Oxidative Stress Flashcards
Reactive oxygen species
ROS
O2 has two unaired electrons
+ e- = O2- superoxide
H2O2 - not a free radicle but can react with fe2+ to produce free radicle X
OH’ hydroxyl radical. - most damaging and reactive free radicle
Reactive nitrogen species
RNS
NO plus superoxide = peroxynitrate ONOO- is not a free radicle but is a powerful oxidant that can damage cells
ROS damage to DNA
can lead to cancer
ROS reacts with base leading to mispairing and mutation
ROS reacts with sugar causing strand break and mutation on repair
The amount if 8-oxo-dG present in the cells can be used as a measurement of oxidative damage
ROS damage to proteins
Backbone - fragmentation and degradation
Side chain - change in protein structure - loss or gain of a function
Disulphide bonds
Important in the folding and stability of some proteins
Formed between thiol groups of cysteine residues
- inappropriate disulphide bond formation can occur if ROS takes an electron from cysteines causing misfolding, crosslinking and disruption of function
ROS damage to lipids
Free radical extracts hydrogen atom from a polyunsaturated FA in membrane lipid
Lipid radical formed which can react with oxygen to form a lipid peroxyl radical
Chain reaction formed as lipid peroxyl radical extracts hydrogen from nearby FA
Hydrophobic environment of bilayer disrupted and membrane integrity fails
- associated with atherosclerosis
Sources of biological oxidants
ENDOGENOUS (within the cell) - ETC - Nitric oxide synthesis - NADPH oxidases EXOGENOUS (from the environment) - radiation - UV, X-Ray's - pollutants - drugs (e.g. anti-malarial)
The ETC as a source of ROS
Occasionally electrons can escape the ETC and react with dissolved O2 to form superoxide
There are mechanisms in place to deal with the superoxide immediately
Nitric oxide synthase
NOS
iNOS - inducible NOS - produces high NO concentrations in phagocytes for direct toxic effect
eNOS - endothelial NOS (signalling)
nNOS - neuronal NOS (signalling)
Respiratory Burst
Rapid release of superoxide and H2O2 from phagocytic cells
ROS and peroxynitrite destroy invading bacteria (destroying phagocytes too)
Part of the anti microbial defence system
- chronic granulomatous disease - causes enhanced susceptibility to bacterial infections
Free radicals
An atom or molecule that contains one or more unpaired electron and is capable of independent existence
- are usually very reactive and tend to acquire electrons from other atoms, molecules or ions (tends to generate another free radical thereby propagating damage)
Cellular defences
Superoxide dismutase and catalase
Superoxide dismutase (for electrons that escaped the ETC)
- converts superoxide to H2O2 and oxygen
Catalase
- converts H2O2 to water and oxygen
- important in immune cells to protect against oxidative burst
- declining levels in hair follicles with age may explain grey hair
Cellular defences
Glutathione
Tripepride synthesised by body to protect against oxidative damage
Thiol group of Cys donates an electron to ROS then reacts with another GSH to form disulphide bonds GSSH
Glutathione peroxidase requires selenium
GSSH reduced back to GSH by glutathione reductase catalyses ten transfer of electrons from NADPH
NADPH from the pentose phosphate pathway is essential for protection against free radical damage
Cellular defences
Free radical scavengers
Vitamin E - lipid soluble antioxidant
- important for protection against lipid peroxidation
Vitamin C - water soluble antioxidant
- important in regenerating reduced form of vitamin e
NONENZYMATIC REACTIONS
Galactosaemia
Increased activity of aldose reductase consumes excess NADPH - compromised defences agains ROS damage - crystallin protein lens of eye denatured - cataracts
