DEFINITION
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen.
THE GENE
CHEMICAL STRUCTURE AND IMAGES
Primary structure
SOD1:
MATKAVCVLKGDGPVQGIINFEQKESNGPVKVWGSIKGLTEGLHGFHVHEFGDNTAGCTS
AGPHFNPLSRKHGGPKDEERHVGDLGNVTADKDGVADVSIEDSVISLSGDHCIIGRTLVV
HEKADDLGKGGNEESTKTGNAGSRLACGVIGIAQ
SOD2:
MLSRAVCGTSRQLAPALGYLGSRQKHSLPDLPYDYGALEPHINAQIMQLHHSKHHAAYVN
NLNVTEEKYQEALAKGDVTAQIALQPALKFNGGGHINHSIFWTNLSPNGGGEPKGELLEA
IKRDFGSFDKFKEKLTAASVGVQGSGWGWLGFNKERGHLQIAACPNQDPLQGTTGLIPLL
GIDVWEHAYYLQYKNVRPDYLKAIWNVINWENVTERYMACKK
- Secondary structure
- Tertiary structure
- Quaternary structure
Protein Aminoacids Percentage
SYNTHESIS AND TURNOVER
mRNA synthesis
Transcriptional regulation of all three isoforms of superoxide dismutase are highly controlled based on extra- and intracellular conditions.
Superoxide dismutase multigene family:a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression
Protein synthesis
SOD is one of the three main endogenous antioxidant enzyme in which the body fights free radicals, especially hydrogen peroxide (hydrogen peroxide formed in the oxidative stress) very toxic to cell; is also very capable of protecting enzymes important as the glutathione-peroxidase. Tthe synthesis of endogenous antioxidant enzymes is dependent on cationic selenium, zinc and copper.
Superoxide dismutase consists of two subunits of identical molecular weight joined by a disulfide bond. The molecular weight is 32,500. There are two Cu(II) and two Zn(II) atoms per molecule. The amino acid sequence and the subunit tertiary structure have reported on the roles of copper and zinc. Zinc has a structural, stabilizing role, while Cu2 is directly involved in the catalytic activity.
Superoxide Dismutase
I.U.B.:1.15.1.1
post-translational modifications
Transcriptional regulation of all three isoforms of superoxide dismutase are highly controlled based on extra- and intracellular conditions. In some eukaryotes have been found Cu/Zn SOD; these forms suffer post-translational modifications, like glycosylation, and are responsible for the dismutation of excess O2- extracellular.
degradation
Studies focused on degradation of pathogenic SOD1 proteins by the proteasome are in their infancy. Two groups demonstrated that the co-chaperone CHIP (C-terminus of Hsc70-interacting protein) associates with mutant SOD1 and promotes its degradation by the ubiquitin-proteasome system.
CELLULAR FUNCTIONS
cellular localization
In humans three forms of superoxide dismutase are present. SOD1 is located in the cytoplasm, SOD2 in the mitochondria, and SOD3 is extracellular. The first is a dimer (consists of two units), whereas the others are tetramers (four subunits). SOD1 and SOD3 contain copper and zinc, whereas SOD2 has manganese in its reactive centre.
Sorgenti di anione superossido:
Reactive oxygen species are
•molecules like hydrogen peroxide
•ions like the hypochlorite ion
•radicals like the hydroxyl radical. It is the most reactive of them all; note how it differs from the hydroxyl ion.
•the superoxide anion which is both ion and radical.
A radical (also called a "free radical") is a clusters of atoms one of which contains an unpaired electron in its outermost shell of electrons. This is an extremely unstable configuration, and radicals quickly react with other molecules or radicals to achieve the stable configuration of 4 pairs of electrons in their outermost shell (one pair for hydrogen).
Reactive oxygen species are formed by several different mechanisms:
- the interaction of ionizing radiation with biological molecules
- as an unavoidable byproduct of cellular respiration. Some electrons passing "down" the electron transport chain leak away from the main path (especially as they pass through ubiquinone) and go directly to reduce oxygen molecules to the superoxide anion.
- synthesized by dedicated enzymes in phagocytic cells like neutrophils and macrophages
- NADPH oxidase
- myeloperoxidase .
In general, numerous metabolic activities are able to generate ROS: NADPH oxidase (is an enzyme that catalyzes the production of superoxide from oxygen and NADPH)
Lipoxygenase, b5 NADH dehydrogenase, Cytochrome ossidasi NADPH, Cytochrome P450, Cytochrome b5NADH, Xanthine oxidase (in the cytosol), Aldehyde oxidase.
biological function
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.
The production of superoxide (O2-) under hyperoxic conditions is markedly accentuated leading to the generation of potent oxidants such as hydrogen peroxide (H2O2), hydroxyl radical (HO) and peroxynitrite (ONOO-). Superoxide dismutase (SOD), by rapidly removing O2-, reduces the tissue concentration of O2 and prevents the production of HO and ONOO-.
Three forms of SOD exist in the lung: Cu,Zn,SOD, MnSOD and extracellular SOD. Evidence suggests that all three forms of SOD are essential for the pulmonary defense against oxygen toxicity and that enhancement of pulmonary SOD has the potential of protecting against oxigen toxicity.
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide.
The SOD-catalysed dismutation of superoxide may be written with the following half-reactions :
• M(n+1)+-SOD + O2− → Mn+-SOD + O2
• Mn+-SOD + O2− + 2H+ → M(n+1)+-SOD + H2O2.
where M = Cu (n=1) ; Mn (n=2) ; Fe (n=2) ; Ni (n=2).
In this reaction the oxidation state of the metal cation oscillates between n and n+1.
Superoxide dismutase and pulmonary oxygen toxicity: lessons from transgenic and knockout mice (Review).
- Cell signaling and Ligand transport
- Structural proteins
SOD1 was found to have a widespread distribution in a variety of cells. The expression of cytoplasmic SOD1 is stable and its activity is often considered as an internal control for SOD1 gene expression.
Despite the fact that SOD2 is expressed in many cell types and tissues at relatively high levels it is also highly regulated by a variety of intracellular and environmental cues. Characterization of the 5′-flanking genomic region from rat, bovine, and human and indicates that the SOD2 promoter is TATA and CAAT-less but contains GC-rich sequences immediately upstream from the transcription initiation site. Computer analysis and foot-printing assays reveal a number of putative binding sites for Sp1 and AP2 transcription factors in the proximal promoter of human SOD2. The two proteins have opposite effects on SOD2 expression: while the Sp1 element positively promotes transcription, the AP2 proteins significantly repress the promoter activity.
In contrast to intracellular SOD1 and SOD2, the expression of SOD3 appears restricted to only a few cell types in several tissues. High levels of SOD3 expression have been documented for alveolar type II cells, proximal renal tubular cells, vascular smooth muscular cells, lung macrophages and few cultured fibroblast cell lines. The features regulating such highly specific expression are not yet known, but analysis of the 5′-flanking region of human SOD3 reveals several potential regulatory sequences such as a glucocorticoid response element, xenobiotic response element, and an antioxidant response element. Computer analysis of murine SOD3 proximal promoter reveals multiple putative binding sites for the Ets family of transcription factors. The importance of these proteins in regulating cell-specific expression has yet to be elucidated. The promoter region of SOD3 lacks typical TATA or CAAT boxes but possesses purine-rich sequences.
Review article
REGULATION
CuZnSOD gene contains regulatory elements such as nuclear factor-1, specificity protein-1, activator protein-1 and -2, glucocorticoid response element, heat shock transcription factor, nuclear factor {kappa} B, and the metal responsive element.
Superoxide Dismutases in the Lung and Human Lung Diseases , regulation
DIAGNOSTIC USE
Mice overexpressing CuZnSOD are resistant to allergen-induced lung toxicity, suggesting that SOD is important in the pathogenesis of allergic inflammation and asthma.
SODs IN HUMAN LUNG DISEASES 2003
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. 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 wealth of information provided in this field over the last few years we are just beginning to understand the significance of SOD in biology and pathology. The further gain of knowledge about the mechanisms of cell and tissue-specific regulation of SOD gene expression and their signal transduction pathways may also lead to the design of new drugs and strategies directed at regulating levels of these enzymes in particular tissues, cell types, and compartments without affecting other cells.
