Disulfide Bond as a Switch for Copper-Zinc Superoxide Dismutase Activity in Asthma.
Summary of "Disulfide Bond as a Switch for Copper-Zinc Superoxide Dismutase Activity in Asthma."
AIM:
Loss of superoxide dismutase (SOD) activity is a defining biochemical feature of asthma. However, mechanisms for the reduced activity are unknown. We hypothesized that loss of asthmatic SOD activity is due to greater susceptibility to oxidative inactivation.
RESULT:
Activity assays of blood samples from asthmatics and healthy controls revealed impaired dismutase activity of copper-zinc SOD (CuZnSOD) in asthma. CuZnSOD purified from erythrocytes or airway epithelial cells from asthmatic was highly susceptible to oxidative-inactivation. Proteomic analyses identified that inactivation was related to oxidation of cysteine 146, which is normally disulfide bonded to C57. Susceptibility of cysteines pointed to alteration in protein structure, likely related to loss of disulfide bond. We speculated a shift to greater intracellular reducing potential might account for the change. Strikingly, measures of reduced and oxidized glutathione confirmed greater reducing intracellular state in asthma, compared to controls. Similarly, greater free thiol in CuZnSOD was confirmed by ~2-fold greater N-Ethylmaleimide binding to C146 in asthma as compared to controls.
INNOVATION:
Greater reducing potential under chronic inflammatory state of asthma thus leads to susceptibility of CuZnSOD to oxidative-inactivation due to cleavage of C57-C146 disulfide bond and exposure of normally unavailable cysteines.
CONCLUSION:
Vulnerability of CuZnSOD influenced by redox, likely amplifies injury and inflammation during acute asthma attacks when reactive oxygen species are explosively generated. Overall, this study identifies a new paradigm to understand the chemical basis of inflammation, in which redox regulation of thiol availability dictates protein susceptibility to environmental and endogenously generated reactive species.
Affiliation
Cleveland Clinic, Pathobiology, Lerner Research Institute, NC2-131, 9500 Euclid Avenue, Cleveland, Ohio, United States, 44195; ghoshs@ccf.org.
Journal Details
This article was published in the following journal.
Name: Antioxidants & redox signaling
ISSN: 1557-7716
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22867017
- DOI: http://dx.doi.org/10.1089/ars.2012.4566
Medical and Biotech [MESH] Definitions
Superoxide Dismutase
An oxidoreductase that catalyzes the reaction between superoxide anions and hydrogen to yield molecular oxygen and hydrogen peroxide. The enzyme protects the cell against dangerous levels of superoxide. EC 1.15.1.1.
Menkes Kinky Hair Syndrome
An inherited disorder of copper metabolism transmitted as an X-linked trait and characterized by the infantile onset of HYPOTHERMIA, feeding difficulties, hypotonia, SEIZURES, bony deformities, pili torti (twisted hair), and severely impaired intellectual development. Defective copper transport across plasma and endoplasmic reticulum membranes results in copper being unavailable for the synthesis of several copper containing enzymes, including PROTEIN-LYSINE 6-OXIDASE; CERULOPLASMIN; and SUPEROXIDE DISMUTASE. Pathologic changes include defects in arterial elastin, neuronal loss, and gliosis. (From Menkes, Textbook of Child Neurology, 5th ed, p125)
Protein Disulfide-isomerases
Sulfur-sulfur bond isomerases that catalyze the rearrangement of disulfide bonds within proteins during folding. Specific protein disulfide-isomerase isoenzymes also occur as subunits of PROCOLLAGEN-PROLINE DIOXYGENASE.
Genes, Switch
Genes that cause the epigenotype (i.e., the interrelated developmental pathways through which the adult organism is realized) to switch to an alternate cell lineage-related pathway. Switch complexes control the expression of normal functional development as well as oncogenic transformation.
Superoxides
Highly reactive compounds produced when oxygen is reduced by a single electron. In biological systems, they may be generated during the normal catalytic function of a number of enzymes and during the oxidation of hemoglobin to METHEMOGLOBIN. In living organisms, SUPEROXIDE DISMUTASE protects the cell from the deleterious effects of superoxides.
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