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31 Cards in this Set
- Front
- Back
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Describe the major metabolic fuels and their sources in the normal adult.
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The major fuels are glucose and fatty acids.
glucose -> glycolysis -> acetyl coA -> TCA Fatty acids -> beta oxidation > acetyl coA > TCA. When glucose levels are low glycogen in liver and muscle-> glucose Triacylglerols in adipose tissue, better storage -> fatty acids. In severe conditions of starvation, fasting or type 1 untreated diabetes mellitus, when there is a low insulin/glucagon ratio and high concentration of fatty acids in the liver, released from adipocytes, then ketone bodies are formed. Glucogenic amino acids, pyruvate, fumarate, sucinate, alpha ketoglutarate, oxyloacetate can all be used in gluconeogenesis to produce glucose. |
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Describe how the blood glucose concentration is controlled and explain why this is necessary.
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Some tissues have an absolute requirement for glucose and can't metabolise other substrates, kidney medulla, lens of eye, RBCs and CNS prefers it. Also the rate of glucose uptake in these tissues is related the glucose blood concentration. Therefore the blood glucose concentration needs to be maintained at a within a particular range to prevent hyoglycaemia -cell death, through lack of energy to fuel activities and hyperglycaemia.
Glucose lower than 3mM -> hypoglycaemia - coma and eventual death. Glucose higher than 7nM > Hyperglycaemia - dammage to nerves, kidney, cardiovascular. When blood glucose is too high eg after a meal, insulin from the islets of langerhans in the pancreas is released into the blood and targets insulin receptors on cells to increase permeability to glucose and activates glucogen synthesis by stimulating dephosphorylation of glycogen synthase by phosphatases. Plasma Glucose concentration is lowered. When plasma glucose is too low the insulin/glucagon ratio is low and glucagon is released into blood targeting cell receptors on muscle cells and liver to undergo glycogenolysis. Glycogen stores only last 8-10hrs and after this glucose is synthesised by gluconeogenesis from glucogenic amino acids, pyruvate, fumarate, sucinare, alpha ketoglutarate, oxyloacetate. |
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Compare and contrast the effect of insulin and glucagon on nutrient storage and mobilisation.
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Insulin:
Increases permeability of cell membranes to glucose. Stimulates glycogenesis in liver and muscle by stimulating the dephosphorylation of glycogen synthase by phosphatase. Stimulates uptake of amino acids and protein synthesis in liver Stimulates lipogenesis and storage of TAGs in adipocytes Glucagon: Targets liver and muscle cells and stimulates glycgoenolysis by stimulating the phosphorylation of glycogen phosphorylase by kinase. lipolysis in adipocytes gluconeogenesis to provide glucose for glucose dependent tissues |
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Describe the metabolic responses to feeding and fasting and explain how they are controlled.
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Regular meals = regular cycle of metabolic changes.
Feeding - absorption of glucose, amino acids and lipids from the gut raises blood concentration, triggering insulin release from pancreas. 1. increases glucose uptake and utilisation by muscle and adipose tissue 2. promotes storage of glucose as glycogen in liver and muscle 3. promotes lipgenesis and storage of fatty acids as TAGs in adipose tissue 4. promotes amino acid uptake and protein synthesis in muscle and liver Fasting: As blood glucose decreases, insulin falls, reducing the uptake of glucose by adipose tissue and muscle and stimulating glucagon secretion - glycogenolysis in the liver and muscle - lipolysis in adipose tissue to provide fatty acids for use by tissues - gluconeogenesis to maintain supplies of glucose to the brain as well as glucose dependent tissues. If fasting proceeds beyond 10hrs all glycogen stores are used and changes associated with starvation begin. |
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Describe the metabolic responses to starvation and explain how they are controlled.
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Starvation begins after 10hrs of fasting when all the glycogen has been used up.
The break down of Glycogen maintains glucose at a steady level of 3.5mM.When they are used up, glucose levels decrease further stimulating the pituitary release ACTH ( adrenocorticotrophin hormone) which stimulates the release of cortisol frpm adrenal cortex ( zona fasciculata) which stimulates gluconeogenesis and the break down of TAGs in liver and proteins to produce glucogenic substrates available ( mainly alanine and glycerol). cortisol and glucagon increase the ammounts and activites of enzymes eg PEPCK and fructose,1,6 bisphosphatase in liver cells. Lipolysis occurs due to activation of hormone sensitvie lipase (by glucagon, adrenaline, cortisol, growth hormone, thyroxine.). Due to the low insulin/glucagon ratio and high concentration of mobilised fatty acids from TAGs in adipocytes, fatty acids becomes the main respiratory substrate, and reduces metabolism of glucose.Fatty acids are converted to ketone bodies which can used in all cells, including CNS as can cross the blood brain barrier. This reduces gluconeogenesis in the liver, preventing metabolism of proteins. The brain becomes more adapted to using ketone bodies as fuel and require less glucose and the kidneys contribute to gluconeogenesis. Urinary nitrogen excretion decreases dramatically so the 5 enzymes involved in the urea cycle decrease in number and activity in the liver. Thus reintoduction of protein into diet must be gradual to prevent inducing death by hyperammoniaemia. When all fat stores are depleted, protein becomes the major fuel and is rapidly used up resulting in death due to a number of reasons related to muscle mass loss eg loss of r espiratory muscle, death by serious infections. |
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Compare and contrast phase 1 and phase 2 of drug metabolism.
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Most drugs are foreign and potentially toxic to the body. Also they are mostly lipid soluble and so can’t be excreted directly by the kidneys – need to be water soluble. Therefore in order to deactivate and eliminate the drug, it is metabolised.
There are 2 phases of drug metabolism: Phase 1: - Most drug molecules are stable and unreactive so Oxidation, reduction and hydrolysis reactions are the most common to either expose or add a reactive group - These reactions require a complex enzyme system – cytochrome P450 (CYP) system. - Co factor – NADPH - the main site is the liver – RES in hepatocytes - contain all the enzymes - other sites include GI tract, kidney, lung, plasma Phase 2 - Some drugs already have a reactive group and so go straight to phase 2 - Conjugation of molecule with a polar group to make water soluble. - Methods of conjugation: - glucuronification ( most common) - require cofactor – UDPG – uridine diphosphate gluturonic acid - conjugate – gluturonic acid ( freely available by product of cell metabolism) - sulphate conjugation, gluthione conjucation - site – liver – cytosolic enzymes |
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Describe pharmacokinetics and pharmacodynamics ?
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Pharmacolgy is the study of drug action and can be devided into pharmacodynamics – what the drugs do to the body and Pharmacokinetics - what the body does to the drug ie the time course of drugs and their metabolites in the body.
ADME of the drug: Absorption, Distribution, Metabolism and Elimination. The pharcodynamics of a drug depends on its pharmacokinetics. |
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Discuss the importance of the cytochrome P450 system
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The main reactions in phase 1 are oxidation, reduction and hydrolysis and they require the complex enzyme system called cytochrome P450 (CYP) system to undergo the reactions or exposing or adding a reactive group.
Humans have 2 alleles for each gene and the population has many different alleles which create great genetic variation. The CYP system comprises of around 50 haem containing enzymes. The main enzyme is isoform CYP3 A4 which accounts for 55% of drug metabolism. Each individual has 2 alleles which code for each enzyme and so there is great variation of CYP systems between people. Some people may lack the gene which codes for an important enzyme in the system and so drug metabolism is affected/might not take place. |
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Explain variation in drug metabolism in the population
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Genetic factors: genes of small of effect: individual variation in CYP systems – each individual has 2 alleles for each gene and within the population there are many different alleles. Therefore drugs are metabolised at slightly different rates in each individual.
Genes of large effect: gene deletions coding for enzymes in hepatic drug acetylation in phase 2, plasma cholinesterases- drugs with ester bonds can’t be metabolised, hepatic deacytlation. Environment: size of patient, Taking multiple drugs – metabolism of one drug affects the metabolism of the other – enzyme inhibition and induction eg pesticides, alcohol, barbiturates, nicotine are enzyme inducers. First pass effect- large does required – drugs such as paracetomol (90%) are absorbed from the ileum pass through portal vein to liver, may be extensively metabolised on the first pass |
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Describe the metabolism of alcohol.
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90% of alcohol is metabolised in the liver. 10% in breath and urine.
Alcohol is oxidised to acetaldehyde by alcohol dehydrogenase and further oxidised to acetate by aldehyde dehydrogenase, using oxidising agents NAD+ -> NADH. Acetate is converted to acetyl CoA. Acetaldehyde is extremely toxic but is removed by acetaldehyde dehydrogenase (low Km for acetaldehyde) as soon as it is formed. |
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What happens when alcohol consumption is long and excessive?
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- acetaldehyde accumulates to cause hepatocyte damage
Damaged hepatocytes cannot perform their normal functions as well causing: hyperbilirubinaemia – cells can’t uptake bilirubin and conjugate it. May lead to jaundice. Hyperammoniaemia and high glutamine levels – reduction in ability to form urea Reduced protein synthesis – albumin – oedema, clotting factors – increased blood clotting time, lipoproteins – TAGs synthesised in liver can’t be transported away causing accumulation and fatty liver. - Decrease in NAD+/ NADH ratio: - less oxidising power for beta oxidation of fatty acids, conversion of lactate to pyruvate and for metabolism of glycerol lactate accumulates in blood and may cause lactate acidosis and reduce kidney’s ability to remove uric acid. Uric acid increases forming crystals of urate which accumulate in tissues causing painful gout. Glucogenesis isn’t activated due to low NAD+ levels and inability to use lactate and glycerol causing hypoglycaemia. Other problems include poor gut absorption of minerals and vitamins. |
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What treatment can be used for alcohol dependence
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Disulfiram inhibits aldehyde dehydrogenase converting acetaraldehyde to acetate. Therefore acetaraldehyde builds up in the blood causing symptoms of a hangover which can last a week.
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How paracetamol metabolised?
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Paracetamol is an antipyretic which at normal dosage is safely metabolised by phase 2 glucuronidation conjugation or sulphation conjugation, skipping phase 1 as already has reactive group. If a toxic dose is ingested these pathways quickly become saturated and paracetomol undergoes phase 1 metabolism producing a toxic metabolite, N-acetyl-p-benzo-quinone imine ( NAPQI). This metabolite is toxic to hepatocytes and undergoes phase 2 conjugation with glutathione, an antioxidant, thus reducing levels of antioxidants which protect against ROS. Liver cells are destroyed and liver failure occurs over several days. Treatment is N-acetyl cysteine.
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Describe why the blood glucose in man is usually held relatively constant and describe how this is acheived.
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Some tissues such as kidney medulla, lens of eye, RBCs and CNS are glucose dependant ( although CNS can metabolise ketone bodies as well). The rate of utilisation of glucose in these tissues is proportional to glucose concentration in the blood. Therefore blood glucose concentration must be kept within a set range 4-6mM. lower than 3mM will stop these cells being functionally active.Blood glucose Higher than 6mM is associated with abnormal glucose metabolism and glycosylation of proteins. Abnormal glucose metabolism involves aldose reductase in the eye converting glucose into sorbitol which causes glaucoma and depletes NADPH levels causing cataracts.
When glucose is high, insulin is secreted from pancreas and stimulates glucose uptake, utilisation and storage by cells. When glucose is low, insulin secretion is reduced and glucagon is secreted which inhibits glucose uptake in cells and mobilises glucose from glycogen stores and synthesis of glucose when stores are depleted. |
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Describe and account for the signs and symptoms of hypoglycaemia.
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Hypoglycaemia is a blood glucose concentration lower than 3mM.
The signs and symptoms are tiredness, trembling, sickness, sweating, slurred speech, staggered walking, ( may look intoxicated) All signs and symptoms are due to lack of glucose for normal functioning of CNS and hormonal response to stress eg adrenalin and noradrenalin |
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Outline the metabolic responses to starvation and describe how they are controlled.
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If fasting persists longer than 10hrs then all glycogen stores are depleted and changes associated with starvation occur.
Insulin levels continue to deplete and glucagon, growth hormone and cortisol levels increases. Muscle proteolysis increases to supply glucogenic amino acids for gluconeogenesis Gluconeogenesis increases to suply glucose dependant tissues with glucose Lipolysis increases to supply fatty acids for metabolism to other tissues and becomes the principal respiratory substrate. Ketone bodies synthesis increases due to very low insulin/glucagon ratio coupled with plenty of fatty acids in the liver. Ketone bodies can be used in CNS and other tissues -not glucose dependant. As ketone bodies synthesis increases, gluconeogenesis decreases but does not stop and eventually gluconeogenesis in the kidneys commences. |
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Compare and contrast the effects of insulin and glucagon on nutrient storage and mobilisation.
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Insulin stimulates nutrient storage and glucagon stimulates nutrient mobilisation.
Insulin affects the metabolism of glucose, fatty acids and amino acids. Glucagon affects the metabolism of glucose and fatty acids. Insulin stimulates uptake of glucose into liver and muscle cells ( glucagon has no affect) Insulin stimulates glycogenesis in liver and muscle ( glucagon inhibits) Insulin inhibits glycogenolysis in liver and muscle ( glucagon stimulates) Insulin stimulates lipogenesis in adipose tissue and liver ( glucagon has no effect) Insulin inhibits lipolysis in adipose tisse and liver ( glucagon stimulates) Insulin stimulates uptake of amino acids and protein synthesis ( glucagon has no affect) Insulin inhibits proteolysis in liver, muscle and adipose tissue ( glucagon has no affect) Insulin inhibits gluconeogenesis in the liver ( glucagon stimulates it) Insulin inhibits ketone body synthesis in the liver ( glucagon stimulates) |
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Explain briefly why the rate at which patients metabolise drugs can vary
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Variation in population may be due to genetic effects or environmental effects.
General genetic variation in the population ( genes of small effect) causes enzyme expression between individuals to vary slightly, changing rates of drug metabolism. Gene deletions ( genes of large effect) may result in a key enzyme of drug metabolism being absent, which significantly affects the metabolism of certain drugs. Some drugs or agents can inhibit enzymes in the cytochrome P450 system which signifcantly affect the metabolism of other drugs taken at the same time. Some drugs or agents are inducers such as alcohol, nicotine, pesticides which induce enzymes in the liver, increasing rate of metabolism of other drugs given at the same time. |
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Explan why patients with PKU require a source of tyrosine in diet.
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Tyrosine is usually not an essential amino acid as it can be synthesised in the body from the essential amino acid phenylalanine by phenylalanine dehydrogenase. However in PKU patients, this enzyme is defective and so tyrosine can't be made in the body.
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why do the signs and symptoms of homocystinuria initially resemble marfan syndrome.
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There are many shared signs and symptoms of marfan's syndrome and homocystinuria.
Both result in dammaged connective tissue which causes stature to be tall, thin and disproportionately long limbs as well as curved spine. Disloccation of one or both lenses is another common sign as well as near sightedness. They also are both associated with cariovascular problems. However mental retardation is seen in homcystinuria and not marfan's. A urine test for homocystine differentiates the 2. |
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Why is homocystinuria associated with increased risk of early onset cardiovascular disease? and how can homocystinuria be treated?
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The disease is prothrombotic - increases risk of thrombosis and proatherosclerotic - increases risk of atherosclerosis.
There is no cure for this autosomal recessive gene defect. It can be managed by diet, low homocysteine, lots of vitamin B6 ( co factor of CBS- cystathionine beta synthase. More vitamin B12 - more homocysteine is converted to methionine which is less harmful. |
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What is the normal daily enery intake requirement based on a 70kg male.
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12000kj/day.
More than this energy intake and the extra energy is stored as TAGs in adipose tissue. fat= 150kg, protein-100kg, carbohydrate-300kg. sufficient minerals, vitamins, fibres, Alcohol metabolism produces acetyl coa -> to TAGs. |
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What is BMR? What is it affected by.
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The energy required to maintain life ie the functioning of tissues of the body at emotional, physical and digestive rest.
It is affected by body weight, gender ( females have more adipose tissue that is less metabolicaly active than lean tissue), pregnancy/lactation, thyoid stauts and reproductive hormones, Temperature. |
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How are antipyretics thought to reduce core temperature.
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Antipyretics such as paracetamol inhibit the enzyme cyclo oxygenase (COX) which catalyses the production of prostaglandisn E2 (inflamatory mediators). Therefore prostaglands can't cause pyrexia by affecting the thermoregulatory centre of hypothalamus.
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Briefly explain how negative feedback is involved in thermoregulation.
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In Negative feedback the effector acts to oppose the stimulus.
If the stimulas is a rise in core temperature above 37.2, which is detected by thermoreceptors in the skin and hypothalamus, the input will be sent to the control centre, the thermoregulatory centre in the hypothalamus, via afferent nerves. The thermoregulatory centre will analyse output and decide output which is sent via efferent nerves to the effectors causing dilation of blood vessels in the skin & increased sweating which reduces the core temperature, opposing the original stimulus of increaed temperature. If the stimulus is a decrease in core temp - below 36.8. The effector produces constriction of blood vessels in skin, decreased sweating, increased metabolism, shivering which all increases temp. |
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Briefly explain how uncoupling proteins are involved in heat generation in the body.
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UCPs uncouple electron transport chain from ATP synthesis in the mitochondria, to produce heat instead of ATP.
UCPs create a leaky inner mitochondrial membrane, allowing H+ atoms to freely cross into the matrix, thus collapsingt the p.m.f. Without the p.mf, ATP synthesis doe not occur and the potential energy is dissipated as heat. UCP1 is found in brown adipose tissue and is involved in non-shivery thermogenesis, It is stimulated in the cold by noradrenalin which also mobilise fatty acids for beta oxidation. |
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Explain why catabolism is generally activated by low energy signals.
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Low energy signals such as ADP and NAD+ indicate that the cell has inadequate energy levels for immediate needs, so catabolism needs to occur to release energy from fuel molcules. Catabolic reactions such as glycogenolysis, glycolysis, pentose phosphate pathway, lipolysis.
ATP & NADP are high energy signals and indicate that the cells has more than enough energy levels for immediate needs so can be used in anabolic pathways for nutirent storage or bioynthetic component synthesis. |
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Why is a patient with heart disease particularlay prone to having muscle cramps during exercie.
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Muscle cramps are caused by lactate acidosis-build up lactate in blood.
This patient will have poor blood suply hence poor oxygen supply to tissues, hence increased anaerobic glycolysis takes place during exercise, especially in skeletal muscle, to produce lactate. The heart, due to low O2 levels, is less able to oxidise the lactate and may be undergoing anaerobic glycolysis itself. |
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Name some molecules that can cause metabolic acidosis and why?
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Ketone bodies. pyruvate, amino acids, fatty acids - all contain carboxlic acid groups.
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Outline the process and functions of oxidative phosphorylation.
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PROCESS:
- reduced coenzymes ( NADH/FAD2H) are reoxidised - electrons move along electron transport chain ending in oxygen-terminal electron acceptor, releasing energy - energy drives H+ transport across inner membrane - H+ gradient produced - proton motive force - H+ ions re-enter matrix via ATPase and pmf drives ATP synthesis - Electron transport chain and ATP synthesis are indirectly coupled Functions: - oxidise NAD+ -> NADH - synthesis ATP |
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How are inhibitors of a key enzyme in ETC different to uncouplers.
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Inhibitors such as cyanide prevent reoxidation of NADH and FAD2H, prevently the electron transport chain and so proton motive force isn;t gnerated. withoute pmf ATP synthesis can not occur and heat cannot be produced.
Uncouplers such as dinitrocresol, increase permeability of the inner membrane to H+ ions, collapsing the pmf and uncoupling electron transport chain from ATP synthesis. ATP cannot by synthesised but the potential energy from pmf is disipitated as heat. |
