Metabolism Flashcards
State the products of pyruvate metabolism by: i. pyruvate dehydrogenase ii. lactate dehydrogenase
acetyl CoA lactate (lactic acid)
Explain why epigenetics is different to genetic mutation.
Genetic mutation involves changes in the nucleotide sequence (changes in the DNA sequence), whereas epigenetics involves methylation of DNA and changes in histone structure that affect gene transcription.
Define the term Basal Metabolic Rate (BMR) and list factors that may affect it.
BMR is the energy required to maintain life i.e. - for the functioning of the various tissues of the body at physical, digestive and emotional rest. (1 mark) Body weight Body temperature Gender Thyroid status
Briefly explain how uncoupling proteins (UCPs) are involved in heat generation in the body.
UCPs allow a leak of protons across the membrane (1 mark), reducing the p.m.f, and the energy is dissipated as heat rather than ATP production. (1 mark) UCP1 is expressed in brown adipose tissue and is involved in thermogenesis. (1 mark)
Briefly explain how the metabolism of alcohol can cause damage to the liver.
•The intermediate metabolite of alcohol metabolism, acetaldehyde, is toxic to liver cells. •The increased availability of acetyl-CoA affects liver metabolism. The conversion of alcohol to acetaldehyde by alcohol dehydrogenase also produces NADH. •The decreased NAD+/NADH ratio favours the formation of triacylglycerols which accumulate in the liver cells, leading to ‘fatty liver’, dyslipidaemia, insulin resistance
Fluoroacetate is a plant toxin that is used as a pesticide. It inhibits aconitase of the TCA cycle. What effect will fluoroacetate have on aerobic metabolism?
Aerobic metabolism will be inhibited, so decreasing ATP production. Anaerobic metabolism will increase and cause lactic acidosis.
List the most common reactions involved in phase I of drug metabolism
Oxidation, reduction, hydrolysis. Other reactions do occur, but these are the most common. The purpose of phase 1 is to add or expose a reactive group on the drug molecule.
List agents in cells which protect against reactive oxygen species.
Three of: Superoxide dismutase Catalase Glutathione NADPH Antioxidant vitamins (e.g. C and E) Other antioxidants in the diet (e.g. polyphenols)
What type of epithelium lines the gut?
Simple columnar
Describe the key features of electron transport and explain how the proton motive force (p.m.f) is produced.
In Electron transport electrons are transferred from NADH (and FAD2H) sequentially through a series of multi-component complexes to molecular oxygen with the release of free energy. The free energy is used to move protons from the inside to the outside of the inner mitochondrial membrane. The membrane itself is impermeable to protons and as electron transport proceeds the proton concentration on the outside of the inner membrane increases. The chemical bond energy of the electrons is transformed into an electro-chemical potential difference of protons. This is known as the proton motive force (p.m.f).
Explain why cortisol, a glucocorticoid, can have mineralocorticoid and androgen-like effects when present in high concentrations.
The actions of cortisol on target tissues are mediated by binding to receptors in the cytoplasm/nucleus. All steroid hormone receptors have similar basic structure with hormone and DNA binding domains. The hormone binding domains of the mineralocorticoid and androgen receptors have over 60% sequence homology with the hormone-binding domain of the glucocorticoid receptor. Thus, cortisol can bind to these receptors to a limited extent causing their partial activation.
Explain why individuals with a defect in the enzyme lecithin-cholesterol acyltransferase produce unstable lipoproteins of abnormal structure. What are the clinical consequences of this defect?
•Lipoproteins particles are only stable if they maintain their spherical shape and this is dependent on the ratio of core to surface lipids. As the lipid from the hydrophobic core is removed and taken up by tissues the lipoprotein particles become unstable as the ratio of surface to core lipids increases. Stability can be restored if some of the surface lipid is converted to core lipid. This is achieved by the enzyme LCAT which is important both in the formation of lipoprotein particles and in maintaining their structure. The enzyme converts cholesterol (a surface lipid) to cholesterol ester (a core lipid) using fatty acid derived from lecithin (phosphatidylcholine). •Deficiency of the enzyme results in unstable lipoproteins of abnormal structure and a general failure in the lipid transport processes. Lipid deposits occur in many tissues and atherosclerosis is a serious problem.
What is hyperlipoproteinaemia?
Any condition in which, after a 12 hour fast, the plasma cholesterol and/or plasma triglyceride is raised.
Explain why insulin & C-peptide are secreted from the beta-cell in equimolar amounts.
Insulin is synthesised as the precursor molecular proinsulin. This molecule contains the A and B chains of insulin joined together by a connecting peptide. The conversion of proinsulin to insulin occurs in the storage vesicles and involves proteolysis. The products are insulin, C-peptide and 4 basic amino acids produced in equimolar amounts. Since these are produced in the storage vesicles they are secreted together during exocytosis.
What role does calcitonin have in the regulation of serum calcium levels?
•Sometimes called the third hormone and is thought to lower serum calcium levels in other mammals. •It does not seem to have much of a role in humans. Higher levels in pregnancy may protect bone from excessive resorption. •The role of calcitonin is controversial in humans.
What is gluconeogenesis and why is it necessary? Name the hormones that stimulate the process and those that inhibit it.
Gluconeogenesis is the production of glucose from precursors such as lactate, pyruvate, glycerol and certain amino acids. It is necessary to provide glucose for glucose-dependent tissues such as the CNS and red blood cells during starvation when the liver stores of glycogen have been exhausted. Insulin inhibits gluconeogenesis Cortisol and glucagon stimulate gluconeogenesis
Describe how cortisol is transported in the blood and how it affects its target tissues.
Cortisol, like all steroids, is lipophilic (hydrophobic) and must be transported bound to plasma proteins. The major transport protein is transcortin and this carries ~90% of the plasma cortisol the remaining ~10% being free and biologically active. Cortisol can cross the plasma membranes of target cells and bind to cytoplasmic receptors. The hormone/receptor complex then enters the nucleus to interact with specific regions of DNA. This interaction changes the rate of transcription of specific genes and may take time to occur.
Primary coenzyme Q is an autosomal recessive genetic condition that affects CoQ synthesis. What are the functional consequences of this deficiency?
Primary CoQ deficiency will prevent electron transfer from complexes I and II, decreasing ATP production. This will result in muscle weakness and exercise intolerance.
Describe the role of the hypothalamus in the control of pituitary function.
The hypothalamus releases a number of substances that act on the anterior pituitary cells, and are known as Releasing or Inhibiting Hormones depending on whether they stimulate or inhibit the release of pituitary hormones. Releasing and Inhibiting hormones travel to the pituitary gland via specialised blood vessels known as the hypophyseal portal vessels. Releasing and inhibiting hormones allows the brain to control pituitary hormone secretion, and explains, for example how the secretion of hormones can change during stress. Examples of releasing or inhibiting hormones include: •Thyrotrophin Releasing Hormone (TRH) - stimulates TSH release •Corticotrophin Releasing Hormone (CRH) -stimulates ACTH release •Somatotrophin Releasing Hormone (SRH) - stimulates GH release •Somatostatin - inhibits GH release
Under anaerobic conditions, the pyruvate produced by glycolysis in skeletal muscle may be reduced to lactate. What advantage is this to the muscle cells?
•There is a fixed amount of NAD+ + NADH in the cell. •The reactions of glycolysis require the presence of NAD+ which is converted to NADH. If all of the NAD+ is converted to NADH glycolysis would stop because of lack of NAD+. •This does not normally occur because, in the presence of oxygen, NADH is converted back to NAD+ by electron transport in the mitochondria. However, in the absence of oxygen (anaerobic conditions) or mitochondria (red blood cell) electron transport cannot occur. •Under these conditions pyruvate is converted to lactate via the enzyme lactic dehydrogenase (LDH) using NADH which is oxidised to NAD+ (2 marks): CH3COCOOH + NADH + H+ ↔ CH3CHOHCOOH + NAD+ •This enables glycolysis to continue so that it can provide the cell with ATP via substrate level phosphorylation.
Briefly explain why the rate at which patients metabolise drugs can vary.
Variation in drug metabolism is due to genetic effects and environmental effects. General genetic variation in the population (polymorphisms) means that enzyme expression varies slightly and thus the rate of drug metabolism varies. Some people may have gene deletions and lack a key enzyme involved in drug metabolism, which can affect metabolism of certain drugs significantly. Some drugs or agents can inhibit enzymes in the cytochrome P450 system, which can affect the metabolism of other drugs given at the same time. Some drugs are well known to cause induction of enzymes in the liver, which increases the rate of metabolism of other drugs given at the same time.
Briefly explain how an oxidative burst is produced by some leukocytes.
Some cells of the immune system, such as neutrophils and monocytes, when stimulated can rapidly produce a release of ROS which is known as an oxidative burst. The oxidative burst is produced by a membrane-bound enzyme complex termed NADPH oxidase. This enzyme is present in the cell membrane and it transfers electrons from NADPH across the membrane to couple these to molecular oxygen to generate superoxide radicals.
Describe the relationship between electron transport and ATP synthesis. Explain how this relationship is altered during thermogenesis in brown adipose tissue mitochondria.
The chemical bond energy of the e- in NADH and FAD2H is used to drive ATP synthesis in the final stage of catabolism (oxidative phosphorylation). This occurs in mitochondria and involves highly organised multi-component systems. Two processes are involved electron transport and ATP synthesis. The p.m.f. created by electron transport, forces protons back into the mitochondrial matrix through an ATP synthase complex driving the synthesis of ATP from ADP and Pi. Normally ET and ATP synthesis are tightly coupled and controlled such that one does not occur without the other. The inner mitochondrial membrane of brown adipose tissue has, in addition to the ATP synthase complex, a special proton conductance protein (thermogenin) that allows the controlled re-entry of protons into the mitochondrial matrix without driving ATP synthesis i.e. it acts to uncouple ATP synthesis from ET. This protein is used to activate heat production (non-shivering thermogenesis) in cold environments. In response to cold, norepinephrine is released from the sympathetic nervous system and stimulates lipolysis releasing fatty acids to provide fuel for oxidation in brown adipose tissue. As a result of b-oxidation of the fatty acids NADH and FAD2H are formed, driving ET and increasing the p.m.f. However, norepinephrine also activates thermogenin allowing the protons to re-enter the mitochondrial matrix without driving ATP synthesis. This dissipates the p.m.f as heat (Marks p320 and Fig. 20.13).
What three synthetic pathways do muscles use to generate ATP during exercise, and what are their effective time courses?
ATP synthetic pathways: Creatine phosphate Lactic acid system Oxidative phosphorylation
Define lactic acidosis and explain why it may occur.
Lactic acidosis is an elevation of plasma lactate that affects the buffering capacity of the plasma i.e. there is a fall in plasma pH due to the accumulation of lactic acid. Situations in which there may be a marked increase in plasma lactate due to increased production include strenuous exercise (up to 10g/min), hearty eating, shock and congestive heart disease. Increases due to decreased utilisation occur in liver disease, thiamine deficiency and during alcohol metabolism.
What would be the expected signs and symptoms in a patient with a deficiency in the ability to store or utilise glycogen?
Deficiency in the ability to store or use glycogen in the liver would result in fasting hypoglycaemia. Deficiency in muscle would result in muscle weakness (exercise intolerance).
How and where is vitamin D formed/ absorbed?
Formed in the skin via UV light or absorbed in the gut from the diet
Compare and contrast the functions of liver and skeletal muscle glycogen.
Glycogen is a storage form of glucose. However, there is no specialised glycogen storage tissue and it has to be stored in tissues that have other important functions. The liver can store up to ~100g glycogen, while skeletal muscle can store up to ~300g glycogen. Glycogen is degraded to glucose 1-phosphate in skeletal muscle in response to exercise and in the liver in response to fasting or as part of the stress response (“fright, fight or flight response”). In both tissues glucose 1-phosphate is converted to glucose 6-phosphate. In muscle, the glucose 6-phosphate enters glycolysis and is used to provide energy for the exercising muscle. Thus, muscle glycogen represents a store of glucose 6-phosphate that can only be used by the muscle cells. In liver during fasting or during stress the glucose 6-phosphate is converted to glucose by the enzyme glucose 6-phosphatase (this enzyme is absent from muscle): glucose 6-phosphate + H2O glucose + Pi catalysed by glucose 6-phosphatase The glucose is released into the blood stream and transported to other tissues. Thus liver glycogen represents a store of glucose that can be made available to all tissues of the body.
Describe, in outline, the processes that enable the triacylglycerols stored in adipose tissue to be used by skeletal muscle cells.
During prolonged aerobic exercise, starvation, stress situations and lactation, adipose tissue triacylglycerols are hydrolysed by the enzyme hormone-sensitive lipase to release fatty acids and glycerol. This process is known as lipolysis. It is activated by adrenaline, glucagon, growth hormone, cortisol and thyroxine and inhibited by insulin. The fatty acids are carried to tissues such as muscle via the blood stream bound non-covalently to albumin. The albumin-bound fatty acids are variously called non-esterified fatty acids (NEFA) or free fatty acids (FFA). The glycerol is not used by muscle cells but is instead metabolised by liver cells. Many tissues including heart muscle and skeletal muscle use the fatty acids as a source of energy. The process by which fatty acids are oxidised to release energy is known as -oxidation and it occurs in mitochondria. In order to be metabolised the fatty acids are activated by linking them to CoA in a reaction that requires ATP. The activated fatty acids are then transported into the mitochondria via a specialised transport process that uses carnitine. The rate of fatty acid transport into the mitochondrion determines the rate of their subsequent oxidation. Once inside the mitochondrion the oxidation of fatty acids occurs via a sequence of reactions (-oxidation pathway) that oxidises the fatty acid and removes a C2 unit (acetate). The shortened fatty acid is cycled through the reaction sequence repeatedly removing a C2 unit each turn of the cycle until only two carbon atoms remain. The overall reaction for -oxidation of stearic acid (C-18) is: C17H35COOH + 9 CoA + ATP + 8 FAD + 8 NAD+ + 8 H2O 9 CH3CO CoA (acetyl CoA) + AMP + 2 Pi + 8 FAD2H + 8 NADH + 8 H+
Why does a deficiency in pyruvate dehydrogenase complex activity cause lactic acidosis?
A deficiency results in a rise in pyruvate, thereby upregulating other reactions of pyruvate metabolism such as reduction to lactate leading to lactic acidosis.
How does the acetylcysteine work?
Its mode of action is through increasing glutathione levels and binding to the toxic metabolic breakdown products of paracetamol.
Outline the metabolic responses to feeding and fasting and describe how they are controlled.
Effects of feeding: Absorption of glucose, amino acids and lipids from the gut raises their blood concentration. As blood glucose rises, the endocrine pancreas responds by releasing insulin. Insulin increases glucose utilisation by muscle and adipose tissue. Insulin promotes production of glycogen in liver and muscle. Insulin promotes amino acid uptake and protein synthesis. Insulin promotes storage of fats. Effects of fasting: As blood glucose falls insulin secretion is depressed. Glucose uptake by tissues especially by muscle and adipose tissue is depressed. Falling blood glucose stimulates glucagon secretion i.e. insulin/anti-insulin ratio ¯. Glycogenolysis in the liver is stimulated to maintain blood glucose for the brain and other glucose dependent tissues. Lipolysis in adipose tissue is stimulated to provide fatty acids for use by tissues. Gluconeogenesis begins to increase to maintain supplies of glucose for the brain.
What are the effects of aldosterone?
Increased Na reabsorption in the kidney Decreased K absorption in the kidney
Compare and contrast the functions of glycolysis in adipose tissue, skeletal muscle and red blood cells.
Glycolysis is used to produce ATP by substrate level phosphorylation in all three tissues: In red blood cells it is the only mechanism for ATP production. In skeletal muscle it enables ATP production to occur under anaerobic conditions. In adipose tissue it is a minor route for ATP production. Glycolysis is used to produce useful intermediates in red blood cells and adipose tissue: 2,3-bisphosphoglycerate is produced from 1,3-bisphosphoglycerate in red blood cells and is important in regulating (decreases) the oxygen affinity of haemoglobin. Glycerol phosphate is produced from dihydroxyacetone phosphate in adipose tissue and is used in the esterification of fatty acids to produce triacylglycerols.
Give 2 reasons why finding out the time of ingestion of the paracetamol overdose is important?
If the paracetamol is taken less than one hour ago activated charcoal can be used if > 150 mg/kg paracetamol is ingested. Patients are at risk of liver damage and requiring acetylcysteine which can be identified from a single measurement of the plasma paracetamol concentration providing it is not less than 4 hours since the tablets were ingested. Less than 4 hours may underestimate the paracetamol level. If it has been longer than 15 hours, then the patient may not benefit from acetylcysteine and if this is the case then you would need to get advice from the National Poisons Information Service.
Outline the pathways by which tissues obtain the cholesterol they need.
Direct synthesis from acetyl CoA within tissues. Obtain cholesterol synthesised in the liver via LDLs.
List four of the signs and symptoms you might expect to find in a 46 year old female who had the following endocrine test results on a fasting blood sample: Total plasma T4 48 nmol/L (normal range 54-142 nmol/L) Free T4 9 pmol/L (normal range 10-26 pmol/L) TSH 15 mU/L (normal range 0.3-3.8 mU/l) Explain, in general terms, why these signs and symptoms occur.
T4 decrease and TSH increase - suggests hypothyroidism due to defect in thyroid gland. •Weight gain due to reduced BMR. •Cold intolerance due to reduced BMR. •Lethargy/tiredness due to reduced uptake of nutrients by muscle. •Bradycardia – slow heart rate due to reduced responsiveness to catecholamines and reduced heart muscle protein synthesis. •Dry skin and hair loss due to reduced synthesis of proteins. •Slow reflexes and clumsiness due to reduced sensitivity to catecholamines. •Constipation due to reduced responsiveness of GI tract Hoarse voice.
Explain how tissues obtain the lipids they need from lipoproteins.
•Triacylglycerols are obtained from chylomicrons and VLDLs by the extracellular enzyme lipoprotein lipase present in the capillary bed of the tissue. •This hydrolyses triacylglycerols to fatty acids and glycerol. •The fatty acids are taken up by tissues and re-esterified to triacylglycerols using glycerol phosphate derived from glucose metabolism. •Cholesterol is obtained from LDLs by receptor mediated endocytosis. •The LDL particles bind to LDL receptors on the surface of target cells. •The receptor with its bound LDL is taken into the cell by endocytosis. •The endosome is attacked by lysosomal enzymes releasing free cholesterol in the cell and destroying the receptor protein. •The cholesterol is converted to cholesterol esters for storage. •When the cell has enough cholesterol, cholesterol inhibits the synthesis of new LDL receptors and the uptake of cholesterol is reduced.
What three effects does parathyroid hormone initiate in response to low calcium ions in extracellular fluid?
Mobilization of calcium from bone Enhancing absorption of calcium from the small intestine Suppression of calcium loss in urine (renal effect)
List four key components of control systems.
• communication • control centre • receptor • effector.
List five of the signs and symptoms you might expect to find in a 10 year old male who had the following test results on a fasting blood sample: Plasma glucose = 10 mmol/L (reference range = 3.9-6.1 mmol/L) Serum insulin = 5 pmol/L (reference range = 35-145 pmol/L) Why do these signs and symptoms occur?
Results suggest type 1 diabetes - lack of insulin in young patient producing hyperglycaemia. Hyperglycaemia caused by reduced glucose uptake in muscle & adipose tissue, reduced storage of glycogen in muscle & liver and increased liver gluconeogenesis. Glycosuria = glucose in urine - blood glucose concentration exceeds renal threshold of ~8mM Polyuria = excess urine production - due to osmotic effects of glucose in urine retaining water in the urine Polydipsia = Thirst - due to excess water loss in urine and osmotic effect of glucose on thirst centres Weight loss - lack of insulin leads to increased lipolysis (loss of adipose tissue) and proteolysis (loss of muscle) Ketoacidosis - nausea, vomiting - lack of insulin and increased lipolysis switches liver to produce ketones from fatty acids Tiredness/weakness - loss of muscle mass, dehydration Disturbances to vision, drowsiness, confusion - dehydration and ketoacidosis Acute clinical emergency refer to diabetologists at hospital. Treatment will include insulin, control of diet, exercise and monitor for development of complications.
Explain why blood ammonia levels are normally kept low and describe the processes involved.
Ammonia levels are kept low as ammonia is toxic especially to the CNS. It interferes with mitochondrial energy metabolism by removing a-ketoglutarate (forms glutamate) from the Krebs cycle. This reduces Krebs cycle activity, interferes with ATP production from glucose and inhibits brain function. Ammonia reacts with water to produce the ammonium and hydroxyl ions thus it is basic and part of its effects on the CNS may be related to pH changes. Ammonia is removed from the body by: Conversion to urea in the liver. The urea is removed from the body in the urine via the kidney. Conversion to glutamine using glutamate and used for purine and pyrimidines synthesis. Excretion as ammonium ion in urine.
Which set of clinical findings in a blood sample is more suggestive of liver disease? A.) Increased ALT, AST and bilirubin, or B.), increased ALT, no change in AST or bilirubin?
Both ALT and AST leak into the blood when liver cells are damaged. The increased bilirubin indicates a problem with hepatic metabolism.
What is haemoglobin A1c (HbA1c)? Explain how it can be used as an index of glycaemic control.
•Glucose reacts non-enzymatically with the terminal valine of haemoglobin to form glycosylated haemoglobin (HbA1c). •Extent of glycosylation depends on blood glucose concentration and half-life of haemoglobin (~60days). •Poor glycaemic control = high blood glucose = high HbA1c. Good glycaemic control = normal blood glucose = normal HbA1c (~5%).
Explain why some women develop gestational diabetes.
In some women the endocrine pancreas is unable to respond to the metabolic demands of pregnancy and the pancreas fails to release the increased amounts of insulin required. As a consequence there is a loss of control of metabolism, blood glucose increases and diabetes results (Gestational Diabetes).
List features of the gut mucosae that increase its surface area for absorption of nutrients.
Micro villi, villi, plicae circulares.
