|Superoxide dismutase 2, mitochondrial|
PDB rendering based on 1ap5.
|Symbols||; IPOB; MNSOD; MVCD6|
|RNA expression pattern|
The SOD2 gene contains five exons interrupted by four introns, an uncharacteristic 5′-proximal promoter that possesses a GC-rich region in place of the TATA or CAAT, and an enhancer in the second intron. The proximal promoter region contains multiple binding sites for transcription factors, including specific-1 (Sp1), activator protein 2 (AP-2), and early growth response 1 (Egr-1). This gene is a the mitochondrial member of the iron/manganese superoxide dismutase family. It encodes a mitochondrial matrix protein that forms a homotetramer and binds one manganese ion per subunit. The manganese site forms a trigonal bipyramidal geometry with four ligands from the protein and a fifth solvent ligand. This solvent ligand is a hydroxide believed to serve as the electron acceptor of the enzyme. The active site cavity consists of a network of side chains of several residues associated by hydrogen bonding, extending from the aqueous ligand of the metal. Of note, the highly conserved residue Tyr34 plays a key role in the hydrogen-bonding network, as nitration of this residue inhibits the protein's catalytic ability. This protein also possesses an N-terminal mitochondrial leader sequence which targets it to the mitochondrial matrix, where it converts mitochondrial-generated reactive oxygen species from the respiratory chain to H2. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.
As a member of the iron/manganese superoxide dismutase family, this protein transforms toxic superoxide, a byproduct of the mitochondrial electron transport chain, into hydrogen peroxide and diatomic oxygen. This function allows SOD2 to clear mitochondrial reactive oxygen species (ROS) and, as a result, confer protection against cell death. As a result, this protein plays an antiapoptotic role against oxidative stress, ionizing radiation, and inflammatory cytokines.
Due to its cytoprotective effects, overexpression of SOD2 has been linked to increased invasiveness of tumor metastasis. Its role in controlling ROS levels also involves it in ageing, cancer, and neurodegenerative disease. Mutations in this gene have been associated with idiopathic cardiomyopathy (IDC), sporadic motor neuron disease, and cancer. A common polymorphism associated with greater susceptibility to various pathologies 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 show to increase lifespan by 20%
When animals are exercised at a relatively high work rate, many exercise training studies report that exercise training promotes an increase in myocardial MnSOD activity. This is significant because two recent studies reveal that increased MnSOD activity is essential to achieve optimal training-induced protection against both ischemia/reperfusion(IR)-induced cardiac arrhythmias and infarction. Specifically, using an antisense oligonucleotide against MnSOD to prevent ExTr-induced increases in myocardial MnSOD activity, Yamashita et al. demonstrated that an increase in myocardial MnSOD activity is required to provide training-induced protection against IR-induced myocardial infarction. Similarly, Hamilton et al. , using a MnSOD gene silencing approach, reported that prevention of the ExTr-induced increase in myocardial MnSOD resulted in a loss of training-induced protection against IR-mediated arrhythmias. In contrast to these findings, training-induced increases in cardiac MnSOD are not required to achieve training-induced cardioprotection against myocardial stunning. (Power et al. 2007)
The SOD2 gene has been shown to bind:
The SOD2 protein has been shown to interact with HIV-1 Tat and HIV-1 Vif.
- "Entrez Gene: SOD2 superoxide dismutase 2, mitochondrial".
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- Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson NL, Baynes JW, Epstein CJ, Huang TT, Nelson J, Strong R, Richardson A (Dec 2003). "Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging". Physiological Genomics 16 (1): 29–37. doi:10.1152/physiolgenomics.00122.2003. PMID 14679299.
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