Review article
Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression

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Abstract

Superoxide dismutases are an ubiquitous family of enzymes that function to efficiently catalyze the dismutation of superoxide anions. Three unique and highly compartmentalized mammalian superoxide dismutases have been biochemically and molecularly characterized to date. SOD1, or CuZn-SOD (EC 1.15.1.1), was the first enzyme to be characterized and is a copper and zinc-containing homodimer that is found almost exclusively in intracellular cytoplasmic spaces. SOD2, or Mn-SOD (EC 1.15.1.1), exists as a tetramer and is initially synthesized containing a leader peptide, which targets this manganese-containing enzyme exclusively to the mitochondrial spaces. SOD3, or EC-SOD (EC 1.15.1.1), 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. What role(s) these SODs play in both normal and disease states is only slowly beginning to be understood. A molecular understanding of each of these genes has proven useful toward the deciphering of their biological roles. For example, a variety of single amino acid mutations in SOD1 have been linked to familial amyotrophic lateral sclerosis. Knocking out the SOD2 gene in mice results in a lethal cardiomyopathy. A single amino acid mutation in human SOD3 is associated with 10 to 30-fold increases in serum SOD3 levels. As more information is obtained, further insights will be gained.

Introduction

The evolution of aerobic organisms that can survive in oxygen-rich environments requires an effective defense system against reactive oxygen species (ROS), which are produced following single electron reductions of molecular oxygen. While physiological concentrations of ROS in aerobic organisms are beneficial and involve cell signaling pathways and survival from invading pathogens, an unbalanced, elevated concentration of ROS may contribute to the development of various diseases, such as cancer, hypertension, diabetes, atherosclerosis, inflammation, and premature aging. The superoxide dismutases (SODs) are the first and most important line of antioxidant enzyme defense systems against ROS and particularly superoxide anion radicals. At present, three distinct isoforms of SOD have been identified in mammals, and their genomic structure, cDNA, and proteins have been described. Two isoforms of SOD have Cu and Zn in their catalytic center and are localized to either intracellular cytoplasmic compartments (CuZn-SOD or SOD1) or to extracellular elements (EC-SOD or SOD3). SOD1 has a molecular mass of about 32,000 Da and has been found in the cytoplasm, nuclear compartments, and lysosomes of mammalian cells [1], [2], [3], [4]. SOD3 is the most recently discovered and least characterized member of the SOD family. The enzyme exists as a homotetramer of molecular weight 135,000 Da with high affinity for heparin [5]. SOD3 was first detected in human plasma, lymph, ascites, and cerebrospinal fluids [6], [7]. The expression pattern of SOD3 is highly restricted to the specific cell type and tissues where its activity can exceed that of SOD1 and SOD2. A third isoform of SODs has manganese (Mn) as a cofactor and has been localized to mitochondria of aerobic cells (Mn-SOD or SOD2) [8]. It exists as a homotetramer with an individual subunit molecular weight of about 23,000 Da [9]. SOD2 has been shown to play a major role in promoting cellular differentiation and tumorgenesis [10] and in protecting against hyperoxia-induced pulmonary toxicity [11]. The numerous studies on the physiological function of SOD1 and SOD2 and their role in protection against ROS are summarized in several excellent reviews [12], [13], [14], [15], [16], [17]. However, the available information related to SOD3 has not been reviewed in a comparative perspective along with the other two isoforms. This review focuses on comparative characteristics of all three SOD genes, their evolution and ontogeny, and their transcriptional regulation by various intra- and extracellular stimuli.

Section snippets

SOD1

The genomic sequence for SOD1 has been identified in the rat [18], [19], mouse [20], and human [21]. The genomic organization of SOD1 gene shows striking similarity among species and has five exons and four introns (Fig. 1). The TATA and CCAAT boxes, as well as several highly conserved GC-rich regions, have been localized in all three species with a similar pattern in the proximal promoter region. Such a high level of homology in the 5′ flanking sequence suggests that intense evolutionary

SOD1

The SOD1 gene has been localized to chromosome 21 (region 21q22) in humans [21], chromosome 1 (1q12 → 14) in bovine species [39], and chromosome 16 (region 16B4 → ter) in the mouse [40]. Human chromosome 21 has been studied intensely because of the association between Down’s syndrome and trisomy 21. Although patients with Down’s syndrome show a 50% increase in SOD1 activity due to higher levels of SOD1 protein, the role of this enzyme in pathology associated with this disease remains

Evolution

The appearance of SOD enzymes was triggered by the proliferation of photosynthetic organisms that began to produce oxygen about 2 billion years ago. A variety of antioxidant enzymes evolved to neutralize the toxic effects of subproducts of oxygen utilization. Two major kinds of superoxide dismutase appeared in prokaryotes at that time, copper/zinc-containing SODs and iron/manganese-containing SODs. Is it possible that all forms of SOD originated from a single protein whose function was to

Transcriptional regulation

Transcriptional regulation of all three isoforms of superoxide dismutase are highly controlled based on extra- and intracellular conditions. In this section we will describe only well-documented and reproducible stimulation or repression of individual SOD gene transcription. An overall summary of factors regulating SOD mRNA levels are summarized in Table 1.

Ontogeny

The developmental regulation of SOD enzymes is crucial for adaptation of fetuses to the relatively high oxygen environment after parturition. The lung is one of the most important organs for protection of newborn organisms against harmful oxygen radicals, but increased SOD activity in the kidney of fetuses may have the same protective effect against extrauterine environment as in the lung. The expression of SOD enzymes in lung and kidney during development differs substantially among the

Conclusion

The past decade has brought us new evidence of SOD’s involvement in a number of diseases and pathologies: ALS, Down’s syndrome, and premature aging are probably just some of the pathological conditions that develop due to altered SOD activity and ROS concentration. What other discoveries await us? New, emerging questions such as what role the extracellular form of SOD plays in cardiovascular and pulmonary diseases, and how it affects our ability to learn, still need to be answered. With a

Acknowledgements

The authors would like to acknowledge Brigham H. Mecham for technical assistance and Mr. Ken Kuzenski (AC4RD) for careful editing of this manuscript. Dr. Mariani is a Parker B. Francis Fellow in Pulmonary Research. This work was funded, in part, by a Claude D. Pepper Aging Center Grant, National Institutes of Health Grant HL55166, HL31992, and by an American Heart Association Grant-in-Aid.

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