SUMMARY PARAGRAPH for SOD1
SOD1 encodes a Cu-Zn superoxide dismutase that plays a role in oxygen radical detoxification and in copper ion buffering. SODs catalyze the breakdown of the superoxide radical, O2-, to an oxygen molecule (dioxygen) and hydrogen peroxide (5, 6). The active form of Sod1p is a homodimer, with each 32kD subunit containing one catalytic copper ion and one zinc ion. Two conserved cysteine residues of each monomer are joined together in a disulfide bond and this bond is critical for enzymatic activity. The specific copper chaperone Ccs1p delivers the copper ion to Sod1p and also facilitates formation of the intramolecular disulfide bond (7). The Cu-Zn-Sod1p is cytosolic; however, a fraction of both Sod1p and its metallochaperone, Ccs1p, localize to the intermembrane space (IMS) of mitochondria where Sod1p performs a physiological role in scavenging mitochondrial reactive oxygen species (ROS). Accumulation of Sod1p within mitochondria is dependent on the presence of the mitochondrial form of Ccs1p, which enhances retention of the immature Sod1p within the IMS (8). S. cerevisiae also synthesizes a Mn-Sod2p, which is mitochondrial.
Null mutations in SOD1 are associated with a number of defects such as sensitivity to oxidative stress, including the inability to grow in aerobic conditions on rich medium, and hypersensitivity to superoxide-generating drugs such as paraquat. Null mutants are also tightly auxotrophic for methionine and lysine and display a leaky leucine auxotrophy, defects considered to result from oxidative damage to relevant metabolic enzymes (9, 10, 11, 12, 13). sod1 null mutants also exhibit mitochondrial defects including poor growth on non-fermentable carbon sources, a deficiency in mitochondrial aconitase, and rapid death in stationary phase.
Increased oxidative damage exhibited by sod1 mutants can be suppressed by mutations or overexpression of several genes. Overexpression of ATX1 or ATX2 or mutation of PMR1 or BSD2 is thought to suppress by altering metal ion homeostasis while overexpression of TKL1 may mediate suppression through enhanced production of NADPH by the pentose phosphate pathway (14). Mutations in SSQ1, JAC1, NFS11 and ISU1 suppress the auxotrophies caused by a sod1 mutations, but do not reverse the sensitivity of sod1delta strains to paraquat (15).
SOD1 and SOD2 are among the first genes to be implicated in the chronological aging of yeast (5, 6, 16). Deletion of SOD1 or both SOD1 and SOD2 dramatically reduces the chronological and replicative life span of yeast (17), while overexpression of both SOD1 and SOD2 extends survival but does not affect metabolic rates (18). Overexpression of SOD1 and CCS1 elevates the levels of Sod1p activity six- to eight-fold in vegetative cultures and increases the survival of stationary phase cells up to two-fold, showing that chronological lifespan is ultimately limited by oxidative stress (19).
Activation of Sod1p in vitro requires both copper-bound Ccs1p and O2 exposure. Transition of anaerobic cultures to aerobic conditions results in the rapid appearance of Sod1p activity. Ccs1p mediates O2 or O-2 responsive activation of apo-Sod1p, thereby playing a direct posttranslational role in controlling the amount of the active form of enzyme (20). Ace1p, a transcriptional activator protein responsible for the induction of metallothionein CUP1, is also responsible for the induction of SOD1 expression in response to copper; the SOD1 promoter contains a single Ace1p binding site (21).
Superoxide dismutases (SODs) are abundant enzymes present in prokaryotes and eukaryotes. Prokaryotes have two forms, one containing iron (Fe) and another containing manganese (Mn). The Cu-Zn form is found in few distantly related bacterial species. Eukaryotes have a Mn-containing form in the mitochondrion and a Cu-Zn containing form in the cytoplasm. The Mn and Fe proteins are related to each other, while the Cu-Zn protein is unrelated to either (6).
Mutations in the human SOD1 are associated with familial Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig's disease, a degenerative disorder of the motor neurons that may be caused by accumulation of reactive oxygen radicals (22, 23, 24, 25).
Last updated: 2007-04-09