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103 Cards in this Set
- Front
- Back
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Oxidation
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is loss of e
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so oxidants want
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to gain (e-)
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Reduction
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is gain
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What do reductants want
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to lose (e-)
(think of Fe picking up H) |
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What is oxygen?
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A good oxidant - wants to accept electrons. The strongest oxidant
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Why do our foods contain energy?
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B/c they're reduced relative to the products formed from metabolism (CO2)
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What has more energy; methane or methanol?
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Methane - it is more reduced.
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What is the one-carbon biological molecule with least energy?
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CO2 - most oxidized
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What are the advantages and disadvantages of using Oxygen for metabolism?
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Advantages: oxygen highly reduced, can accept electrons easily. Enzyme substrate.
Disadvntgs: use generates ROS |
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What is ROS and ROI?
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Reactive oxygen species
Reactive oxygen intermediates |
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What element contributes to free radicals?
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Free iron
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4 strategies for minimizing ROS:
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1. Minimize formation
2. Use enzymes and small antioxidants to Quench ROS 3. Keep free iron in body low 4. Repair systems for ROS damage |
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When are ROS good?
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When used by the immune system for killing tumor cells and invading pathogens.
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How does the net energy yield compare for Aerobic vs. Anaerobic glycolysis?
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Aerobic: 30-32 ATP (including TCA and oxid. phosphorylation)
Anaerobic: 2 ATP |
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What are 3 enzyme reactions that use oxygen as a substrate?
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1. Monooxygenase
2. Dioxygenase 3. Oxidase |
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What takes place in a monooxygenase reaction?
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-One Oxygen of O2 is incorporated into the substrate.
-One Oxygen of O2 is reduced to water. |
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What alternate term is used for enzymes that catalyze monooxygenase reactions?
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Mixed-function oxidase
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What is an example of a monooxygenase?
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Phenylalanine hydroxylase - converts phenylalanine to tyrosine.
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Why are monooxygenases termed "Mixed function"?
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B/c O2's function is mixed;
-one O oxidizes SUBSTRATE -other O oxidizes COsubstrate (NADPH) |
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How are dioxygenases different from monooxygenases?
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Both O atoms of O2 are incorporated into substrate to form product.
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What are 2 exemples of dioxygenase reactions?
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1. Tryptophan forms Formylkynurenine (first step of Trp catabolism)
2. Cys -> cysteinesulfinate (Cysteine catabolism) |
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How do oxidases differ from mono or dioxygenases?
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O2 is simply an electron acceptor; not incorporated into substrate, but simply reduced to H2O2.
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2 examples of oxidase enzymes:
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1. D-amino acid oxidase
2. Monoamine oxidase |
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How is O2 used in the D-amino acid oxidase reaction?
How is O2 used in Monoamine oxidase? |
1. During amino acid oxidation FMNH2 is formed.
2. O2 oxidizes FMNH2 to regenerate FMN. Monoamine oxidase: 1. O2 accepts 2 e- from amine as NH2->C=O; makes H2O2 |
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The 4 most dangerous ROS:
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-Singlet oxygen
-Hydroxyl radical -Peroxynitrite -Hypochlorite |
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What is Singlet oxygen?
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An activated form of triplet oxygen
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What is triplet oxygen?
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The ordinary form of oxygen
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What do repeated 1-electron additions to triplet oxygen produce?
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1. Superoxide O2-
2. H2O2 3. Hydroxyl radical 3. Water |
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What kind of radical is normal O2 (triplet oxygen)?
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A diradical - one unpaired electron in each of two P orbitals.
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What actually results from adding 4 e' to O2?
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2 molecules of water
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2 forms of dioxygen:
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Triplet (ground state
Singlet (excited state) |
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What is the difference between triplet and singlet dioxygen?
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Triplet has 2 unpaired electrons in each of 2 p orbitals
Singlet has the 2 electrons paired in one p orbital, so it has an empty p orbital available. |
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How reactive is Triplet dioxygen?
Is it a radical? |
Relatively unreactive
Yes; a diradical |
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Is singlet oxygen a radical? What is the result?
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No; reacts with virtually anything.
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What causes conversion of triplet dioxygen to singlet?
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-Light + photosensitizer (pigment)
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What is a pigment related to heme?
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Porphyrin - accumulation in porphyrias leads to ROS damage.
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Which intermediates in adding 4 e' to O2 are radicals?
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-Triplet = diradical
-Superoxide = O2- [not peroxide] -Hydroxyl radical |
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What are by far the 2 most toxic ROS's?
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-Singlet oxygen
-Hydroxyl radical |
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Why are Singlet O2 and Hydroxyl radical so damaging?
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Because they have a very short T1/2 - react very quickly.
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Why are Superoxide and H2O2 less reactive?
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-Superoxide has a longer T1/2
-H2O2 is destroyed by enzymes. |
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What is the order of ground state O2 -> H2O in terms of energy?
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Triplet
Singlet Superoxide Anion Hydrogen Peroxide Hydroxyl radical Water |
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Why are these the reactive oxygen species we're focusing on?
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B/c they're all present at physiological pH.
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Which of these ROS are radicals?
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-Triplet
-Superoxide -Hydroxyl radical |
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Other than adding electrons to O2, how does Hydroxyl radical develop?
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Via the homolytic cleavage of H2O2 - yields 2 Hydroxyl radicals
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What is a biological molecule that catalyzes homolytic peroxide cleavage?
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Heme
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Recap; what are the 2 most damaging and toxic ROS's?
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-Singlet Oxygen (not a radical)
-Hydroxyl radical (OH*) |
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3 important antioxidants:
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Ascorbate
Butylated hydroxytoluene Glutathione |
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What makes a good antioxidant?
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Short rate constant for reaction w/ radicals
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What molecules have rate constants (not t1/2) similar to those of antioxidants?
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-Adenosine
-AMP -Deoxyribose |
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What more or less controls the rates of reaction of ROS?
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Diffusion
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What are the 2 nitrogen-containing RNS?
Which is a radical? |
-Nitric oxide (NO*)
-Peroxynitrite (ONOO-) |
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How does the toxicity of RNS compare to ROS?
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-Less toxic than Singlet O2 and OH*
-More toxic than O2- |
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What is O2-?
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superoxide
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What ROS is immunologically important?
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HOCL - hypochlorite
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What forms singlet O2?
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Porphyria - accumulated protoporphyrin is a pigment that absorbs light
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How do pigments cause singlet O2 production?
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1. Pigment absorbs lite energy
2. Transfer to O2 3. Electrons pair up; leaves empty orbital 4. Empty orbital seeks 2 paired electrons to grab |
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What are 5 other pigment-type molecules that make Singlet O2?
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-Methylene blue
-Bilirubin (bile pigment) -Riboflavin (FAD/FMN) -Retinal -Hypericin (ST. john's wort) |
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What is methylene blue used for?
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Treating methemoglobinemia in nitrate or nitrite poisoning.
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What is phototherapy for?
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Excessive bilirubinemia in jaundiced newborns - to isomerize it to excreteable product; also increases singlet O2.
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How is superoxide O2- formed? (Chemical reaction)
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By adding one electron to O2.
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What 4 physiologic processes cause Superoxide formation?
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1. Drug redox cycling
2. Inappropriate dissociation of oxyHb -> MetHb + Superoxide 3. Inadvertant reaction with ETC 4. Neutrophil respiratory bursts |
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In what 2 ways can superoxide act?
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1. As a reductant - converts itself back to O2
2. As an oxidant - converts itself to H2O2 |
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What occurs in the process of HbO2 spontaneously dissociating?
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Iron converts from ferrous to ferric Hb (methemoglobin) as superoxide radical is generated.
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What molecule reduces oxidized Methemoglobin?
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(Reduced) Cyt b5
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What reduces Oxidized Cyt b5 after it reduces MetHb?
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NADH - redox reaction catalyzed by metHb reductase.
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What pathologic conditions result in increased levels of MetHb?
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-Nitrite poisoning
-Inherited defic of Cyt b5 of MetHb reductase |
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What is the main purpose of the alternate NADPH-metHb reductase?
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When reduced, acts rapidly on methylene blue to reduce metHb; that's why it's the treatment for nitrite poisoning.
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What is the main source of superoxide anions in the body?
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The ETC
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What component of the ETC generally produces superoxide?
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Coenzyme Q Semiquinone - it picks up half an O2 molecule and leaves the rest as free O2 superoxide.
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Why is cytochrome oxidase unique?
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Because it doesn't generate peroxide like most oxidases
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How much of the electrons flowing through the ETC are lost to O2?
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3-5% - mostly from CoQ Semiquinone
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What/where are protons transported in the ETC?
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Complex I - 4
Complex III - 2 Complex IV - 4 |
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Why is superoxide so damaging?
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Because it is the major contributor to oxidative stress and has a short half life.
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Why is superoxide the major contributor to oxidative stress?
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Because it is produced at Ubiquinone (Coenzyme Q) in ETC. A lot of oxygen goes through here so lots of O2-1 produced.
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What controversial herbicid creates superoxide in humans?
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Paraquat - marijuana herbicide
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By what other reaction is superoxide produced in the body? (vs. ubiquinone)
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metHB - inappropriate loss of O2 creates ferric Hb
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What 3 mechanisms generate HYDROGEN PEROXIDE?
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1. Oxidase enzymes
2. SOD (superoxide dismutase) 3. Nonenzymatic formation from superoxide |
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Why is H2O2 dangerous?
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Can undergo homolytic cleavage to 2 OH*
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What 2 reactions produe hydroxyl radical?
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1. HaberWeiss (too slow to care about)
2. Fenton (most important) |
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What are the 2 steps in the fenton reaction?
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1. Superoxide/Fe3+ -> O2/Fe2+
2. Fe2+/H2O2 -> OH*/Fe3+/H2O |
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What variations can be done to the Fenton rxn?
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-Substitute GSH, Ascorbate or Thiols for superoxide
-Substitute Cu2+/Cu+ for iron |
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What clinical condition increases the rate of Fenton rxn?
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Iron overload
-Beta thallasemia -Idiopathic hemochromatosis |
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What 3 things will limit the fenton reaction?
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1. Use SOD to elim superoxide
2. Eliminate H2O2 3. Sequester Fe3+ |
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How much iron is stored in the body?
How much is taken in daily and excreted? |
-About 4.5 GRAMS
-Eat about 1 mg/day -Excrete about 2 mg/day |
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Where is the body's iron burden controlled?
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At the gut - by absorption.
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What 2 diseases exhibit iron overload?
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1. Idiopathic hemochromatosis
2. B-thalassemia (cooley's) major |
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Why do patients with B-thal get iron overload?
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Because they depend on many transfusions.
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What is the bad effect of blood transfusions on patients w/ B-thal?
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they don't use their iron
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How is iron overload treated?
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Iron chelators - desferal
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Why do patients that get blood transfusions but no iron chelators die early?
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B/c of iron-catalyzed oxidative stress damage.
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What reaction causes the production of these ROS?
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Fenton
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Where is most of the body's iron?
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Bound to heme
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What is the metabolically active pool of iron bound to?
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Transferrin
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What does transferrin do?
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Carries 2 Fe3+ if HCO3- is bound.
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What is the purpose of Transferrin?
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Transfer of iron from RES (senescent RBCs) to bone marrow (make new RBCs)
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What is the majority of stored iron found in?
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Ferritin
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In what form does Ferritin store iron?
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Rust - Fe(OH)3
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How many Fe atoms are stored per ferritin?
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About 4500!!!
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Where does ferritin store iron?
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Inside cells.
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What is hemosiderin?
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Iron precipitated from ferritin spheres
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What is hemosiderosis?
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A syndrome that develops when hemosiderin levels accumulate to several x higher than ferritin
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Hemopexin
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plasma protein that binds free heme
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Haptoglobin
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plasma protein that binds hemoglobin
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