Oxidative Stress Flashcards
What is a free radical?
An atom or molecule that contained one or more unpaired electrons and is capable of independent existence
True or False:
Reaction of a radical with a molecule usually just affects that molecule only.
False
Reaction of a radical with a molecule typically generates a second radical thereby propgating damage - sets off a chain reaction
What are some common reactive oxygen species?
Superoxide, hydrogen peroxide, hydroxyl radical
What are some common reactive nitrogen species?
Nitric oxide, peroxygnitrite
What is produced when superoxide reacts with nitric oxide?
Peroxygnitrite (ONOO-)
How is superoxide produced?
By adding an electron to molecular oxygen
Why is hydrogen peroxide dangerous if it is not itself a free radical?
It can react eg with Fe2+ to produce free radicals and is readily diffusible
What is the most reactive and damaging free radical?
Hydroxyl radical
What are the two main types of damage to DNA caused by ROS?
1) ROS reacts with base, leading to mispairing and mutation
2) ROS reacts with sugar, causing strand break and mutation on repair
What can be used as measurement of oxidative damage?
Amount of 8-oxo-dG present in cells
How can ROS damage proteins?
1) Modification of side chains, eg introduction of disulphide bonds
2) Reacting with backbone - fragmentation of protein leading to protein degradation
How can the modification of amino acid side chains by ROS cause damage?
Cause change in protein structure leading to loss/gain of function
What is the role of disulphide bonds?
Folding and stability of some proteins
What are disulphide bonds formed between?
Thiol groups of cysteine residues
How can inappropriate disulphide bond formation occur as a result of ROS damage?
If ROS takes electrons from cysteines causing misfoldng, crosslinking and disruption of function
How can ROS cause damage to lipids?
Free radical extracts H from a polyunsaturated fatty acid in membrane lipid,
Lipid radical forms which can react with oxygen to form a lipid peroxyl radical,
Chain reaction formed as lipid peroxyl radical extracts hydrogen from nearby fatty acid,
Hydrophobic environment of bilayer disrupted and membrane integrity fails
What are some endogenous sources of biological oxidants?
Electron transport chain, nitric oxide synthases, NADPH oxidases, peroxidases, lipooxygenases
What are some exogenous sources of biological oxidants?
Radiation (cosmic, UV light, X-rays), pollutants, drugs (eg primaquine - an anti-malarial), toxins (paraquat - herbicide)
How can the electron transport chain sometimes produce free radicals?
Occasionally electrons can accidentally escape chain and react with dissolved oxygen to form superoxide
What does nitric oxide usually do?
Signalling molecule
Activates guanylyl cyclase which produce cGMP which activates protein kinase G
What are the 3 types of nitric oxide synthase?
Inducible nitric oxide synthase
Endothelial nitric oxide synthase
Neuronal nitric oxide synthase
What is respiratory burst?
Rapid release of superoxide and hydrogen peroxide from phagocytic cells (eg neutrophils) - part of antimicrobial defence system
What is chronic granulomatous disease?
Genetic defect in NADPH oxidase complex causing enhanced susceptibility to bacterial infections
What does speroxide dismutase do?
Converts superoxide to hydrogen peroxide and oxygen
What does catalase do?
Converts hydrogen peroxide into water
What is glutathione?
Tripeptide syntehsised by body to protect against oxidative damage
How does glutathione protect against oxidative damage?
Thiol group of Cysteine donates e- to ROS. GSH (reduced form) then reacts with another GSH to form disulphide (GSSG)
What does glutathione peroxidase require as a cofactor?
Selenium
What enzyme reduces GSSG back to GSH?
Glutathione reductase - catalyses the transfer of electrons from NADPH to disulphide bond
True or False:
NADPH from pentose phosphate pathway is not essential for protection against free radical damage
False!
It is essential for regeneration of GSH
What are the free radical scavengers?
Vitamin E and Vitamin C
also carotenoids, flavonoids, uric acid, melatonin
Is vitamin E lipid soluble or water soluble?
Lipid soluble so important for protection against lipid peroxidation
Is vitamin C lipid soluble or water soluble?
Water soluble so important in regenerating reduced form of vitamin E
How do free radical scavengers reduce free radical damage?
By donating hydrogen atom (and its electron) to free radicals in a nonenzymatic reaction
What is galactosaemia?
High levels of galactose in blood
What 3 enzymes are involved in metabolism of galactose?
Galactokinase, uridyl transferase and UDP galactose epimerase (deficiency in any of these leads to galactosaemia)
What causes cataracts?
1) Build up of galacitol
2) Increased activity of aldose reductase consumes excess NADPH, compromised defences against ROS damage, crystallin protein in lens of the eye is denatured
What is the antidote to paracetamol overdose and how does it work?
Acetylcysteine - works by replenishing glutathione levels
What toxic metabolite accumulates with high levels of paracetamol?
NAPQI
What are Heinz bodies?
Inclusions within red blood cells composed of denatured hemoglobin.
Which fat soluble vitamin plays an important role in protecting cells against oxidative damage by acting as a free radical scavenger?
Vitamin E plays an important role in protecting cells against lipid peroxidation. Vitamin C (Ascorbic acid) is a water soluble antioxidant that plays an important role in regenerating the reduced form of Vitamin E.
