Oxygen Toxicity Flashcards
Describe the structure of oxgyenated hemoglobin
There are 4 subunits, two alpha and two beta
Inside each subunit there is a heme group, composed of iron that loosely attaches oxygen, making it an oxidizing agent
Why are RBC susceptible to oxidative stress?
Heme groups promote the production of ROS. This can cause the RBC to become fragile because of lipid peroxidation caused by H2O2 and damages to the plasma cell membrane
What does it mean that the oxygen molecule is bi-radical?
it has two unpaired electrons in its outer shell
Describe the reduction of oxygen to water. Where do the electrons that contribute to this formation come from?
The electrons come from reduced electron carriers in the ETC, such as NADP (NADPH), radical form of coenzyme Q
What is the Fenton Reaction?
The reaction of hydrogen peroxide with a transition metal to form a hydroxyl radical
This is not common because accessibilty to transitiuon metals is highly restricted, but since hydrogen peroxide is lipid soluble, it can diffuse through cell membrane, generating a hydroxyl radical at localized site that contain transition metals, such as in the ETC.
Where does supeoxide ion cause the most damage?
In the location where it is produced becasue it cannot diffuse far
What are the 3 major sources of ROS formation?
- CoQ in the ETC
- oxidases, oxygenases, and peroxidases
- monoamine oxidase (H202)
- xanthine oxidases (O2-)
- cytochrome P450
- High energy ionizing radiation
How can ROS affect lipids? proteins? DNA?
- Lipids
- lipid peroxidation can cause damage to cellular mitochondrial, ER, and nuclear membranes
- Proteins
- aa Pro, His, Cys and Met are susceptible to hydroxy radical attacks, cross-linking of protein
- DNA
- base alteration and cause break in DNA strand (kind)
How does NO function at low concentrations? How does it function at high concentrations?
At low concentrations, it acts as a neurotransmitter or as a hormone
At high concentratiosn, it combines with O2 or with a superoxide to form RNOS, which is involved in neurodegenerative diseases such as Parkinsons, or chronic inflammatory disease such as rheumatoid arthritis
What are the three types of nitric oxide synthases? Which aa do they interact with to form NO?
- nNOS- neuronal NOS
- iNOS- indicuble NOS
- eNOS- endothelial NOS
They interact with Arginine
What are the 5 RNOS and where do they usually have a toxic effect?
- ONOO- (peroxy nitrate)
- N203
- HONO2
- NO2+
- NO2 (radical)
They affect places with Fe (Fe-S centers ETC, Fe-heme ptroteins ie Hb)
Which structure during phagocytosis and inflammations is a major source of ROS production?
What enzyme is responsible for its development?
Respiratory burst– part of the microbial defense system
NADPH oxidase catalyzes the transfer of an electron from NADPH to O2 to form superoxide
What enzyme is repsonsible for the formation of HOCl (a powerful toxin) from H202 in phagocytic cells?
Myeloperoxidase
Whic enzyme is co-activated with NADPH oxidase during an immune response? What species is therefore produced?
Is this reaction always helpful?
iNOS, which produces NO
NADPH odidase produces superoxide, which then combines with NO to produce RNOS (perody nitrate)
No, during a stroke or myocardial infarction, phagocytic cells tha tmove into the ishcemic area to remove dead cells may increase the area and extent of damage by releaseing free radicals
Which 3 enzymes are particulary important for antioxidant scavenging?
- Superoxide disumtase (SOD)
- Converts superoxide to hydrogen peroxide
- Primary defense against oxidative stress
- Mutation in SOD leads to ALS
- Catalase
- found in peroxisomes (kidney and liver)
- Converts hydrogen peroxide to water
- Glutathione peroxidase
- found in cytosol an mitochondria
- remove H2O2 (reduce it to water)
- two glutathione molecules are oxidized to form a single molecule (glutathione disulfide)
- then PPP provides NADPH for reduction oxidized glutathione, catalyzed by glutathione reductase
What are the major non-enxymatic antioxidants both endogenous and exogenous. What do they do?
Antioxidants convert free radicals to a nonradical, nontoxic form in non-enzymatic reaction by donating a hydrogen atom and neutralizing the free radical.
- Endogenous
- uric acid- degradation of purines
- melatonin- pineal hormone
- Exogenous
- Vit. C (ascorbic acid)
- can be used to regenerate Vit. E
- Vit. E
- most widely distributed and potent antioxidant
- lipid soluble that protects agains lipid peroxidation in membranes
- vegetable oils, liver, egg yolk and cereals
- Caretenoids
- pigments in fruits and vegetables (bright colors)
- Favonoids
- have 2 aromatic rings– in red wine, green tea, and chocolate
- Polyphenols in
- green tea, blueberries, grapeskin
- Vit. C (ascorbic acid)
What is the name for the protective effect of separating species and sites involved in ROS generation from the rest of the cell?
Provide an example.
Compartmentalizaion of free-radicals
- many of the enzymes that produce hydrogen peroxide are sequestered in peroxisomes with a high concentration of antioxidant enzymes
- Metals are bound to a wide range of proteins within the cells, preventign their participation in the Fenton reaction
What is the condition that results from a deficiency in Glucose-6-phosphate dehydrogenase?
What triggers this condition?
Hemolytic Anemia (x-linked, occurs in 11% of African Americans)
With less G-6-PDH, less NADPH is produced, which is required for the glutathione cycle. If the glytathione cycle cannot continue, this leads to an increase in ROS, which can lyse the red blood cells (hemolysis)
This condition is triggered by a sudden rush of oxygen
- strenous exercise
- certain drugs Quinones which are potent oxidants
- some foods (favism)
