Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the enzyme Cu,Zn-superoxide dismutase (SOD1) involves several posttranslational modifications including copper and zinc binding, as well as formation of the intramolecular disulfide bond. The copper chaperone for SOD1, CCS, is responsible for intracellular copper loading in SOD1 under most physiological conditions. Recent in vitro and in vivo assays reveal that CCS not only delivers copper to SOD1 under stringent copper limitation, but it also facilitates the stepwise conversion of the disulfide-reduced immature SOD1 to the active disulfide-containing enzyme. The two new functions attributed to CCS, (i.e., O(2)-dependent sulfhydryl oxidase- and disulfide isomerase-like activities) indicate that this protein has attributes of the larger class of molecular chaperones. The CCS-dependent activation of SOD1 is dependent upon oxygen availability, suggesting that the cell only loads copper and activates this enzyme when O(2)-based oxidative stress is present. Thiol/disulfide status as well as metallation state of SOD1 significantly affects its structure and protein aggregation, which are relevant in pathologies of a neurodegenerative disease, amyotrophic lateral sclerosis (ALS). The authors review here a mechanism for posttranslational activation of SOD1 and discuss models for ALS in which the most immature forms of the SOD1 polypeptide exhibits propensity to form toxic aggregates.
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PMID:Posttranslational modifications in Cu,Zn-superoxide dismutase and mutations associated with amyotrophic lateral sclerosis. 1677 75

Mutations in the Cu,Zn-superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (FALS). Lowering intracellular Cu improves the FALS-like phenotype of mutant SOD1 mice. Using immobilized Cu-affinity chromatography, we have previously shown that mutant SOD1 is expressed as two affinity fractions, one with high affinity for Cu (SOD1(HAC)) and one with low affinity (SOD1(LAC)), whereas wild-type SOD1 is expressed only as SOD1(LAC). Here we further characterize SOD1(HAC) to ascertain the toxicity of mutant SOD1 species. We found that SOD1(HAC) was modified at cysteine residues (Cys) and could be generated from wild-type SOD1 by oxidation of Cys. SOD1(HAC) mainly consisted of monomer, whereas SOD1(LAC) was a dimer. Mutant SOD1s possessed ectopic thiol oxidase activity that was exaggerated by loading it with adventitial Cu, but this activity was minimal in wild-type SOD1. Wild-type SOD1 could be induced to develop the activity by oxidation of Cys. Conversely, mutant SOD1 decreased the activity by being forced away from its monomeric state with a cross-linker. A significant decrease in free thiol concentration was observed in Neuro2a cells transfected with mutant SOD1s when they were treated with Cu. SOD1(HAC) may be pathogenic in FALS by being a monomeric species that gains a redox activity by aberrantly coordinating Cu(2+).
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PMID:Monomerized Cu, Zn-superoxide dismutase induces oxidative stress through aberrant Cu binding. 2007 23