New version page

UNC-Chapel Hill ENVR 132 - Reactive Oxygen Species I

Documents in this Course
Load more
Upgrade to remove ads

This preview shows page 1-2-3-25-26-27 out of 27 pages.

Save
View Full Document
Premium Document
Do you want full access? Go Premium and unlock all 27 pages.
Access to all documents
Download any document
Ad free experience
Premium Document
Do you want full access? Go Premium and unlock all 27 pages.
Access to all documents
Download any document
Ad free experience
Premium Document
Do you want full access? Go Premium and unlock all 27 pages.
Access to all documents
Download any document
Ad free experience
Premium Document
Do you want full access? Go Premium and unlock all 27 pages.
Access to all documents
Download any document
Ad free experience
Premium Document
Do you want full access? Go Premium and unlock all 27 pages.
Access to all documents
Download any document
Ad free experience
Premium Document
Do you want full access? Go Premium and unlock all 27 pages.
Access to all documents
Download any document
Ad free experience

Upgrade to remove ads
Unformatted text preview:

1Reactive Oxygen Species I:Reactive Oxygen Species I:• History• Definitions• Key reactions• Sources of ROS• Damage to proteins• Damage to lipids• Damage to DNA• Antioxidants• The Earth was originally anoxic• Metabolism was anaerobic• O2started appearing ~2.5 x 109years agoAnaerobic metabolism-glycolysisGlucose + 2ADP + 2PiLactate + 2ATP + 2H2OO2an electron acceptor in aerobic metabolismGlucose + 6O2+ 36ADP + 36Pi 6CO2+ 36ATP + 6H2O2• Ground-state oxygen has 2-unpaired electronsO:O::::..• The unpaired electrons have parallel spins• Oxygen molecule is minimally reactive due to spin restrictionsBefore 1950s: “golden age” of chemistryMany free radicals have been discovered and describedHaber & Weiss (1934): Superoxide + Hydrogen peroxide Hydroxyl radicalBaeyer & Villiger (1901): discovered peroxynitriteEarly 1950s: presence of radicals in biological materialsCommoner et al. (1954) Nature 174: 689-6911956: Radicals may be formed as by-products of enzymatic reactions in vivo?Harman (1956): radicals are “pandora’s box” of evils (aging, mutations, cancer,…)1969: Discovery of superoxide dismutase (SOD)McCord & Fridovich (1969) JBC 244: 6049-6055Free radicals must be important for biology if the body has a defense enzyme(s)!Intensive investigations on the role of oxidants in disease begunSince late 70s: Radicals are important for normal biologyMittal & Murad (1977): superoxide anion stimulates formation of cGMPIgnarro & Kadowitz (1985) and Moncada (1987): NO• is important in circulation3Term DefinitionOxidation Gain in oxygenLoss of hydrogenLoss of electronsReduction Loss of oxygenGain of hydrogenGain of electronsOxidant Oxidizes another chemical by takingelectrons, hydrogen, or by adding oxygenReductant Reduces another chemical by supplyingelectrons, hydrogen, or by removing oxygenBasics of Redox ChemistryBasics of Redox ChemistryFree RadicalsFree Radicals: Any species capable of independent existence that contains one or more unpaired electrons A molecule with an unpaired electron in an outer valence shellR3C.Carbon-centeredR3N.Nitrogen-centeredR-O.Oxygen-centeredR-S.Sulfur-centeredProoxidantsProoxidantsNon-Radicals: Species that have strong oxidizing potential Species that favor the formation of strong oxidants (e.g., transition metals)H2O2Hydrogen peroxideHOCl-Hypochlorous acidO3Ozone1O2Singlet oxygenONOO-PeroxynitriteMen+Transition metals4Reactive Oxygen Species (ROS)Reactive Oxygen Species (ROS)Radicals:O2.-SuperoxideOH.HydroxylRO2.PeroxylRO.AlkoxylHO2.HydroperoxylNon-Radicals:H2O2Hydrogen peroxideHOCl-Hypochlorous acidO3Ozone1O2Singlet oxygenONOO-PeroxynitriteReactive Nitrogen Species (RNS)Reactive Nitrogen Species (RNS)Radicals:NO. Nitric OxideNO2.Nitrogen dioxideNon-Radicals:ONOO-PeroxynitriteROONO Alkyl peroxynitritesN2O3Dinitrogen trioxideN2O4Dinitrogen tetroxideHNO2Nitrous acidNO2+Nitronium anionNO-Nitroxyl anionNO+Nitrosyl cationNO2Cl Nitryl chloride5““Longevity” of reactive speciesLongevity” of reactive speciesReactive Species Half-lifeHydrogen peroxideOrganic hydroperoxides ~ minutesHypohalous acidsPeroxyl radicals ~ secondsNitric oxidePeroxynitrite ~ millisecondsSuperoxide anionSinglet oxygen ~ microsecondAlcoxyl radicalsHydroxyl radical ~ nanosecond“An imbalance favoring prooxidants and/or disfavoring antioxidants, potentially leading to damage” -H. SiesAntioxidantsProoxidantsOxidative StressOxidative Stress6RadicalRadical--mediated reactionsmediated reactionsAdditionR.+H2C=CH2R-CH2-CH2.Hydrogen abstractionR.+LH RH+L.Electron abstractionR.+ArNH2R-+ArNH2.+TerminationR.+Y.R-YDisproportionationCH3CH2.+ CH3CH2.CH3CH3+ CH2=CH2Hydroxyl radical (Hydroxyl radical (..OH)OH)O2.-+ Fe3+O2+ Fe2+H2O2+ Fe2+OH-+ .OH + Fe3+O2.-+ H2O2OH-+ O2+ .OHHaber-WeissFenton•Transition metal catalyzed•Other reductants can make Fe2+ (e.g., GSH, ascorbate, hydroquinones)•Fe2+ is an extremely reactive oxidant7Important EnzymeImportant Enzyme--Catalyzed ReactionsCatalyzed ReactionsBiological Pathways for Oxygen ReductionBiological Pathways for Oxygen ReductionFrom: McMurry and Castellion “Fundamentals of general, organic and biological chemistry”8Important physiological functions that Important physiological functions that involve free radicals or their derivatesinvolve free radicals or their derivatesFrom Droge W (2002) Physiol Rev 82: 47-95Endogenous sources of ROS and RNSEndogenous sources of ROS and RNSMitochondriaLysosomesPeroxisomesEndoplasmic ReticulumCytoplasmMicrosomal Oxidation, Flavoproteins, CYP enzymesMyeloperoxidase(phagocytes) Electron transportOxidases,FlavoproteinsPlasma MembraneLipoxygenases,Prostaglandin synthaseNADPH oxidaseXanthine Oxidase,NOS isoformsFeCuTransition metals9Mitochondria as a source of ROSMitochondria as a source of ROSTurrens, J Physiol, 2003PeroxisomesPeroxisomesas a source of ROS and RNSas a source of ROS and RNSFatty AcidAcyl-CoAEnoyl-CoAHydroxyacyl-CoAKetoacyl-CoAAcetyl-CoA Acyl-CoA shortened by two carbonsFatty acyl-CoA synthetaseAcyl-CoA oxidaseEnoyl-CoA hydrolaseHydroxyacyl-CoAdehydrogenaseThiolaseH2O2Fatty AcidAcyl-CoAEnoyl-CoAHydroxyacyl-CoAKetoacyl-CoAAcetyl-CoA Acyl-CoA shortened by two carbonsFatty acyl-CoA synthetaseAcyl-CoA oxidaseEnoyl-CoA hydrolaseHydroxyacyl-CoAdehydrogenaseThiolaseH2O2Enzymes in mammalian peroxisomes that generate ROSSchader & Fahimi, Histochem Cell Biol, 200410NADPH oxidase as a source of ROSNADPH oxidase as a source of ROSPresent mainly in neutrophils (oxidative burst), but also in many other cell typesPHSProstaglandin H Prostaglandin H SynthaseSynthase(PHS) as a source of ROS(PHS) as a source of ROSCo-oxidation of xenobiotics (X) during arachidonic acid metabolism to PGH211xanthine oxidase xanthine oxidaseCytoplasmicCytoplasmicsources of ROS and RNSsources of ROS and RNSNO•Nitric Oxide Synthases (NOS):neuronal nNOS (I)endothelial eNOS (III)inducible iNOS (II)LysosomeLysosomeas a source of ROS and RNSas a source of ROS and RNSMyeloperoxidase undergoes a complex array of redox transformations and produces HOCl, degrades H2O2to oxygen and water, converts tyrosine and other phenols and anilines to free radicals, and hydroxylates aromatic substrates via a cytochrome P450-like activity12MicrosomesMicrosomesas a source of ROS (I)as a source of ROS (I)A scheme of the catalytic cycle of cytochrome P450-containing monooxygenases. The binding of the substrate (RH) to ferric P450 (a) results in the formation of the substrate complex (b). The


View Full Document
Download Reactive Oxygen Species I
Our administrator received your request to download this document. We will send you the file to your email shortly.
Loading Unlocking...
Login

Join to view Reactive Oxygen Species I and access 3M+ class-specific study document.

or
We will never post anything without your permission.
Don't have an account?
Sign Up

Join to view Reactive Oxygen Species I 2 2 and access 3M+ class-specific study document.

or

By creating an account you agree to our Privacy Policy and Terms Of Use

Already a member?