Oxidative Stress Flashcards
Cellular damage cause by ROS (reactive oxygen species) & RNS (reactive nitrogen species) is a significant component in a wide range of disease states. Name some diseases?
CVS disease MS Parkinson's Pancreatitis Cancer COPD Crohn's Rheumatoid arthritis
Name some ROS & RNS
Ros; superoxide, hydrogen peroxide (when reacted with fe2+), hydroxyl radical (V. Damaging and reactive)
Rns; nitric oxide
What are the two ways in which ROS damage DNA?
React with base; modified base can lead to mispairing and mutation
React with sugar (ribose or deoxyribose); can cause strand break and mutation on repair
How can ROS damage lead to cancer?
ROS reacts with DNA
DNA damage
Failure to repair can lead to mutation
Can lead to cancer
In what ways do ROS damage proteins? What are the consequences?
Effect side chain or back bone
If Backbone= fragmentation which leads to protein degradation
If sidechain= risk of modified amino acids which leads to changes in the protein structure. Which in turn may lead to gain of function/ loss of function (and protein degradation)/ protein degradation
What is the role of disulphides bonds in proteins?
Folding and stability
How are disulphide bonds formed?
Between thiol groups of cysteine residues
When can inappropate disulphide bond form? What are the consequences?
If ROS effects the side chains on a protein, taking an electron from cysteines causing misfolding, cross-linking and disruption of function of protein (enzyme/hormone ie insulin)
What damage can ROS cause to lipids? What are the consequences?
They can react to form lipid peroxyl radicals which set off chain reactions as the nearly formed radical steals an electron from the adjacent lipid.
This leads to the hydrophobic environment of bilayer to be disrupted and the membrane integrity fails.
What are source of biological oxidants, both exogenous and endogenous?
Endogenous;
- ETC
- peroxidases
- nitric oxide synthesis
- NADPH oxidises
Exogenous;
- radiation (cosmos rays, UV light, x-rays)
- pollutants
- drugs (anti-malarial)
- toxins (herbicides)
How are ROS formed in the electron transport chain?
NADH & FADH2 supply electrons
Electrons are passed through ETC and reduce oxygen to form water at complex IV
Occasionally electron can accidentally escape chain and react with dissolved oxygen to form superoxide
How is nitric oxide synthase (NOS) a source of free radicals?
Arginine is converted by NOS to citrulline and nitric oxide
When is respiratory burst?
Rapid release of superoxide and hydrogen peroxide from phagocytic cells ( ie monocytes and neutrophils) to kill pathogens (beneficial)
There are some diseases in which a genetic defect in the NADPH oxidase complex causes enhanced susceptibility to bacterial infection. Name some of these infections
Pneumonia
Abscesses
Impetigo
Cellulitis
What are the defences that we have against free radicals?
Superoxide dismutase
Catalase
Glutathione
Free radical scavengers
How does superoxide dismutase (SOD)defend against free radicals?
Converts superoxide to hydrogen peroxide and oxygen
The h2o2 can then be converted further by catalase and isn’t itself actually a free radical
How does catalase defend against free radicals?
It works after superoxide dismutase and converts the hydrogen peroxide (that the superoxide dismutase has produced from superoxide) into water and oxygen.
It it important in immune cells to protects against oxidative burst
**declining levels in hair follicles with age may explain grey hair, is the hair bleaching itself?
How does glutathione defend against free radicals? What enzyme is needed and what does that enzyme require?
It donates an electron from a cysteine in its structure and then forms a disulphide bond with another glutathione structure
[GSH + GSH = GSSG] and free radical gets its electron.
Reaction needs glutathione peroxidase and selenium is required
After glutathione has done its job it needs to be recycled back into its reduced form (GSH). How does this work?
Glutathione reductase uses a NADPH (from the pentose phosphate pathway) and produced 2x GSH from GSSG
What is the pentose phosphate pathway an important source of?
NADPH
Required for;
Reducing power for biosynthesis
Maintenance of GSH levels
Detoxification reactions
Name some free radical scavengers. How do they work?
Vitamins E
Vitamin C
Carotenoids
Uric acid
Flavonoids
Melatonin
Reduce free radical damage by donating hydrogen atoms to free radicals in non-enzymatic reactions
How do vitamin e and c work together to defend against free radicals?
Vit E- lipid soluble antioxidant - important for protection against lipid peroxidation (takes a lipid radical and turns it into a lipid again)
Vit C-water soluble antioxidant- important role in regenerating reduced form of vit E so it can continue its work.
What membrane bound enzyme complex produced the respiratory burst? How does it work?
NADPH oxidase
It transfers electrons from NADPH across the membrane to couple these to molecule oxygen to generate superoxide radicals
