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Oxidative stress Vadim Gladyshev Redox Biology Center, University of Nebraska

Oxidative stress Vadim Gladyshev Redox Biology Center, University of Nebraska. Origin of oxidative stress. Redox Biology and the Evolution of Life. Formation of earth: ~4.5 billion years Chemical evidence of life on earth : ~3.85 billion years ago

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Oxidative stress Vadim Gladyshev Redox Biology Center, University of Nebraska

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  1. Oxidative stress Vadim Gladyshev Redox Biology Center, University of Nebraska

  2. Origin of oxidative stress

  3. Redox Biology and the Evolution of Life • Formation of earth: ~4.5 billion years • Chemical evidence of life on earth : ~3.85 billion years ago • Initially, the Earth had a reducing environment • Gaseous mixtures of NH3, CH4, H2O, H2 • No molecular oxygen, excess metals • Oxygen is a potent oxidant • - Easy transfer of electrons to oxygen • - Oxidative metabolism (respiration) • Oxygen toxicity and reduced solubility of metals

  4. Utilization of Oxygen by Organisms All animals and plants (and ancestral eukaryote) use oxygen to generate energy 2~3 billionyears ago, probably due to the evolution of oxygen-evolving photosynthetic organisms A prevalent element (53.8% atomic abundance in the earth’s crust, 21% in atmosphere) Oxygen is soluble in pure water (surface water is generally in equilibrium with the atmosphere) However, diffusion of oxygen through tissues is very low (evolution of oxygen transfer mechanism) Intermediates of oxygen metabolism are also utilized for physiological purposes (e.g. signaling).

  5. Oxidative stress High Low

  6. Oxygen Toxicity • Generation of reactive oxygen species • A free radical is any species capable of independent existence • that contains one or more unpaired electrons • Sources of oxygen free radicals (reactive oxygen species) • Mitochondrial electron transport chain • Transition metal-mediated reactions • Designated systems for ROS generation • Reactive oxygen species-mediated reactions • Moderately or highly reactive

  7. Fe2+ (Cu+) + H2O2 <-> HO.+ HO- + Fe3+ (Cu2+)

  8. Neutrophil-mediated killing of bacteria

  9. Adaptations to Oxygen Toxicity Anaerobic life Defense mechanisms against oxygen toxicity Prevention of generation of reactive oxygen species - Metal sequestration Antioxidants and antioxidant enzymes - Scavenge reactive oxygen species Damage repair systems - DNA and protein damage repair

  10. Cu Zn Superoxide Dismutase

  11. Catalase

  12. Peroxiredoxin

  13. Signaling by hydrogen peroxide

  14. Oxidation of Cys residues as the basis for peroxide signaling

  15. Nitric Oxide

  16. CO is an important regulator of hypoxic sensing by the carotid body

  17. Are antioxidants effective in human health and disease?

  18. Thiol oxidoreductases Among proteins with functional Cys, some utilize this residue for redox catalysis: thiol oxidoreductases variety of unrelated folds fRMsr MsrA MsrB The main fold: Thioredoxin fold (3 layers, a/b/a; mixed beta-sheet of 4 strands, order 4312) TRX GRX

  19. Thiol oxidoreductases - catalytic and resolving Cys residues Two types of redox active Cys: Catalytic Cys (k) and Resolving Cys (r) PDI MsrB1 fRMsr 1-Cys Prx k k r k k r r Different organization of resolving Cys in thiol oxidoreductases

  20. Thiol oxidoreductases: catalytic Cys and Sec Selenocysteine (Sec) in proteins: Sec is always placed in the active site, and it serves the function of the catalytic redox Cys Fomenko et al (2007)

  21. Thiol oxidoreductases - functions Involved in many biochemical processes and play central roles in redox homeostasis Thioredoxin system: TRXs, TR.. Glutathione/Glutaredoxin system:GRXs, GR.. Removal of ROS: AhpC, PRXs.. Met oxidative stress repair: MsrA, MsrB .. Formation of disulfide bonds: Dsbs, Ero1, PDI … V ≈ -250 mV V ≈ -150 mV Structure / AA composition around catalytic Cys: Modulation of pKa and Redox potential

  22. Cys modifications Trans-nitrosylation: effects on apoptotic pathways + Normal Apoptotic GSNO-protein AND protein-protein interaction Specificity

  23. Trace elements (micronutrients)

  24. Molybdenum (Mo) - Prokaryotes ModABC Nitrogenase (Fe-Mo) WtpABC TupABC Sulfite oxidase (SO) Xanthine oxidase (XO) - Eukaryotes Molybdopterin (MPT) Dimethylsulfoxide reductase (DMSOR) MOT1 Aldehyde:ferredoxin oxidoreductase (AOR) Mo-MPT (Moco) Precursor Z GTP

  25. Chicken sulfite oxidase 3D structure (PDB code: 1SOX) Sulfite oxidase active site

  26. Copper (Cu) - Prokaryotes Azurin family Rusticyanin (RC) Nitrosocyanin (NC) Nitrous oxide reductase (N2OR) CtaA (Cyanobacteria) NADH dehydrogenase 2 (NDH-2) Particulate Methane monooxygenase (pMMO) Cytochrome c oxidase subunit I (COX I) Cytochrome c oxidase subunit II (COX II) Plastocyanin family CopA [Cu,Zn] superoxide dismutase (CuZn SodC) Copper amine oxidase (CuAO) CutF Multicopper oxidases (MCOs) NiR, CueO, laccase, bilirubin oxidase, etc. CutC Tyrosinase CusCBA CusF

  27. Copper (Cu) - Eukaryotes Cytochrome c oxidase subunit I (COX I) Ctr1 Cytochrome c oxidase subunit II (COX II) Plastocyanin family [Cu,Zn] superoxide dismutase (CuZn SodC) ATP7 Copper amine oxidase (CuAO) Multicopper oxidases (MCOs) Laccase, Fet3p, hephaestin, ceruloplasmin, etc. CutC? Tyrosinase Plantacyanin (PNC) Umecyanin, mavicyanin, stellacyanin, etc. Peptidylglycine alpha-hydroxylating monooxygenase (PHM) Dopamine beta-monooxygenase (DBM) Hemocyanin Cnx1G Galactose oxidase (GAO)

  28. Cu homeostasis in bacteria Cu(I) or Cu(II) Blue copper proteins ? CueO CopA Cu(I) ? ADP ATP Cu(II) COX CopZ CutC ? Cu(I) ? CutF Ndh2 ? CusCBA Cu(II) Cu(I) CusF Cu(I)

  29. Cu homeostasis in eukaryotes Cu ion Ctr1 Atx1 Cox17 ATP7 CCS chaperone ATP7 Tyrosinase Golgi Cox11 Metallothioneins Sco1 Cu-Zn SOD COX Mitochondrion Nucleus

  30. Human Cu-Zn SOD copper (blue-green sphere) and zinc (grey spheres) (PDB code: 1HL5)

  31. Nickel (Ni) and cobalt (Co) Urease Ni-Fe hydrogenase Carbon monoxide dehydrogenase (Ni-CODH) Acetyl-coenzyme A decarbonylase (CODH/ACS) Ni-containing superoxide dismutase (SodN) Methyl-coenzyme M reductase (MCR) Nik/CbiQ Nik/CbiO Nik/CbiM Nik/CbiL Nik/CbiMNQO (Nik/CbiKMLQO) Nik/CbiK B12-dependent isomerase - Methylmalonyl-CoA mutase (MCM) - Isobutyryl-CoA mutase (ICM) - Glutamate mutase (GM) - Methyleneglutarate mutase (MGM) - D-lysine 5,6-aminomutase (5,6-LAM) - B12-dependent ribonucleotide reductase II - Diol/glycerol dehydratase (DDH/GDH) - Ethanolamine ammonia lyase (EAL) B12-dependent methyltransferase - B12-dependent methionine synthase (MetH) - B12-dependent methyltransferases Mta, Mtm, Mtb, Mtt, Mts, Mtv and Mtr B12-dependent dehalogenase Nik/CbiQ Nik/CbiO Nik/CbiN Nik/CbiM NikE NikC NiKA NikABCDE NikB NikD HupE/UreJ Vitamin B12 (cobalamin) NiCoT UreH

  32. Overview of trace element utilization Phyla Ni Mo Se (Sec) Cu Co (B12) Bacteria Total 432(80%) 319(59%) 410(76%) 401(74%) 139(26%) Archaea Eukarya Total 26(55%) 39(83%) 45(96%) 46(98%) 6(13%) Total 154(96%) 51(32%) 49(31%) 105(66%) 76(48%) • Cu utilization is widespread in bacteria and eukaryotes, but restricted in archaea • Only a few organisms utilize all five trace elements • Bacteria: 94 • Archaea: 3 • Eukaryotes: 9 • >50% prokaryotic organisms use the four metals • Only 9 eukaryotes use the four metals • Many Saccharomycotina lost the ability to use most of the five trace elements

  33. Mo Metalloproteomes and selenoproteomes in eukaryotes O. sativa (76) Cu Ni D. discoideum (3) Co (B12) O. sativa (13) D. rerio (34) Se (Sec) Perkinsea Nematoda Ciliophora Cryptophyta Microsporidia Streptophyta Rhodophyta Amphibia Entamoebidae Stramenopiles Diplomonadida Basidiomycota Dictyosteliida Arthropoda Chlorophyta Zygomycota Pezizomycotina Apicomplexa Saccharomycotina Chordata/Others Coelomata/Others Kinetoplastida Parabasalidea Schizosaccharomycetes Mammals Viridiplantae Fungi Metazoa • Land plants possess the largest Mo- and Cu-dependent metalloproteomes in eukaryotes

  34. Are antioxidants effective in human health and disease?

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