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78 Cards in this Set

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  • Back
How does singlet oxygen typically cause damage?
To lipids - creates lipid peroxide.
What 3 ways does Superoxide usually cause damage?
1. Reduces Fe3+ to Fe2+ and keeps Fenton reaction going
2. Reduces Fe3+ to Fe2+ inside Ferritin; Fe escapes to do dmg
3. Reacts w/ NO* to form ONOO-
What can Superoxide form?
H2O2 - has its own toxicity
In what 2 ways does Hydrogen Peroxide cause damage?
1. Homolytic cleave - yields 2 Hydroxyl radicals (very bad)
2. Fe2+ reduces it to OH- / OH*
What actually is the reaction name for H2O2 + Fe2+ producing Hydroxyl radical + anion?
Fenton reaction
What 2 things catalyze homolytic H2O2 cleavage?
Pigments (heme)
Why is Hydroxyl radical so dangerous?
Reacts with whatever it hits!
What 3 ways does Hydroxyl radical cause damage?
1. Mutates DNA via base hydroxylation
2. Oxidizes/splits proteins
3. Starts lipid chain rxn of oxidation
How does Hydroxyl radical cause lipid chain oxidation?
1. Creates radical
2. Rearranges/forms trans double bond with O2 binds
3. LOO* reacts like OH* and attacks a NEW lipid (propgn)
How is Nitric Oxide damage caused?
1. Binds Fe to desroy Iron-Sulfur centers in ETC
2. Inhibits cytochrome oxidase
3. Inhibits RiboNT reductase (for DNA synthesis)
What 3 molecules w/ Iron Sulfur centers are destroyed by NO*?
1. Complex I (ETC)
2. Complex II (ETC)
3. Aconitase (TCA)
How does Peroxynitrite damage?
1. Reactive like OH* but not as strong as NO* (except....)
2. Destroys Iron-Sulfur centers worse than NO*
3. Nitrosates things
4. Inactivates Cysteine
What important amino acid does Peroxynitrite (ONOO) nitrosate?
Tyrosine -> Nitrotyrosine
At what complex in ETC does O2 get reduced to H2O via four electron addition?
Cytochrome Oxidase (Complex IV)
How are ROS not freed as electrons are added to O2?
Cu of cytochrome oxidase binds intermediates very tightly!! (Also the terminal Cyt a3)
How much of the body's oxygen is used by cytochrome oxidase?
90-95% - but no ROS formed!
What 2 things are essential for minimizing Fenton type reactions?
They keep free iron in tissues and plasma very low.
What 2 types of defenses do we have for destroying ROS if they ARE formed?
-LMW defenses

-Enzymatic defenses
What are the 4 most important NONenzymatic antioxidants in the body?
-Vit E (a-tocopherol)
-Ascorbate (Vit C)
-Glutathione (GSH)
What are the 4 most important ENZYMATIC antioxidants in the body?
-Superoxide Dismutase (SOD)
-GSH peroxidase
-GSSG redutase
What are the 2 isoforms of SOD that are important? Where are they?
-CuznSOD - in cytosol

-MnSOD - in mitochondria
What does SOD do?
"Dismutates" Superoxide into O2 + H2O2
How does dismutation work?
One O2- reduced as it oxidizes the other O2-.
So superoxide is a major source of:
Hydrogen peroxide H2O2
What disease is associated w/ mutation of CuZnSOD gene?
ALS - lou gehrig's
What 2 enzymes destroy H2O2?
-GSH peroxidase
What is Catalase responsible for?
Destroying H2O2 in peroxisomes
How does the Catalase reaction compare to the SOD reaction?
Catalase rxn is a 2e- dismutation (SOD is 1e-)
Why is GSH peroxidase important?
What is an important part of its structure?
-It's the only ENZYME that can work on ORGANIC peroxides (LOOH) (GSH by itself can't but Vit E can)
-Active site Se - dietary requirement for selenium
What is the structure of GSH?
A Tripeptide - contains:
What are the 2 main purposes of GSH?
1. Keep antioxidants Vit C/E reduced.
Vit E - membrane
Vit C - cytosol
2. Detoxify reactive drugs (Tylenol and Melphalan)
How is GSH made?
By a 2 step reaction:
1. Glu + Cys -> Glutamylcysteine
2. Add Glycine -> GSH
-Both steps require ATP
What are the enzymes used in making GSH?
1. y-glutamylcysteine synthetase
2. don't really know
How are tissue GSH levels controlled? (4 ways)
1. Control enzyme (esp first)
2. Feedback inhibition of GSH on y-gultamylcysteine synthetase
3. L-cysteine availability
4. Rate of GSH transport out of cell
Why is GSH important?
It's the main intracellular reductant
What does GSH reduce?
Vit C and Vit E
What keeps GSH reduced (from GSSG)?
GSH reductase
What enzyme oxidizes GSH?
GSH Peroxidase - when it does its job of quenching ROS's
What does GSH reductase (GR) need in order to reduce GSSG?
NADPH - gets oxidized.
Where does NADPH come from?
In what cell compoments do the vitamens C and E act as antioxidants?
Vit C = cytosolic antioxidant

Vit E = membrane antioxidant
What are the 3 main bad actions of OH* hydroxyl radical?
1. Hits DNA and mutates it by hydroxylating bases.
2. Oxidizes & splits proteins
3. Starts lipid chain rxn of oxidation.
What are the 4 steps of the lipid oxidation chain reaction?
1. Initiation (by OH*)
2. Rearrangmnt to create trans double bond
3. Propogation by Reaction with O2 ->LOO*
4. Products
What are the products of lipid oxidation by OH*?
Hydroperoxylipid (LOOH) + Cyclic peroxide
How is the spontaneous homolytic cleavage of H2O2 -> 2OH* avoided?
By Glutathione Peroxidase - uses 2 GSH to reduce H2O2 -> ROH + H2O
Where in the cell is GPx (glutathione peroxidase)?
In the cytosol
Where are LOOH mostly?
Hydroperoxylipids are mostly in the membrane
How does GPx get at hydroperoxylipids?
They are insoluble in the internal cell membrane; so they migrate out to the edge; then GPx can get at them.
What drugs does GSH protect against?
Tylenol (Acetominophen)
Melphalan (Phe-mustard, Alkeran)
How is damaged DNA repaired?
By excision repair
How are damaged proteins repaired?
They arent - just get degraded
How is degrading damaged proteins different from normal?
It's accelerated b/c the proteins are more unstable.
What are the 2 exceptions to repairing damaged proteins?
1. Protein disulfides
2. Methionine Sulfoxide
How are protein disulfides repaired?
How is Methionine Sulfoxide repaired?
Met Sulfoxide Reductase uses NADPH to reduce it to Met.
How are damaged membrane lipids repaired?
1. GSH peroxidase QUENCHES
2. Hydroxyacid removed by phospholipases, replaced.
What is the effect of increasing amounts of oxidative stress?
Apoptosis, then necrosis
What is respiratory burst?
The increased O2 consumption by phagosomes during increased metabolism.
What enzyme is essential in respiratory burst?
NADPH oxidase
Where is NADPH oxidase?
Loosely at the inner plasma membrane surface -> so it can end up on outer vacuole surf)
What is the result of NADPH oxidase action?
Forms superoxide in the phagocytic vacuole
What happens to superoxide in the phagocytic vacuole?
Converted to H2O2 by SOD
What happens to H2O2 in the phagocytic vacuole?
Used by Fenton/Haber-weiss rxns to make OH* radicals
What do OH* radicals do in the phagocytic vacuole?
Kill bacteria.
What other enzyme kills bacteria in phagosomes?
What type of protein is myeloperoxidase?
Green hemeprotein
What reaction does Myeloperoxidase catalyze?
Formation of HOCL (clorox)
What are 2 diseases associated with deficient respiratory bursts?
1. CGD (worse)
2. Inherited defic of myeloperoxidase
What causes CGD?
Inherited defic of NADPH oxidase
What results from deficient NADPH oxidase?
Ability to engulf bacteria, inability to kill
What 2 enzymes are important in purine degradation? Which one predominates in vivo?
Xanthine Oxidase
Xanthine Dehydrogenase (XD)
Why is XD predominant?
B/c it oxidizes Hypoxanthine and Xanthine w/out making ROS
What can cause conversion of Xanthine DEHYDROGENASE to OXIDASE?
Ischemia - Ca2+ influx activates protease that converts the enzyme.
Why is Xanthine oxidase bad?
It produces H2O2 as Xanthine is oxidized.
What sequence results from ATP Depletion?
ADP, AMP, IMP, Hypoxanthine
What is required for Hypoxanthine oxidation?
Oxygen; which is not available to ischemic tissue; hypoxathine accumulates.
Where does the injury occur in ischemia?
When clot is taken away and O2 is available - suddenly lots of H2O2 forms.
What 2 injuries do we see this reperfusion injury in?