Oxidative Stress Flashcards
Describe some diseases caused by oxidative stress
- multiple sclerosis
- cardiovascular disease
- alzheimer’s disease
- rheumatoid arthritis
- crown’s disease
- COPD
- ischaemia
- cancer
- pancreatitis
- parkinson’s disease
List some sources of biological oxidants
Endogenous:
- electron transport chain
- peroxidases
- nitric oxide synthases
- lipooxygenases
- NADPH oxidases
- xanthine oxidase
- monoamine oxidase
Exogenous:
radiation
pollutants
drugs
toxins
Describe some reactive nitrogen species
- Nitric Oxide
- Nitric Oxide + Superoxide = Peroxynitrite (ONOO-)
- Peroxynitrite is not a free radical, but a strong oxidising agent
Describe some reactive oxygen species
- Superoxide
- Hydrogen Peroxide (not a free radical, but reacts to form free radicals e.g by reacting with Fe2+. Readily diffusable)
- Hydroxyl radical (most damaging radical)
How do ROS interact with DNA?
- ROS reacts with base leading to mispairing and mutation (can lead to cancer)
- ROS reacts with sugar (ribose or deoxyribose) causing strand to break or mutation on repair
- Levels of 8-oxo-2-deguanosine is a marker of oxidative stress in cells
How do ROS interact with proteins
ROS can react with sidechain leading to a modified amino acid:
carbonyls hydroxylated adducts ring opened species dimers (e.g. di-tyrosine) disulphide bond (cys)
Ultimately protein structure is changed, leading to possible loss or gain of function
ROS can also react with backbone:
this leads to fragmentation and protein degradation
Describe the action of free radicals
- The electrons of atoms, molecules and ions usually associate in pairs, which move in orbitals.
- A free radical contains one or more unpaired electrons and is capable of independent existence
- Free radicals are usually highly reactive and tend to acquire electrons from other atoms, molecules or ions
- Reactions of radicals with radicals typically generates a second radical
How can ROS affect disulphide bonds?
- Disulphide bonds play important role in folding and stability of some proteins (usually secreted proteins or in extracellular domains of membrane proteins)
- Formed between thiol groups of cysteine residues
- Inappropriate disulphide bond formation can occur if ROS takes electrons from cysteine causing misfolding, cross linking and disruption of function
How can ROS affect lipid membranes?
- Free radical extracts hydrogen atom from a polyunsaturated fatty acid 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 fatty acids
- Hydrophobic environment of bilayer disrupted and membrane integrity falls
How is the electron transport chain a source of ROS?
- NADH and FADH2 supply electrons (e-) from metabolic substrates
- e- pass through ETC and reduce oxygen to form H20 at Complex IV
- occasionally electrons can escape chain and react with dissolved oxygen to form superoxide
Describe the action of nitrogen oxide synthase
- Converts arginine to citrulline. NADPH oxidised in process.
- Nitric Oxide is toxic at high concentrations, however it is a signalling molecule. It is involved in vasodilation, neurotransmission and S-Nitrosylation
iNOS: phagocytosis (toxic effects)
eNOS: (signalling)
nNOS: (signalling)
Describe the process of respiratory burst
- Rapid release of superoxide and H202 from phagocytic cells
- ROS and peroxynitrite destroy invading bacteria
- Part of antimicrobial defence system
- NADPH provides reducing power to form superoxide
Outline the pathophysiology of Chronic Granulamatous Disease
Genetic defect in NADPH oxidase complex causes enhanced susceptibilty to bacterial infections:
- Atypical infections
- Pneumonia
- Abscesses
- Impetigo
- Cellulitis
Describe the action of Superoxide Dismutase
- Converts superoxide to H2O2 and oxygen
- Primary defence as superoxide is a strong initiator of chain reactions
- 3 isoenzymes: Cu+, Zn2+ (cytosolic or extracellular), Mn2+ in Mitochondria
Describe the action of catalase
- Converts hydrogen peroxide to water and oxygen
- widespread enzyme, important in immune cells to protect against oxidative burst.
- secondary defence
