MCP, Reactive Oxygen Species
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42 terms
Terms | Definitions |
|---|---|
 Reactive Oxygen Species | Species formed from incomplete reduction of oxygen Those with an unpaired electron are free radicals |
| Free radicals | Generated by one electron transfers e.g. Superoxide, Hydroxyl Radical |
| Superoxide | ⋅O2⁻ Free Radical and Oxidant Primary ROS Moderate Reactivity Formed from 1 electron reduction of O2 |
| Hydrogen Peroxide | H₂O₂ Oxidant (Not a Free Radical) Secondary ROS Low Reactivity Formed from reduced Superoxide |
| Hydroxyl Radical | ⋅OH Free Radical Secondary ROS Highest reactivity Very short in vivo half life Oxidizes substrates to produce water, but also leads to buildup of oxidized substrates |
| Oxidative Stress | Over oxidation of biological components in cell Accumulation of oxidized substrates |
| Generation of Superoxide by Mitochondria | Mitochondrial byproduct during ATP synthesis Complex III: Semiquionone produces superoxide injected into intermembrane space Complex I: Superoxide released exclusively into membrane Membrane is not permable to anioning ⋅O₂⁻ |
| Conditions that increase ⋅O₂⁻ Production | High membrane potential increases electron leak to O₂ High NADH/NAD+ ratio causes over reduction Damage to electron transport chain: electron leak Hypoxia: Increase ROS production (unclear how) Xenobiotics: Can increase rate of ⋅O₂⁻ production by blocking electron transport or other mechanisms |
| Generation of ROS by Oxidases | NADPH Oxidases (Nox) Xanthine Oxidase Monoamine Oxidase |
| NADPH Oxidases | Dedicated superoxide producers in phagocytes for killing pathogens, and other non-phagocytic cells like cardiomyocytes for signaling. |
| Monoamine Oxidase | Produce ROS as byproducts. Monoamine oxidase type b forms ROS during dopamine catabolism |
| Xanthine Oxidase | Produces ROS as a byproduct of purine catabolism |
| Non-enzymatic conversions of ROS | Auto-dismutation Fenton Reaction Ionizing Radiation |
| Auto-dismutation | O₂ spontaneously dismutes (very slowly) to superoxide, then to H₂O₂ |
| Fenton Reaction | Converts hydrogen peroxide (H₂O₂) to hydroxyl radical, using a metal (e.g. Iron) as a catalyst, which is converted from Fe2+ to Fe3+ in the process. Non-enzymatic |
| Reactive Nitrogen/Oxygen Species | Primary is Nitric Oxide (NO⋅) Produced by nitric oxide synthase (NOS) which metabolizes arginine to citrulline and forms NO⋅ as an intermediate |
| NO⋅ | Nitric Oxide. Mild radical produced by nitric oxide synthase. Reacts with superoxide (⋅O₂⁻) to form peroxynitrite Peroxynitrites produce hydroxyl radicals |
| Peroxynitrite | Formed from reaction of superoxide with nitric oxide Very reactive oxidant |
| 5 Major ROS | Superoxide Hydrogen Peroxide Hydroxyl Radical Nitric Oxide Peroxynitrite |
| DNA Damage by ROS | Nucleic acid binds iron well ⋅OH generated from Fenton reaction target DNA Hydroxyl radical extracts electrons from DNA sugar/base and produces DNA radicals 8-hydroxy-2'-deoxyguanosine formed from guanosine oxidation Replicative mispairing |
| 8-hydroxy-2'-deoxyguanosine | Formed from oxidation of guanine Biomarker for DNA damage |
| Lipid damage by ROS | ROS oxidize lipids, generating lipid radicals Lipid peroxidation damages membranes Breakdown of lipid peroxidation products produces highly reactive aldehydes (e.g. MDA and 4-HNE, used as biomarkers for lipid peroxidation) |
| Malondialdehyde (MDA) | Highly reactive aldehyde produced as a non-enzymatic breakdown product of lipid peroxidation Biomarker for lipid peroxidation and ROS damage |
| 4-hydroxy-nonenal (4-HNE) | Highly reactive aldehyde produced as a non-enzymatic breakdown product of lipid peroxidation Biomarker for lipid peroxidation |
| Protein damage by ROS | Hydroxyl radicals directly oxidize amino acid side chains Leads to covalent modification and carbonylation of proteins Affects activity of target proteins or causes them to be degraded |
| Hydrogen peroxide on Proteins | Can oxidize cysteine residues on some proteins, leading to the formation of disulfide cross-links and protein aggregation |
| Defense against ROS (Enzymatic) | Convert superoxide into hydrogen peroxide Dispose of hydrogen peroxide |
| Superoxide Dismutase | Converts Superoxides into hydrogen peroxides 2 different enzymes, compartmentalized in the cell SOD1: Cytosol contains Cu and Zn SOD2: Mitochondrial, uses Mn. Primarily degrades ⋅O₂⁻ in the matrix, b/c ⋅O₂⁻ can diffuse across outer mitochondrial membrane but not inner |
| Glutathione Peroxidase Pathway | 1 of 3 methods of recycling hydrogen peroxide generated from ⋅O₂⁻ destruction Converts hydrogen peroxide into water Contains selenium |
| G6PD | Catalyzed pentose phosphate shunt, which, in erythrocytes, generates the NADPH for the glutathione reductase reaction |
| Glutathione reductase | Regenerates reduced glutathione NADPH dependent pathway In RBCs, NADPH is generated by G6PD |
| Peroxiredoxin Pathway | Peroxiredoxin (sulfur containing) reactions with hydrogen peroxide and is oxidized, then reduced by Thioredoxin, and then oxidized thioredoxin is reduced by NADPH dependent thioredoxin reductase NADPH generated from Penthose Phosphate Shunt or from TCA |
| Thioredoxin | In the Peroxiredoxin Pathway, enzyme that reduces oxidized peroxiredoxin and is then reduced by Thioredoxin reductase |
| Catalase Pathway (Myeloperoxidase) | Heme-containing Catalyzes decomp of hydrogen peroxide to water and oxygen Usually found in peroxisome Thought to be a minor method of scavenging H₂O₂ in cells |
| Non-enzymatic antioxidant defenses | In vivo synthesized antioxidants Dietary antioxidants |
| Glutathione | In vivo antioxidant Free Glutathione: Scavenges for free radicals, and generates thiyl radicals and ultimate superoxide Keeps cysteine or sulfhydryl proteins from being reduced and maintains their biological activity Gets oxidized to GSSG |
| GSH/GSSG Ratio | Indicator for the redox state of the cell GSH should be in much higher concentrations than GSSG If GSH becomes lower than GSSG, the formation of covalent linked proteins is favored |
| Coenzyme Q (Ubiquinone) | In vivo synthesized antioxidant Part of ETC in mitochondria, and in other places Rduced form (CoQH₂) is an antioxidant and inhibits lipid peroxidation |
| Dietary oxidants | Vitamin E (protects lipids) Vitamin C Plant Phenols (inhibits LDL oxidation) Flavonoids (green tea) |
| Physiological Roles of ROS/RNOS | Cell proliferation Cell signaling Apoptosis Necrosis |
| ROS and Cancer | Elevates levels of ROS can lead to DNA mutations |
| Environmental factors increasing ROS generation | Asbestos contains 30% Iron --> increased Fenton reaction Tobacco smoke --> Increases ROS production |
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