Lecture 8 - Free radicals Flashcards
Oxygen is essential to life but
can be toxic
How is oxygen essential and toxic?
Essential:
- ) oxidation reactions
- ) Generation of ATP (ox phos)
- ) Detoxification reactions
- ) Biosynthetic reactions
Toxic:
- ) When oxygen accepts single electrons it is transformed into highly reactive oxygen radicals that damage:
- cellular lipds
- Proteins
- DNA
Oxygen is a biradical and so it can form?
- ) O2- superoxide
- ) H2O2 Hydrogen peroxide
- ) OH Hydroxyl radical
What is ROS
Reactive o2 species:
Its generation is a natural everyday process . It is formed as an accidental product of enzymatic and non enzymatic reactions. It is also formed during the inflammatory process as a deliberate part of teh process.
What can increase the formation of toxic oxygen containing compounds?
UV radiation and pollutants in the air.
What are the major sources of ROS in the cell?
- ) CoQ generates superoxide in ETC
- ) oxidases, oxygenases, and peroxidases
- ) ionising radiation
What do ROS do?
They react with lipids, proteins, carbs and DNA to exrtract electrons.
How many diseases are shown to be due to free radical damage?
over 100 have shown evidence of it, either as the primary cause or by enhancing complications
What does ROS do?
Superoxide and hydroxyl radical initiate lipid peroxidation in the cellular, mitochondrial, nuclear and ER membranes.
This increases permeability and so there is an influc of Ca2+ which causes further mitochondrial damage.
The cysteine sulfhydryl groups and other AA residues on proteins are oxidised and degraded.
Nuclear and mitochondria DNA can be oxidized resulting in strand breaks and other damage
RNOS has a similar effect.
What is the membrane attack in ROS?
Chain reactions to form lipid radicals and lipid peroxides in membranes
There is membrane lipid damage which leads to loss of structural integrity of membrane. This disruption of mitochondria membrane may augment free radical damage.
What are the overall issues:
Peroxidation of lipids dammage lipid moelcular structure
The aldehydes formed can cross link proteins
What is the biomarker for free radical damage?
Malondialdehyde appears in blood and urine
What AA can be sesceptible to hydroxyl damage attack and oxidative damage?
Proline, histidine, arginine, cysteine and methionine.
Consequence - protein may fragment and residues cross link with other residues
What disease has evidence of protein damage?
cataracts - proteins in the lens of the eye exhibit ROS damage which contain methionine and sulphoxide residues and trytophan degredation products.
What are lipofuscin granules?
liver spots - heterogenous mix of cross linked polymerized lipids and proteins formed by reactions between AA residues and lipid perroxidation products such as malondialdehyde.
What DNA damage takes place because of oxygen derived free radicals?
non specific bonding of Fe2+ to DNA facilitates localised production of the hydroxyl radical which can cause base alterations.
It can also attack the deoxyribose backbone and cause the strands to break
DNA repair mechanisms exist or avoided by apoptosis.
What is the difference between the damage ROS can do on mmitochondrial vs nuclear DNA?
Nuclear DNA has histones which protects it from damage by radicals wheras mitochondrial DNA lacks histones and its DNA is proximal to the cellular membrane.
Where are most radical species formed?
coenzyme q which is found in the mitochondria
Functions of NO?
- ) neurotransmitter
2. ) As a hormone that causes vasodilation
How many electrons does NO have and what does it bind to?
one electron and binds to other compounds with one electron like Fe3+
How is RNOS formed?
NO combines with O2 or superoxide to form additional reactive and toxic species that contains both - RNOS
What is RNOS involved in?
- ) neurodegenerative diseases like parkinsons
2. ) in chronic inflammatory diseases like rheumatoid arthiritis
What are the toxic effects of NO?
By combining to Fe containing compounds that also have one electron, the major sites of destruction are Fe-S centres, Fe-Heme proteins
Consequences of the formation of RNOS?
- ) Inhibition of enzymes
- ) Mitochondrial lip peroxidation
- ) Inhibition of ETC and energy depletion
- ) SS or DS breaks in DNA
- ) Modification of bases in DNA
What is the formation of free radicals during phagocytosis?
NADPH Oxidase: Transfers electrons from NADPH to O2 to form superoxide which is effective agaiinst bacterial infection.
Myeloperoxidase and hypochlorous acid - bacteria lose membrane transport and ability to synthesize ATP or ETC damage.
Part of the human antimicrobial defence system.
What are the antioxidant scavenging enzymes?
Superoxide dismutase
Catalase
Glutathione peroxidase
Glutathion reductase
What are the non enzymatic antioxidants?
VItamin: E, C, cartenoids (precursor of vitamin A) and dietary antioxidants like flavonoids (red wine, green tea and chocolate).
What are the endogenous antioxidants?
Uric acid - degredation product of purines
Melatonin - receptor functions but also a free radical scavenger
ALS?
both environment and genetic disease where it is caused by mutations in superoxide leading to a difficulty in disposing of superoxide radicals, leading to cell damage caused by excessive ROS.
