Oxygen friend or foe Flashcards
Name of bonds in ATP
Phosphoanhydride
What is BMR?
Rate of energy expenditure per unit time by endothermic animals at rest
Liver function in BMR
Maintains blood glucose levels
Examples of redox reactions
Photosynthesis, respiration, combustion, corrosion, rusting
What does GLUT do?
Help body use glucose for energy
Two forms of GLUT1
One is glucose-binding site facing outside of membrane
One is inwards
What are FAD and NAD derived from?
B vitamins
NAD+ + 2e- + 2H+
NADH and H+
FAD + 2e- + 2H+
FADH2
How is glucose made into glycogen?
Converted to glucose-6-phosphate in cytoplasm
Glycogenesis
Conversion of glucose-6-phosphate to glycogen
Glycogenolysis
Breaking down glycogen into glucose
What is citrate used for?
Forming fatty acids
What is lactic acid fermentation
Pyruvate converted to lactate using lactate dehydrogenase
Process of glycolysis
- Phosphate form hydrolysis of ATP is added to glucose to form glucose-6-phosphate
- Glucose-6-phosphate is rearranged into fructose-6-phosphate
- Second phosphate from ATP hydrolysis is added to fructose-6-phosphate to form fructose-1,6-biphosphate
- Fructose-1,6-biphosphate split into two molecules of glyceraldehyde-3-phosphate (3C)
- Oxidation and phosphorylation of each glyceraldehyde-3-phosphate produces 1,3-biphosphoglycerate with high energy phosphate bond and NADH
- Phosphorylation means phosphate removed from 1,3-biphosphoglycerate and transferred to ADP, forming ATP and 3-phosphoglycerate
- Each 3-phosphoglycerate is oxidised to form molecule of phosphoenolpyruvate with high energy phosphate bond
- Through phosphorylation, phosphate is removed and transfered to ADP forming ATP and pyruvate
Where does glycolysis take place
Cytoplasm
Link reaction
- Pyruvate moves into mitochondria
- It is oxidises and converted to acteyl CoA
- Electrons transferred to NAD+, making NADH and carbon dioxide
Kreb’s cycle
- Mitochondrial matrix
- Glucose broken down by acetyl-CoA to form CO2
- Acetyl CoA binds to starting compounds
- Redox reactions mean all carbons, hydrogens and oxygens in pyruvate end up as CO2 and H2O
- 8 NADH, 2 FADH2, 2 ATP and 6 CO2 are produced for each glucose molecule
- NADH and FADH2 carry electrons to electron transport system for further production of ATP by oxidative phosphorylation
Electron transport chain
- Electrons passed from one component to the next
- Electrons reduce oxygen to produce water
- A complex is a structure of a central atom/molecule/protein weakly connected to surrounding atoms/molecules/proteins
- Electrons from NADH and FADH2 are passed along chain
- They lose energy which is used to pump H+ from mitochondrial matrix to intermembrane space
- In 4th complex, electrons are accepted by oxygen (final acceptor)
- Forms water
Chemiosmosis
- This is the movement of ions across a partially permeable membrane down their electrochemical gradient
- Electron carriers like NADH and FADH donate electrons to electron transport chain
- Cause conformational changes in shapes of proteins to pump H+ across partially permeable membrane
- Uneven distribution of H+ establishes concentration and electrical gradients
- If membrane was open to diffusion of H+, they would move back into matrix via electrochemical gradient
- Chemiosmosis generated 90% of ATP in aerobic glucose catabolism - oxidative phosphorylation
How many ATP made from one glucose molecule?
32
Can NADH enter mitochondria?
No
Why will less ATP be produced when FAD is carrier?
It can transport fewer ions
Where do NAD+ and FAD+ each primarily function?
NAD+ in liver, FAD+ in brain
Why might less ATP be made?
FAD+ acts as carrier
Intermediates can be used to make lipids
What causes haemolytic anaemia?
Deficiency in hexokinase type I
What does hexokinase type ii do?
Glucose sensor in tissues - defect causes type ii diabetes
What is glucokinase?
Glucose sensor and low activity and low stability mutants explain MODY
What is Tarui’s disease?
Different amino acid substitutions of muscle phosphofructokinase cause exertion myopathy and haemolytic syndrome
What is phosphofructokinase?
Tetrameric enzyme that has 3 sub-units - PFKL (liver), PFKM (muscle) and PKFP (platelet)
Why is it bad when phosphofructokinase mutates?
Impairs ability to phosphorylate fructose-6-phosphate
Prevents formation of ATP - muscle cramping and pain
Fumarase deficiency
- Fumarase deficiency is autosomal recessive metabolic disorder in Kreb’s cycle characterised by deficiency of fumarate hydratase
- Fumarase deficiency affects nervous system, especially brain - infants may have microcephaly, abnormal brain structure, severe developmental delay, weak muscle tone, failure to gain weight and grow at expected rate
- Some have unusual features - prominent forehead, low-set ears, small jaw, widely spaced eyes, depressed nasal bridhe
- Enlarged liver and spleen, excess RBCs, deficiency of WBCs in infancy
- Affected individuals only survive a few months
Mitochondrial disease
Dysfunction of oxidative phosphorylation
Huntington’s disease
- Chorea, psychiatric disturbances, dementia, loss of long neurones in cortex and striatum
- Autosomal dominant manner and is due to expansion of CAG trinucleotide repeat in huntingtin (HTT) gene = expanded polyglutamine stretch in corresponding protein
- NMR shows increased lactate in cortex and basal ganglia
- Decreased complexes ii and iii of ETC in human brain
Oxygen cascade
- O2 and CO2 are independent
- When blood leaves through pulmonary veins, pO2 = 100mmHg and PCO2 = 40 mmHg
- As blood enters systemic capillaries, blood loses oxygen and gain CO2 due to pressure difference
- In systemic capillaries, PO2 = 100mmHg and in tissues PO2 = 40 mmHg, this drives diffusion of oxygen from capillaries to cells and CO2 into capillaries
- Oxygen delivered to alveoli and then across the membrane into the blood
- Oxygen moves down pressure gradient
Hypoxia
Deficiency in oxygen reaching tissues
Hypoxemia
Inadequate amount of oxygen travelling in blood
Cyanosis
Blue/purple skin because low oxygen concentration
Anaemic
Lungs working perfectly but O2 carrying capacity of blood is reduced
Hypoxic hypoxia
Low PaO2 , inadequate Hb saturation - pulmonary diseases
Circulatory hypoxia
Decreased O2 delivery to tissues - cardiac failure, hypotension, shock
Histotoxic hypoxia
Inability to use oxygen but normal delivery - cyanide poisoning
Cellular effects of hypoxia
- Body goes into anaerobic respiration
- Oxygen tension in cell decreases
- Loss of oxidative phosphorylation and ATP production
- Less ATP means Na+ pumps fail = loss of K+, influx of Na+ and water = cell swelling
- Loss of glycogen and protein syntheesis
- More fluid distends cell and organelles are spaces out
- Fluid in ER so regions of it burst and become encapsulated in vacuoles containing chunks of ER = vacuole degeneration
What is a free radical?
Species capable of independent existence that contains 1+ unpaired electrons
Normally unstable and reactive
Reactive oxygen species
Includes oxygen radicals and non-radicals that are oxidising agents and/or are easily converted into radicals
What can ROS lead to?
Cancer, inflammatory diseases, lupus, Parkinson’s and ageing
Too much ROS
Oxidative stress
Too low ROS
Reductive stress = cancer and cardiomyopathy
What is oxidative stress?
Disturbance in pro-oxidant -antioxidant balance in favour of former
Superoxide
Anionic oxygen
Product of one-electron reduction of dioxygen - occurs in nature
One unpaired electron means it is a free radicals;
Biologically toxic and cytotoxic
What id H2O2?
ROS produced in respiratory burst
Bactericidal at high concentrations but can pass through cell membranes easily
Haber-Weiss reaction
Occurs between superoxide and H2O2 to produce
Fenton reaction
Reaction between H2O2 and transition metals produces hydroxyl radicals
Iron used in redox
In oxidative stress, iron homeostasis disrupted, releasing labile iron which can enter Fenton reaction = more hydroxyl
Singlet oxygen
Two high energy, excited states of oxygen
Produced when photo-sensitisers absorb appropriate wavelength of radiation in presence of oxygen
How are mitochondrial ROS produced?
ETC on inner membrane of mitochondria in oxidative phosphorylation
Electron leakage at complex I and iii = partial reduction of oxygen to form superoxide
Superoxide dismutated to H2O2 in mitochondrial matrix and inter-membrane space
Superoxide and H2O2 generated in this process are mROS
Contributors to oxidative stress
Air pollutants, tobacco smoke, radiation, food, drugs
How do ROS lead to DNA lesion?
Modification of nucleotides, apurinic sites, single strand and sometimes double strand can break
Why is guanine most susceptible to damage?
Lower reduction potential and hydroxyl radicals react with imidazole ring at positions C4/5/8
What is produced when guanosine oxidised by HO?
8-hydroxydeoxyguanosine
How are lipid peroxides formed?
Free radicals;s + lipids
Also forms aldehydes
What happens when cysteine is oxidised?
Cysteine can suffer irreversible oxidation, forming S-carboxymethylcysteine - formation of fumarate and dicarbonyl groups covalently bound to cysteine residues
What is lipofuscin used for?
Resistant to proteolysis so used as age marker
What is cancer?
Unchecked cell division caused by breakdown of mechanisms that regulate cell cycle
Change in DNA sequence that codes for regulatory molecules
porto-oncogenes
When mutated, they form Onco-genes which cause cancer
What are tumour suppressor genes?
Code for negative regulator proteins
Why is p53 bad?
Mutant is found in over half of tumour cells
Faulty p53 can’t detect errors in DNA
What do CAT and GPx do?
Prevent hydrogen peroxide accumulation
What is SOD1?
Cu,Zn
Found in mitochondria and cytoplasm
Where is SOD2 found?
Mitochondrial matrix
Where is SOD3 found?
Extracellular
Cu, ZN
What do SODs do?
Dismutate superoxide to H2O2 which is metabolised to water and oxygen by catalase and glutathione peroxidase
What does catalase do?
Catalyses decomposition of H2O2 to water and oxygen
What does glutathione peroxidase do?
Reduces lipid hydroperoxides to alcohols and reduce free hydrogen peroxide to water
What is respiratory burst?
Rapid release of reactive oxygen species from different cell types
Release of chemicals from immune cells as they come into contact with bacteria or fungi
Occurs in phagocytes to degrade internalised particles and bacteria
What do immune cells use NADPH oxidase for?
Reduce O2 to oxygen free radicals and then H2O2
What is myeloperoxidase used for?
Combine H2O2 with Cl- to produce hypochlorite, which destroys bacteria
What is hyperbaric oxygen\?
Exposing patient to oxygen with pp greater than one atm
Oxygen inhaled, dissolved in plasma and transported around body
High PP of oxygen in capillaries leads to larger gradient for oxygen from blood to tissues
HBO therapy reaches damaged tissues and body supports its own healing process
Photodynamic therapy
Three main components - photosensitiser, tissue oxygen and light (destruction of cells by ROS)
Applications of photodynamic therapy
- Lung cancers
- Non-melanoma skin cancers
- Bladder cancers
- Gynaecological cancers
- Brain tumours
- Acne
- Age related macular degeneration
- Warts
- Exposure of microbial cultures in presence of dyes and light results in cell death
What does aminolaevuliniv acid used for?
Pro-drug that is converted into protoporphyrin IX by enzymes of haemolytic biosynthesis pathway
ALA converted to photo-sensitiser PPIX within cells
What does ALA-PDT do?
Accumulates in malignant cells for light irradiation - makes treatment specific to bad cells and minimises damage to healthy cells because they absorb PPIX more slowly
