

The effects of calcium supplementation (as calcium citrate malate, 1000 mg elemental Ca/d) with and without the addition of zinc (15.0 mg/d), manganese (5.0 mg/d) and copper (2.5 mg/d) on spinal bone loss (L2-L4 vertebrae) was evaluated in healthy older postmenopausal women (n = 59, mean age 66 y) in a 2-y, double-blind, placebo-controlled trial. Changes (mean +/- SEM) in bone density were -3.53 +/- 1.24% (placebo), -1.89 +/- 1.40% (trace minerals only), -1.25 +/- 1.46% (calcium only) and 1.48 +/- 1.40% (calcium plus trace minerals). Bone loss relative to base-line value was significant (P = 0.0061) in the placebo group but not in the groups receiving trace minerals alone, calcium alone, or calcium plus trace minerals. The only significant group difference occurred between the placebo group and the group receiving calcium plus trace minerals (P = 0.0099).

These data suggest that bone loss in calcium-supplemented, older postmenopausal women can be further arrested by concomitant increases in trace mineral intake.

Department of Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, PA. USA, Michael T. Lotze, MD Professor of Surgery University of Pittsburgh Cancer Institute 5117 Centre Avenue, Suite G.27a Pittsburgh, USA.

Cancers often arise as the end stage of inflammation in adults, but not in children. As such, there is a complex interplay between host immune cells during neoplastic development, with both an ability to promote cancer as well as limit or eliminate it, most often complicit with the host. In humans, defining inflammation and the presence of inflammatory cells within or surrounding the tumor is a critical aspect of modern pathology. Groups defining staging for neoplasms are strongly encouraged to assess and incorporate measures of the presence of apoptosis, autophagy, and necrosis as well as the nature and quality of the immune infiltrate.

Both environmental, as well as genetic factors, enhance the risk of cigarette smoking, H. pylori, hepatitis B/C, human papillomavirus, solar irradiation, asbestos, pancreatitis, or other causes of chronic inflammation.

Identifying suitable genetic polymorphisms in cytokines, cytokine receptors, and Toll-like receptors among other immune response genes are also seen as high value as genomic sequencing becomes less expensive. Animal models that incorporate and assess not only the genetic anlagen but also the inflammatory cells and the presence of microbial pathogen [PAMPs] and damage-associated molecular pattern molecules [DAMPs] are necessary. Identifying micro-RNAs involved in regulating the response to damage or injury is seen as highly promising. Although no therapeutic strategies to prevent or treat cancers based on insights into inflammatory pathways are currently approved for the common epithelial malignancies, there remains substantial interest in agents targeting COX2 or PPARγ, ethyl pyruvate, as well as steroids and several novel agents on the horizon.

Low et. al., 10.2337/diab.46.2.S38 Diabetes September 1997 vol. 46 no. Supplement 2 S38-S42

Oxidative stress is present in the diabetic state. Our work has focused on its presence in peripheral nerves. Antioxidant enzymes are reduced in peripheral nerves and are further reduced in diabetic nerves. That lipid peroxidation will cause neuropathy is supported by evidence of the development of neuropathy de novo when normal nerves are rendered α-tocopherol deficient and by the augmentation of the conduction deficit in diabetic nerves subjected to this insult. Oxidative stress appears to be primarily due to the processes of nerve ischemia and hyperglycemia auto-oxidation.

Centro de Investigación en Nutrición y Salud, Instituto Nacional de Salud Pública, Cuernavaca, Morelos, México; U.S. Department of Agriculture Western Human Nutrition Research Center, University of California Davis, Davis, CA; and Children’s Hospital Research Center at Oakland, Oakland, CA

Zinc Absorption from Zinc Oxide, Zinc Sulfate, Zinc Oxide + EDTA, or Sodium-Zinc EDTA Does Not Differ When Added as Fortificants to Maize Tortillas

The fortification of staple foods with zinc may play an important role in achieving adequate zinc intakes in countries at risk of zinc deficiency. However, little is known about the relative bioavailability of different zinc compounds that may be used in food fortification. The objective of this study was to measure and compare fractional zinc absorption from a test meal that included a maize tortilla fortified with zinc oxide, zinc sulfate, zinc oxide + EDTA, or sodium-zinc EDTA.

A double isotopic tracer ratio method (67Zn as oral tracer and 70Zn as an intravenous tracer) was used to estimate zinc absorption in 42 Mexican women living in a periurban community of Puebla State, Mexico. The test meal consisted of maize tortillas, yellow beans, chili sauce, and milk with instant coffee; it contained 3.3 mg zinc and had a phytate: zinc molar ratio of 17. Fractional zinc absorption did not differ significantly between the test groups (ANOVA; P > 0.05). Percent absorptions were (mean ± SD) zinc oxide, 10.8 ± 0.9; zinc sulfate, 10.0 ± 0.02; zinc oxide + EDTA, 12.7 ± 1.5; and sodium-zinc EDTA, 11.1 ± 0.7. We conclude that there was no difference in zinc absorption from ZnO and ZnSO4 when added as fortificants to maize tortillas and consumed with beans and milk. The addition of EDTA with zinc oxide or the use of prechelated sodium-zinc EDTA as fortificants did not result in higher zinc absorption from the test meal.

Life Sciences Division, Lawrence Berkeley National Laboratory, California.

Human aging is characterized by chronic, low-grade inflammation, and this phenomenon has been termed as “inflammaging.” Inflammaging is a highly significant risk factor for both morbidity and mortality in elderly people, as most if not all age-related diseases share an inflammatory pathogenesis. Nevertheless, the precise etiology of inflammaging and its potential causal role in contributing to adverse health outcomes remain largely unknown. The identification of pathways that control age-related inflammation across multiple systems is therefore important in order to understand whether treatments that modulate inflammaging may be beneficial in old people.

U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993

This database allows access to opinions and conclusions from 115 SCOGS reports published between 1972-1980 on the safety of over 370 Generally Recognized As Safe (GRAS) food substances. The GRAS ingredient reviews were conducted by the Select Committee in response to a 1969 White House directive by President Richard M. Nixon (see History of GRAS and SCOGS). The SCOGS database allows users to search for the SCOGS opinion and conclusion and includes the United States Code of Federal Regulations (21 CFR) citation for those GRAS food substances that have been codified in the CFR. Many of the SCOGS reports reviewed more than one GRAS substance and each substance was evaluated and assigned its own individual type of conclusion on safety; Type 1, 2, 3, 4, or 5, as shown in the table below.

The SCOGS conclusions were made by scientific experts outside of FDA. The complete background of the Select Committee is described in the History of GRAS and SCOGS.

Department of Public Health, Sapporo Medical University

Superoxide dismutase (SOD) is an antioxidant enzyme that acts to degrade superoxide, a major causative factor for oxidative stress associated with cancer, cardiovascular disease, and various other ailments. Here, to assess an association between antioxidants and lifestyle factors related to cancer risk, we analyzed serum SOD activity among the subjects within a large-scale cohort study in Japan. As result, significant differences in serum SOD activity were found between the sexes (lower in males), among female age groups (lower in younger individuals), and in males with the BMI (lower in those with a high BMI). The linear increase in serum SOD activity with aging and decrease with BMI were observed in females. Significantly low SOD activity was evident in male heavy smokers. In contrast, elevation was noted in female frequent drinkers. In conclusion, our findings do suggest associations between serum SOD activity and lifestyle factors. However, for further study, the establishment of a standard measurement method for SOD activity should be a high priority.

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