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Metals and Oxidative/Nitrosative Stress

Metals and Oxidative/Nitrosative Stress oxidative/nitrosative stress : high levels of ROS (Reactive Oxygen Species) and RNS (Reactive Nitrogen Species) such as free radicals and peroxides which damage cellular components (DNA, proteins, lipids)

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Metals and Oxidative/Nitrosative Stress

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  1. Metals and Oxidative/Nitrosative Stress oxidative/nitrosative stress: high levels of ROS (Reactive Oxygen Species) and RNS (Reactive Nitrogen Species) such as free radicals and peroxides which damage cellular components (DNA, proteins, lipids) NO, O2 - , OH, ONOO(H), H2O2 , ROO, ROOH, HOCl, NO2- Elevated ROS/RNS is linked to diseases associated with chronic inflammation and aging e.g. atherosclerosis, neurological diseases, cancer (Free Radical Theory of Aging) A biochemical imbalance occurs between processes which produce ROS/RNS and processes that destroy ROS/RNS ROS/RNS: are essential in biological systems e.g. cell signaling, immune response against pathogens Antioxidants (enzymes and small molecules) play a key role in controlling ROS/RNS levels

  2. Nitric Oxide, NO (NO) Roles in Biology include • Produced in the immune response against pathogens • Inducing relaxation in the smooth muscles lining the blood vessels  vasodilation (binds to guanylate cyclase, a heme enzyme) • Inhibiting cell proliferation • A neurotransmitter • NO prodrugs used to treat hypertension (high blood pressure) angina (insufficient oxygen to the heart muscles) nitroglycerin

  3. Superoxide (O2•-) • A byproduct of mitochondrial respiration and enzyme reactions e.g. xanthine oxidase • Immune system: the enzyme NADPH oxidase produces high levels of O2•- to kill pathogens • O2•- levels augmented in acute and chronic inflammation Nitric oxide synthase can produce peroxynitrite under stress conditions: O2•- is a precursor of OH

  4. Peroxynitrite, ONOO(H) A strong oxidizing Eº (ONOO-, 2H+/NO2, H2O) = 1.6 V, pH 7, nitrating and hydroxylation agent (especially for Tyr) ONOOH spontaneously decomposes: (% yield at pH 7.4) Synthesis of ONOO-:

  5. Hydroxy Radical, •OH One of the most potent ROS in biology since it reacts with all biomolecules at essentially diffusion controlled rates ( 109 M-1 s-1) OH is generated from: H2O2 (Fenton reaction) peroxynitrite decomposition O2 and H2O2 (Haber-Weiss reaction) H2O ionization

  6. Antioxidants: react rapidly (scavenge) ROS/RNS, preventing their reactions with biomolecules A) Important small molecule antioxidants: vitamin C, vitamin E, carotenoids, thiols (glutathione, thioredoxin and lipoic acid), flavonoids, melatonin Example: glutathione scavenging of radicals (R•) GSH + R• → GS• + RH GS• + GS• → GSSG • the ratio of GSH/GSSG is a good measure of oxidative stress of an organisms

  7. B) Antioxidant enzymes: a) Superoxide dismutase (SOD) • b) Catalase • c) Glutathione peroxidase • a) Superoxide Dismutase, SOD b) Catalase found within the peroxisome; a heme protein - one of the highest turnover rates for all enzymes: ∼6 x106 H2O2 /min cytosolic Zn,Cu-SOD: k = 2 x 109 M-1 s-1

  8. Metals Can Protect and Cause Oxidative/Nitrosative Stress 1. Free Metal Cations generate ROS in Biological Systems via Redox Chemistry Elevated levels of Fe2+/Fe3+ and/or Cu+, Cu2+ implicated in many diseases associated with oxidative/nitrosative stress hemochromatosis Wilson’s disease

  9. 2. Metal Complexes can Prevent Oxidative/Nitrosative Stress e.g. porphyrin complexes, cobalamins Cobalamins as ROS/RNS Scavengers There is considerable evidence that Cbl scavenges NO to form NOCbl in biological systems Evidence supporting NOCbl formation in vivo includes: • NO inhibits the two mammalian B12-dependent enzymes (in vitro and in cell studies) • Cbl suppresses NO-induced relaxation of smooth muscle in rodents, NO-induced vasodilation and NO-mediated inhibition of cell proliferation • Cbl reverses NO-induced neural tube defects • Cbl regulates pro-inflammatory cytokines and growth factors assoc. with the immune response

  10. Patients with severe Cbl deficiency have high TNF- levels and low EGF levels which are corrected by Cbl replacement • The transcobalamin receptor is upregulated by TNF- • Inflammatory diseases associated with increased levels of transcobalamin and its receptor • Cbl depletion is associated with reversible immunodeficiency and can promote HIV infection • Cbl supplementation beneficial for wide variety of diseases associated with oxidative stress and chronic inflammation (chronic fatigue syndrome, trauma, sepsis, asthma, arthritis, AD, MS, eczema) Note: Cbl supplementation results in considerable amounts of free (non-protein bound) Cbl in cells

  11. Chemistry model studies show that the reaction between Cbl(II) and NO is rapid: Furthermore, expts have shown that Cbl(III)’s are reduced to Cbl(II) in cells making the reaction catalytic Can other ROS/RNS react with Cbl(II)? Our work:

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