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103 Cards in this Set

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Oxidation
is loss of e
so oxidants want
to gain (e-)
Reduction
is gain
What do reductants want
to lose (e-)

(think of Fe picking up H)
What is oxygen?
A good oxidant - wants to accept electrons. The strongest oxidant
Why do our foods contain energy?
B/c they're reduced relative to the products formed from metabolism (CO2)
What has more energy; methane or methanol?
Methane - it is more reduced.
What is the one-carbon biological molecule with least energy?
CO2 - most oxidized
What are the advantages and disadvantages of using Oxygen for metabolism?
Advantages: oxygen highly reduced, can accept electrons easily. Enzyme substrate.

Disadvntgs: use generates ROS
What is ROS and ROI?
Reactive oxygen species
Reactive oxygen intermediates
What element contributes to free radicals?
Free iron
4 strategies for minimizing ROS:
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
When are ROS good?
When used by the immune system for killing tumor cells and invading pathogens.
How does the net energy yield compare for Aerobic vs. Anaerobic glycolysis?
Aerobic: 30-32 ATP (including TCA and oxid. phosphorylation)

Anaerobic: 2 ATP
What are 3 enzyme reactions that use oxygen as a substrate?
1. Monooxygenase
2. Dioxygenase
3. Oxidase
What takes place in a monooxygenase reaction?
-One Oxygen of O2 is incorporated into the substrate.

-One Oxygen of O2 is reduced to water.
What alternate term is used for enzymes that catalyze monooxygenase reactions?
Mixed-function oxidase
What is an example of a monooxygenase?
Phenylalanine hydroxylase - converts phenylalanine to tyrosine.
Why are monooxygenases termed "Mixed function"?
B/c O2's function is mixed;
-one O oxidizes SUBSTRATE
-other O oxidizes COsubstrate (NADPH)
How are dioxygenases different from monooxygenases?
Both O atoms of O2 are incorporated into substrate to form product.
What are 2 exemples of dioxygenase reactions?
1. Tryptophan forms Formylkynurenine (first step of Trp catabolism)
2. Cys -> cysteinesulfinate (Cysteine catabolism)
How do oxidases differ from mono or dioxygenases?
O2 is simply an electron acceptor; not incorporated into substrate, but simply reduced to H2O2.
2 examples of oxidase enzymes:
1. D-amino acid oxidase
2. Monoamine oxidase
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
The 4 most dangerous ROS:
-Singlet oxygen
-Hydroxyl radical
-Peroxynitrite
-Hypochlorite
What is Singlet oxygen?
An activated form of triplet oxygen
What is triplet oxygen?
The ordinary form of oxygen
What do repeated 1-electron additions to triplet oxygen produce?
1. Superoxide O2-
2. H2O2
3. Hydroxyl radical
3. Water
What kind of radical is normal O2 (triplet oxygen)?
A diradical - one unpaired electron in each of two P orbitals.
What actually results from adding 4 e' to O2?
2 molecules of water
2 forms of dioxygen:
Triplet (ground state

Singlet (excited state)
What is the difference between triplet and singlet dioxygen?
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.
How reactive is Triplet dioxygen?
Is it a radical?
Relatively unreactive
Yes; a diradical
Is singlet oxygen a radical? What is the result?
No; reacts with virtually anything.
What causes conversion of triplet dioxygen to singlet?
-Light + photosensitizer (pigment)
What is a pigment related to heme?
Porphyrin - accumulation in porphyrias leads to ROS damage.
Which intermediates in adding 4 e' to O2 are radicals?
-Triplet = diradical
-Superoxide = O2-
[not peroxide]
-Hydroxyl radical
What are by far the 2 most toxic ROS's?
-Singlet oxygen
-Hydroxyl radical
Why are Singlet O2 and Hydroxyl radical so damaging?
Because they have a very short T1/2 - react very quickly.
Why are Superoxide and H2O2 less reactive?
-Superoxide has a longer T1/2

-H2O2 is destroyed by enzymes.
What is the order of ground state O2 -> H2O in terms of energy?
Triplet
Singlet
Superoxide Anion
Hydrogen Peroxide
Hydroxyl radical
Water
Why are these the reactive oxygen species we're focusing on?
B/c they're all present at physiological pH.
Which of these ROS are radicals?
-Triplet
-Superoxide
-Hydroxyl radical
Other than adding electrons to O2, how does Hydroxyl radical develop?
Via the homolytic cleavage of H2O2 - yields 2 Hydroxyl radicals
What is a biological molecule that catalyzes homolytic peroxide cleavage?
Heme
Recap; what are the 2 most damaging and toxic ROS's?
-Singlet Oxygen (not a radical)
-Hydroxyl radical (OH*)
3 important antioxidants:
Ascorbate
Butylated hydroxytoluene
Glutathione
What makes a good antioxidant?
Short rate constant for reaction w/ radicals
What molecules have rate constants (not t1/2) similar to those of antioxidants?
-Adenosine
-AMP
-Deoxyribose
What more or less controls the rates of reaction of ROS?
Diffusion
What are the 2 nitrogen-containing RNS?
Which is a radical?
-Nitric oxide (NO*)
-Peroxynitrite (ONOO-)
How does the toxicity of RNS compare to ROS?
-Less toxic than Singlet O2 and OH*
-More toxic than O2-
What is O2-?
superoxide
What ROS is immunologically important?
HOCL - hypochlorite
What forms singlet O2?
Porphyria - accumulated protoporphyrin is a pigment that absorbs light
How do pigments cause singlet O2 production?
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
What are 5 other pigment-type molecules that make Singlet O2?
-Methylene blue
-Bilirubin (bile pigment)
-Riboflavin (FAD/FMN)
-Retinal
-Hypericin (ST. john's wort)
What is methylene blue used for?
Treating methemoglobinemia in nitrate or nitrite poisoning.
What is phototherapy for?
Excessive bilirubinemia in jaundiced newborns - to isomerize it to excreteable product; also increases singlet O2.
How is superoxide O2- formed? (Chemical reaction)
By adding one electron to O2.
What 4 physiologic processes cause Superoxide formation?
1. Drug redox cycling
2. Inappropriate dissociation of oxyHb -> MetHb + Superoxide
3. Inadvertant reaction with ETC
4. Neutrophil respiratory bursts
In what 2 ways can superoxide act?
1. As a reductant - converts itself back to O2

2. As an oxidant - converts itself to H2O2
What occurs in the process of HbO2 spontaneously dissociating?
Iron converts from ferrous to ferric Hb (methemoglobin) as superoxide radical is generated.
What molecule reduces oxidized Methemoglobin?
(Reduced) Cyt b5
What reduces Oxidized Cyt b5 after it reduces MetHb?
NADH - redox reaction catalyzed by metHb reductase.
What pathologic conditions result in increased levels of MetHb?
-Nitrite poisoning
-Inherited defic of Cyt b5 of MetHb reductase
What is the main purpose of the alternate NADPH-metHb reductase?
When reduced, acts rapidly on methylene blue to reduce metHb; that's why it's the treatment for nitrite poisoning.
What is the main source of superoxide anions in the body?
The ETC
What component of the ETC generally produces superoxide?
Coenzyme Q Semiquinone - it picks up half an O2 molecule and leaves the rest as free O2 superoxide.
Why is cytochrome oxidase unique?
Because it doesn't generate peroxide like most oxidases
How much of the electrons flowing through the ETC are lost to O2?
3-5% - mostly from CoQ Semiquinone
What/where are protons transported in the ETC?
Complex I - 4
Complex III - 2
Complex IV - 4
Why is superoxide so damaging?
Because it is the major contributor to oxidative stress and has a short half life.
Why is superoxide the major contributor to oxidative stress?
Because it is produced at Ubiquinone (Coenzyme Q) in ETC. A lot of oxygen goes through here so lots of O2-1 produced.
What controversial herbicid creates superoxide in humans?
Paraquat - marijuana herbicide
By what other reaction is superoxide produced in the body? (vs. ubiquinone)
metHB - inappropriate loss of O2 creates ferric Hb
What 3 mechanisms generate HYDROGEN PEROXIDE?
1. Oxidase enzymes
2. SOD (superoxide dismutase)
3. Nonenzymatic formation from superoxide
Why is H2O2 dangerous?
Can undergo homolytic cleavage to 2 OH*
What 2 reactions produe hydroxyl radical?
1. HaberWeiss (too slow to care about)
2. Fenton (most important)
What are the 2 steps in the fenton reaction?
1. Superoxide/Fe3+ -> O2/Fe2+
2. Fe2+/H2O2 -> OH*/Fe3+/H2O
What variations can be done to the Fenton rxn?
-Substitute GSH, Ascorbate or Thiols for superoxide
-Substitute Cu2+/Cu+ for iron
What clinical condition increases the rate of Fenton rxn?
Iron overload
-Beta thallasemia
-Idiopathic hemochromatosis
What 3 things will limit the fenton reaction?
1. Use SOD to elim superoxide
2. Eliminate H2O2
3. Sequester Fe3+
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
Where is the body's iron burden controlled?
At the gut - by absorption.
What 2 diseases exhibit iron overload?
1. Idiopathic hemochromatosis

2. B-thalassemia (cooley's) major
Why do patients with B-thal get iron overload?
Because they depend on many transfusions.
What is the bad effect of blood transfusions on patients w/ B-thal?
they don't use their iron
How is iron overload treated?
Iron chelators - desferal
Why do patients that get blood transfusions but no iron chelators die early?
B/c of iron-catalyzed oxidative stress damage.
What reaction causes the production of these ROS?
Fenton
Where is most of the body's iron?
Bound to heme
What is the metabolically active pool of iron bound to?
Transferrin
What does transferrin do?
Carries 2 Fe3+ if HCO3- is bound.
What is the purpose of Transferrin?
Transfer of iron from RES (senescent RBCs) to bone marrow (make new RBCs)
What is the majority of stored iron found in?
Ferritin
In what form does Ferritin store iron?
Rust - Fe(OH)3
How many Fe atoms are stored per ferritin?
About 4500!!!
Where does ferritin store iron?
Inside cells.
What is hemosiderin?
Iron precipitated from ferritin spheres
What is hemosiderosis?
A syndrome that develops when hemosiderin levels accumulate to several x higher than ferritin
Hemopexin
plasma protein that binds free heme
Haptoglobin
plasma protein that binds hemoglobin