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98 Cards in this Set
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Define cell metabolism.
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A highly integrated network of chemical pathways, some of which take place in all cells, some are specific to certain cells. Metabolic reactions derive energy and raw materials from food stuffs.
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explain the functions of cell metabolism.
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Provide energy for
- cell function and synthesis of cell components (ATP), - building block molecules --> synthesis of components needed for growth, repair, maintenance and cellular division. - organic precursor molecules ( acetyl-coA) which allow the inter-conversion of building block molecules - reducing power NADPH |
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Describe origins and fates of cell nutrients.
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Origins: diet, synthesis from body tissue, released from body stores
Fates: waste products, stored, inter-converted, utilised |
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Describe the relationship between catabolism and anabolism.
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Catabolic reactions are exergonic and release energy and hydrogens on breaking down large molecules into multiple smaller molecules. Anabolic reactions are endergonic and require energy and reducing power ( H atoms) to build large molecules from multiple smaller molecules. The H atoms from catabolic reactions are transferred to H carriers eg NADH which provide the reducing power for anabolic reactions. The H carriers are recycled and used again ( only a certain concentration of oxidised and reduced forms)
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Explain why cells need a continuous supply of energy
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Biosynthetic work: synthesising new organelles to replace old ones, growth, repair, development, division, maintenance
Electrical work: nervous communication between cells Transport work: movement of ions and molecules acroos membrane, active transport Mechanical work: structural integrity of cells Osmotic work: maintaining osmotic balance specialised function eg muscle contraction |
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Explain the biological role of ATP.
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ATP- adenosine triphosphate is a free energy carrier. The conversion of ATP<--> ADP is the intermediate process which couples catabolic and anabolic reactions. ATP has a high energy of hydrolysis due to it's phosphate group alowing phosphoryl group transfer. It is a high energy signal and stimulates cells to undergo anabolic reactions.
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Explain the biological role of creatine phosphate.
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Creatine phosphate is an immediate free energy store found in skeletal and cardiac muscle cells. It is formed from creatine when ATP levels are high catalysed by creatine kinase. When ATP level decreases, it is used to form ATP - provides energy for the first few seconds of vigourous exercise.
[creatine phosphate] is proportional to skeletal muscle mass. |
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Explain the clinical implications of unsual measurements of creatine kinase and creatinine.
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High concentration of creatine kinase in blood is a marker for M.I
creatinine is non-enzymatic break down product of creatine and creatine phosphate. It has no function and is readily excreted by kidneys. Daily creatinine excretion - indicater of skeletal muscle mass, increased secretion - muscle wasting. High creatinine blood concentration and low urinary creatinine - reduced kidney function. |
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Define oxidation and explain how fuel molecules are oxidised during catabolism.
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Oxidation is the removal of electrons or protons (usually 2) from atoms or molecules. Oxidation reactions are coupled with reduction reactions - REDOX. When a molecule is oxidised the protons are picked up by hydrogen carriers eg NAD+, NADP, FAD+ which become reduced. They transfer these protons to molecules in reduction reactions.
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Why is it important for hydrogen carriers to be reoxidised after being reduced and vice versa?
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The concentration of both forms, oxidised and reduced, of hydrogen carriers is constant and so in order for cells to function they must cycle between oxidative and reductive processes.
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List the major roles of the following tissues in whole body metabolism: CNS, heart muscle, skeletal muscle, liver and adipose tissue.
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CNS- energy from glucose and ketone bodies (prefers glucose), no fuel storage therefore requires continuous supply of metabolic substrate.
Heart muscle - absorbs lactate and oxidises it to CO2, has creatine phophate to produce ATP in short term boosts liver - stores glucose as glycogen skeletal muscle - has glycogen stores and creatine phosphate stores, also has myokinase enzyme and so can convert ADP (high energy of hydrolysis)--> ATP + AMP Adipose tissue - stores triacylglycerols which are metabolised when glucose levels low. |
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Describe the general structure of carbohydrates.
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-(CH20)n
- aldehydes ( 3C aldoses )or ketones (3C ketoses) - multiple OH groups - partially oxidised so less oxygen than in fats is needed for full oxidation - hydrophillic - exist as monosaccharides(3-9C) - disaccharides ( 2 monosaccharides joined by glycosidic bond C-O-C) - polysaccharides |
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Describe the functions of carbohydrates.
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- metabolised to CO2 and H2O to provide energy to fuel cellular activity
- stored as glycogen in liver and skeletal muscle - dihydroxyacetone phosphate ( ketose 3C) from glycolysis forms glycerol phosphate, a component of triacylglycerol stored in adipose tissue - components of polymers eg nucleic acids, glycolipids, glycoproteins |
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Describe how dietary carbohydrates are digested and absorbed.
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- salivary amylase breaks down large polysaccharides ( starch and glycogen) into monosaccharides
- monosaccharides, disaccharides and dextrins (oligosaccharides) are broken down by glycosidase enzymes ( lactase, isomaltase- breaks 1-6 alpha glycosidic bonds,glycoamylase, sucrase) which are attached to the brush border of columnar epithelial cells lining the small intestine. - Glucose, galactose and fructose are absorbed by active transport into the small intestine - The monosaccharides are then transported into and out of the blood and into target cells,all by facilitated diffusion, to be metabolised. - Glucose is metabolised by all cells whereas galactose are fructose are mainly metabolised in the liver |
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Explain why cellulose is not digested in the human GI tract.
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cellulose is a polymer of glucose found in plants. It has 1-6 beta glycosidic bonds which cannot be broken down in human GI tract as there is no adequate enzyme to do so. Cellulose still plays a vital role as dietary fibre which aids the function of GI tract.
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Describe glucose dependancy of some tissues.
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Some tissues have an absolute requirement for glucose and can't metabolise any other substate. These tissues include lens of eye, kidney medulla, RBC & WBCs. CNS prefers glucose but can metabolise ketone bodies produced from beta oxidation of fatty acids.
Therefore it is very important to maintain a constant level of blood glucose. These tissues don't require insulin to uptake glucose. |
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Describe key features of glycolysis.
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- 10 steps
- glucose oxidised to 2 pyruvate - 2 ATP & 2 NADH produced - all intermediates are phosphorylated by substrate level phosphorylation ( high phosphoryl group transfer potential due to high energy of hydrolysis) - exergonic overall - 3 irreversible pathways allowing regulation - only 3C &6C compounds --> some 3C have specific functions eg dihydroxyacetone phosphate which forms glycerol phophate a component of TAG - No CO2 produced |
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Describe the 3 irreversible pathways of glycolysis.
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Rate limiting steps:
Reaction 1. glucose+ ATP --> glucose 6-phosphate + ADP - hexokinase (glucokinase in liver) - makes sugar anionic (-ve) - prevents it crossing the plasma membrane - increases reactivity of sugar so it can be metabolised in several different pathways: glycolysis, glycogen synthesis, pentose phosphate pathway - allows formation of compounds with high phosphoryl-group transfer potential that can transfer their phosphoryl group to ADP to form ATP (Substrate level phosphorylation) REACTION 3: unique to glycolysis - commiting step fructose 6 phosphate --> fructose 1,6 bis phosphate - phosphofructokinase (PFK) regulation: alosteric regulation (muscle) inhibited by high ATP, stimulated by high AMP, hormonal regulation (liver) insulin (catabolic state) stimulates and glucagon (anabolic state) inhibits. Reaction 10 - phosphoenolpyruvate -> pyruvate by pyruvate kinase. |
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Explain why lactic acid production is important in anaerobic glycolysis.
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NAD+ is reduced to NADH in glycolysis. This carrier has a fixed concentration and so must be oxidised back for further glycolysis to occur. In aerobic respiration this is achieved in the mitochondria in the krebs cycle. In anaerobic glycolysis 2 pyruvate + 2NADH +2H+ --> 2 lactate + 2 NAD+
catalysed by lactate dehydrogenase (reversible reaction) |
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Explain how blood concentration of lactate is controlled.
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lactate is transported in the blood and absorbed in:
- heart: oxidised> pyruvate> acetyl coA > TCA (tricarboxylic acid) cycle > energy - liver: some may provide energy but most is converted to glucose by gluconeogenesis, acetyl coA >lipid synthesis ( fatty acids, ketone bodies, cholesterol) rate of lactate utilisation = rate of lactate production so [blood plasma] fairly constant. If conc is high effects buffer capacity > lactate acidosis > hyperventilation, vomiting. Causes are hearty eating, strenuous exercise, alcohol metabolism, shock and congestive heart disease, decreased liver function. Thiamine deficiency ( VIT B) which is a cofactor of pyruvate dehydrogenae- multienzyme complex which convert pyruvate into acetyl coA so it can enter the TCA cycle. If this complex doesn't function aerobic respiration can't take place, instead anaerobic glycolysis will take place to produce lactate. |
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Mrs J usually has very little dairy products in her diet. At her childs birthday party she ate birthday cake, ice cream and drank lots of milk shake. Several hours after the party she developped severe stomach cramps, and violent diarrhoea that lasted 24hrs. No-one else was affected. What do you think the likely cause of her illness was.
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It is unlikely to be food poisoning as no one else was affected. It may be lactase deficiency due to specificity of the illness and the amount of dairy containing foods at the party. Some adults suffer from this disease due to the loss of lactase activity and so lactose isn't hydrolysed into glucose and galactose. Instead it is fermented by bacteria in the GI tract and causes cramps and diarrhoea untill all the lactose has been metabolised.
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List the end products of glycolysis under aerobic and anaerobic conditions in RBCs and skeletal muscle
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Aerobic anaerobic
RBC lactate lactate skeletal pyruvate lactate muscle RBC has no mitochondria so can't undergo aerobic respiration. |
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DEFINE AND GIVE APPROPRIATE VALUES TO THE COMPONENTS OF YOUR DAILY ENERGY EXPENDITURE
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Daily energy expenditure includes the energy needed to maintain BMR, the energy required for voluntary physical activity and the energy required to process dietary intake.
calculations: ∑(BMR + physical activity) + 10% of ingested food BMR(Kg/24hrs) - functioning of tissues when at physcial, dietary and emotional rest. maintain life. rough estimate: 100 x weight (kg) skeletal muscle: 30%, liver and CNS: 20%, heart: 10% voluntary physical activity: cardiac and skeletal muscle. add 30% of BMR of sedentary person to BMR, add 60-70% of 2hr moderate exercise per day person and add 100% of several hrs heavy exercise person. DIT- dietary induced thermogenesis. add 10% of energy of ingested food |
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List the essential components of the diet and explain why they are essential.
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Carbohydrates:
1. provide energy (ATP) which fuels cellular activity 2. Interconversion to other components ( glycosylation) Proteins: 1. Catabolism forms amino acids - building blocks of molecules eg Hb 2. Essential amino acids - can't be synthesised in body 3. Nitrogen synthesis: normal person nitrogen intake and loss is balanced, in pregnant women ang growing children there is a positive balance and in starvation or muscle degradation diseases there is a negative balance. Fats: 1. essential fatty acids - linoleic and linolenic acids --> cell membranes and regulatory molecules. 2. transport of lipid soluble vitamins ( A,K,D & E) 3. insulation (adipose tissue), protection, energy store Fibre: functioning of GI tract Vitamins and minerals: deficiency causes disease and illness Water: transport, osmoregulation, thermoregulation ( sweat), site of many reactions |
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what is malnutrition and describe somes diseases associated with it.
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Malnutrition is the inbalance of what an individual eats what that individual requires to maintain health.
over- nutrition can lead to obesity. under- nutrition - starvation Malabsorption diseases: coeliac disease and crohn's disease - failure to digest or absorb ingested nutrients Under-nutrition - anorexia nervosa, bulimia nervosa, reduced availabilty to food --> protein energy malnutrition ( kwashiorkor and marasmus) |
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Explain the clinical consequences of a man with protein energy deficiency.
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Protein energy malnutrition - starvation in adults and children
adults: loss of weight by loss of subcutaneous fat and muscle wasting, complain of coldness, weakened immune system --> infections of GI tract and lungs. Children: marasmus: under 5, emaciated --> muscle wasting (breakdown of muscle protein to provide energy), stunted growth, prone to infections ( lack of antibodies, WBC), brittle naills & hair, dry skin, kwashiorkor: not breastfed- low protein diet, pot belly - swollen abdomen due to hepatomegaly (enlarged fatty liver - no lipoproteins made to transport fat which accumulates around liver) also due to ascites (oedema in peritoneal cavity) , anaemia (lack of Hb) - apathetic, oedema - low serum albumin ( no difference in water potential so tissue fluid not reabsorbed into capilaries), moon face - wasting Treatment: slow introduction of proteins - few and slow activity of 5 enzymes in urea cycle therefore large amounts of protein would causer hyperammoniaemia. correct electrolyte and fluid imbalance, treat infection, vitamin and mineral supplements |
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Determine BODY MASS INDEX of a patient and interpret the valule.
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BMI = weight (Kg) / Height2 (M)
underweight: <20(men), <19 (women) normal: 20-25, 19-24 overweight:26-30, 25-30 obese: >30 |
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Define obesity and describe the factors involved in the regulation of body weight.
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Obesity is a BMI over 30 where excess body fat is present due to over eating or under exercising. associated with early death
Regulation: food choices, eating behaviour, exercise, lifestyle,(genetic, drug therapy endocrine disorders eg leptin deficiency) starvation not good - initially a lot of weight loss, mainly water as main component in hydrophillic glycogen stores, after these are used fats are mobilised and they proteins are metabolised --> muscle wasting, liver converts fatty acids to ketone bodies for CNS, blood pH drops--> ketoacidosis increased risks due to obesity:hypertension, diabetes type 2, gall bladder disease, cardiovascular diseases, stroke, certain cancers, osteoarritis. |
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Define homeostasis and explain its importance
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The maintenance of the internal environments within set limits and is a dynamic equilibrium rather than a fixed steady rate. Failure of homeostasis leads to disease.
Controls: supply of nutrients, supply of oxygen, removal of waste products, blood flow, thermoregulation, osmoregulation, pH levels |
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Describe the main features of control systems in the body.
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1. communication
- nervous - endocrine - paracrine: hormones released and act locally instead of into blood to far away target tissues - autocrine: agents released by cell affect releasing cell. 2. control system: - determines reference set points, analyses input, determines response - CNS - brain or spinal cord 3. receptor - detects stimuli (eg changes in enviroment) - communicates with control centre via afferent nerves (PNS) 4. effector - carries out change - recieves output from control centre via efferent nerves (PNS) - paraplegic patients have loss of this response (effector= sweat gland) and so have reduced abiltity to lose heat. |
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Explain the hypothalamic-pituitary-adrenal axis
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The HPA axis the body's normal response to stress and the levels of cortisol ( glucocorticoid- middle sugar layer of cortex - fasciculita) and ACTH correlate with stress levels.
Hypothalamus receives input from afferent nerves and releases CTH- corticotrophin releasing hormone which targets anterior pituitary to secrete ACTH - adrenocorticotrophic hormone. ACTH targets the adrenal cortex and stimulates them to secrete cortisol. Cortisol inhibits ACTH and CTH release by negative feedback. |
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Discuss examples of biological rhythms.
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circadian rhythm - the biological clock - controlled by melatonin (identifies night and day) secreted from superchiasmatic nucleus( collection of cell bodies in CNS) in hypothalamus
free running time - 24hrs 11 minutes, enviromental reminders help us keep to 24hrs, primarily daylight. menstrual cycle |
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Define osmolarity and explain how it is controlled in the blood plasma.
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Osmolarity is a measurement of solute concentration. If osmolarity of blood plasma increases (water potenital decreases), osmoreceptors in the supraoptic and paraventricular nuclei in the hypthalamus recieve stimulus. They create feelings of thirst and stimulate the posterior pituitary gland via a nerve impulse. The posterior pituitary responds by secreting ADH- antidiuretic hormone into the blood to target the collecting ducts in kidneys, to increase their permeability to water. Therefore more water is reabsorbed and urine becomes mores concentrated. The loss of water is decreased and osmolarity is decreased (water potential increased)
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Give examples of homeostasis working at different levels in the body eg cellular, organ and whole body.
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Cellular: calcium ion levels are kept at 10-7 M in cells. If the concentration increases it acts as a stimulus eg muscle contraction
Organ: In skeletal muscle, autoregulation adjusts the blood flow to the muscle depending on it's metabolic activity eg bohr effect. Whole body: Thermoregulation |
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Briefly discuss one example of negative feedback and one example of positive feedback.
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Negative feedback is seen in osmoregulation where the effector inhibits the stimulus, appropriate water potential regained inhibits ADH release.
Positive feedbakc is seen in the blood clotting cascade where the response increases the effect, output adds to input. This leads to catastophic (change in state) change: liquid to solid |
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Define catabolism and explain how it differs from anabolism? Explain why catabolism is generally inhibited by high energy signals and activated by low energy signals.
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Catabolic reactions breakdown large molecules into multiple smaller molecules, releasing energy and reducing agents. They are exergonic reactions. Anabolic reactions build large molecules from multiple smaller molecules and require energy and reducing agents to achieve this. They are endergonic reactions.
High energy signals eg ATP and NADH2 favour anabolic reactions where as low energy signals eg ADP and NAD+ favour catabolic reactions. |
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Describe 2 important substances produced from intermediates of glycolysis?
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Glycerol phosphate - made from dihydroxyacetone phosphate (3c)(intermidiate of glycolysis) in adipose tissue. Needed for the synthesis of TAGs in liver and adipose. Liver is less dependant on glycerol phosphate as it can phosphorylate glycerol from glycerol kinase + ATP- enzyme lacking in adipose tissue.
2,3- bisphosphoglycerate - regulation of haemoglobin, decreases affinity for oxygen so tissues recieve more oxygen - increases at high altitudes. Made from 1,3-bisphosphoglycerate (intermediate of glycolysis) in red blood cells. |
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Outline the pentose phosphate pathway.
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In the pentose phosphate pathway, glucose 6 phosphate is decarboxylated to C5 sugar phosphate, catalysed by glucose-6-phosphate dehydrogenase
Glucose 6 phosphate + NADP+ > C5 sugar phosphate + NADPH + H+ + CO2 Glucose 6 phosphate is formed from the phosphorylation of glucose in the first reaction of glycolysis by hexokinase ( glucokinase in liver). the second phase of the pathway converts unused C5 sugar phosphates to intermediates of glycolysis: fructose 6 phosphate and glyceraldehyde-3-phosphate( which is also made in fructose metabolism) |
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Explain why the pentose phosphate pathway is an important metabolic pathway in some tissues.
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-C5 sugar phosphate is a component of nucleotides
- NADPH has many functions: maintains free -SH groups on cysteine residues. If these groups become oxidised (low [NADPH]) cross links form by disulphide bridges. This is very important in RBCs as without NADPH disulphide bonds form between haemoglobin molecules creating aggregations of haemoglobins - heinz bodies. This triggers early haemolysis and can lead to anaemia if [Hb] is too low and can cause jaundice by build up of unconjugated bilirubin in the blood ( yellow skin and sclera). NADPH is also important in the lens of the eye where it prevents disulphide bonds forming which can cause cataracts. -NADPH also provides reducing power for lipid synthesis in adipose tissue -NADPH is also involved in detoxification reactions in the liver. |
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Describe and explain the effects of glucose-6-phosphate dehydrogenase deficiency and its signs and symptoms. What chemicals can make this condition worse? Which populations is this condition more common for?
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Glucose-6-phosphate dehydrogenase is the first enzyme in the pentose phosphate pathway and is the enzyme which is regulated by NADP+/NADPH ratio. Glucose 6-phosphate dehydrogenase deficiency is an x linked gene defect caused by a point mutation. This causes reduced activity of the enzyme and so low levels of NADPH. The sufferer may have anaemia from increased haemolysis, jaundice - high unconjugated bilirubin in blood, dark brown urine- biliruibin in urine, yellow skin and sclera, high levels of reticulocytes (new, immature red blood cells) potential cataracts. Acute haemolytic episodes are precipitated by chemicals that reduce NADPH levels such as antimalarials. Populations originating from the mediterranean region and black USA males are more likely to have the defect.
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Which enzyme is regulated in the pentose phosphate pathway and how?
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Glucose 6 phosphate dehydrogenase (the first enzyme in the pathway) is regulated by NADP+/ NADPH ratio in the cell. High NADP+ levels activate enzyme, High NADPH levels inhibit the enzyme.
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Explain the biochemical basis of lactose intolerance.
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Lactose is broken down into galactose and glucose by lactase enzymes attached to the brush border of epithelial cells lining the small intestine. In lactose intolerance, lactase activity is very low and so lactose isn't broken down but instead is fermented in the gut by organic bacteria which irritage the GI tract causing cramps and severe diarrhoea which lasts until all lactose has been metabolised.
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Explain the biochemical basis of galactosaemia.
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Galactose is usually metabolised to glucose-6-phosphate in the liver and sometimes in the kidney by the enzymes galactokinase( phosphorylation to galactose 1-phosphate) and galactose 1-phosphate uridyl transferase ( to glucose 6 phosphate).
Galactosaemia is the build up galactose in the blood due to a deficiency in one of the above enzymes. Galactose is reduced to galactitol which uses up NADPH sources. Levels of NADPH deplete and this decreases lipid synthesis in adipose tissue and decreases detoxification reactions in liver. It also allows oxidation of -SH groups in cysteine residues so that disulphide bridges form between haemoglobin molecules and can cause anaemia- increased haemolysis, jaundice, disulphide bond between proteins in lens of eye can cause cataracts. Cataracts is made worse by high levels of galactose which may cause glycosylation of proteins. Also the build up galactose and galactitol in the eye causes high intra-occular pressue glaucoma and may lead to blindness. Galactose 1 phosphate uridyl transferase deficiency is more common and worse as it involves an accumulation of galactose and galactose 1 phosphate. Galactose 1 phosphate damages the brain, kidney and liver and may be involved in the sequestion ( compounds from ions) of Pi which then can't be used in ATP synthesis. |
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How is fructose metabolised?
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Fructose is formed from the metabolism of sucrose by sucrase enzymes in the small intestine to form glucose and fructose. These monosaccharides are absorbed by active transport into the small intestine and then into and out of the blood by facilitated diffusion. Fructose is mainly metabolised in the liver to glyceraldehyde 3 phosphate - an intermediate of glycolysis. ( same intermediate is made in second phase of pentose phosphate pathway, where excess C5 is converted to fructose 6-phosphate and glyceraldehyde 3-phosphate)
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Explain the key role of pyruvate dehydrogenase ( PDH)?
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Pyruvate dehydrogenase (PDH) is a multi-enzyme complex that dephosphorylates pyruvate to acetyl coA ( which then enters TCA cycle), producing CO2 and NADH. Multi-enzyme complex requires several co factors which come from 4 B vitamins. Therefore vitamin B deficiency reduces activity of enzyme. PDH is irreversible therefore - loss of CO2, acetyl coA cannot be converted to glucose by gluconeogenesis.
Control mechanisms: - acetyl coA from beta oxidation of fatty acids inhibit the enzyme allosterically > so that acetyl coA from fatty acids rather from glucose enters the TCA cycle. - ATP and NADH ( High energy signals) inhibit - ADP - activates - High levels of glucose activate it - insulin activates enzyme by promoting its dephosphorylation.( covalent modification) |
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Describe the roles of the tricarboxylic acid cycle (TCA) in metabolism.
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The TCA cycle is essential in all mitochondria containing cells as it produces the most amount of ATP. Therefore a genetic mutation of any enzyme involved in the cycle would be lethal- not compatible with life.
roles are: - produce GTP and ATP - produce CO2 and H+ ions - break C-C bonds within acetyl coA - produce biosynthetic precursors - requires O2 - To form reduced NADH + FADH2 |
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Explain how the TCA cycle is regulated.
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isocitrate dehydrogenase - enzyme catalyses decarboxylation of citrate(6C)> alpha-ketoglutarate (5C)
regulated by rate of utilisation of ATP: ATP/ADP ratio, NADH/NAD+ ratio - High energy signals inhibit eg ATP, NADH - Low energy signals activate eg ADP, NAD+ ( allosteric activation) In order to use some of the intermediates of the cycle for haem synthesis, amino acid synthesis, glucose synthesis, fatty acid synthesis, TCA cycle components must be replenished. Pyruvate carboxylase convert pyruvate to oxyloacetate. Pyruvate carboxylase is activated by acetyl coA. Citrate allosterically inhibits pyruvate carboxlase as it is a high energy signal energy signals. |
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explain why and how glucose is produced from non- carbohydrate sources.
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When carbohydrates are absent from the diet due to starvation or fasting, glucose dependant tissues still require glucose. Therefore initially the break down of liver glycogen supplies the needed glucose. After 8-10 hrs all glycogen stores have been metabolised and so the body has to produce glucose by gluconeogenesis from mainly the liver and kidney cortex can during starvation.
The metabolism of glucose shares of lot of the same intermediates as amino acid and TAG metabolism, Therefore some of these intermediates can be used to synthesis glucose: pyruvate, lactate, glycerol. Amino acids whose metabolism involved pyruvate or intermediates of the TCA cycle can be used. Acetyl coA cannot be converted to glucose due PDH (pyruvate dehydrogenase reaction being irreversible). |
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Which pathways are involved in gluconeogenesis from pyruvate?
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All 7 reversible steps of glycolysis can be used in the synthesis of glucose.
Reactions 1,3 and 10 have to be by passed. Reaction 1 in glycolysis glucose is converted (phosphorylated) to glucose 6 phosphate by hexokinase (glucokinase). In gluconeogenesis glucose-6-phosphate is converted to glucose by a thermodynamicaly spontaneous reaction catalysed by glucose-6-phosphatase. Reaction 3: In glycolysis fructose-6-phosphate is phosphorylated to fructose-1,6-bisphosphate by phosphofructokinase (PFK). In gluconeogenesis fructose 1,6- bisphosphate is converted to fructose-6-phosphate by a thermodynamically spontaneous reaction catalysed by fructose 1,6-bisphosphatase. Reaction 10 in glycolysis is phosphorylation of phosphoenolpyruvate to pyruvate by pyruvate kinase. In gluconeogenesis 2 reactions are involved: 1. Catalysed by pyruvate carboxylase ( activated by acetyl coA) pyruvate + ATP + CO2 + H2O> oxyloacetate + ADP + Pi + 2H 2. Catalysed by PEPCK ( Phosphoenolpyruvate carboxylkinase) oxyloacetate + GTP +2H+ > PEP + GDP+CO2. GTP and ATP and CO2 are produced in the TCA cycle. This reaction provides the link between the TCA cycle and gluconeogenesis and enables products of amino acid catabolism that are intermediates of the TCA cycle to be used to synthesise glucose. |
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How is gluconegenesis regulated?
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Mainly hormonal control of PEPCK (phophoenolpyruvate carboxylkinase) and fructose 1,6-bisphophotase.
- glucagon and cortisol increase the activity of PEPCK and insulin decreases the activity all by increasing or decreasing the amount of enzyme - Same affects on fructose 1,6-bisphosphatase however the hormones affect both the activity and the amount of enzyme -inhibit and activate. Diabetes - absense of adequate levels of effective insulin, increased rates of gluconeogenesis contribute to hyperglycaemia. |
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List the functions of the TCA cycle.
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The TCA cycle has catabolic and anabolic roles. the catabolic role is to oxidise acetyl coA into 2 moles of CO2 to form NADH & FAD2H which are used in the electron transport chain to produce ATP and GTP by oxidative phosphorylation. The anabolic role is to provide biosynthetic precursors which are used to make haem, amino acids, fatty acids, gluconeogenic amino acid.
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Describe the key features of oxidative phosphorylation.
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- Takes place on cristae in mitochondria using proton translocater complexes.
- Produces ATP by oxidative phosphorylation along an electron transport chain - the reducing power of H atoms and electrons supplied by NADH & FAD2H are used to synthesise ATP. The hydrogen carriers are reoxidised and so can be used in aerobic glycolysis. - Oxygen is required - terminal acceptor |
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Explain the processes of electron transport and ATP synthesis and how they are coupled.
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Electron tranport and ATP synthesis are indirectly linked by the production and utilisation of the proton gradient.
Electrons from NADH and FAD2H are released and move down a series of electron carriers, releasing energy of which 30% is used to actively pump H+ ions from the hydrogen carriers across proton translocator complexes in the inner mitochondrial membrane into inter mitochondrial space. This forms an electrochemical gradient which forms the proton motive force. The inner membrane is impermeable to Hydrogen ions and so in order to enter the matrix they pass through ATPsynthase proteins. As they cross the ATPase, the proton motive force drives ATP synthesis from ADP + Pi. |
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Describe how, when and why uncoupling of electron transport chain and ATP synthesis occurs in some tissues.
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Electron transport chain and ATP synthesis are uncoupled by uncoupling proteins ( UCP) in order to generate heat instead of ATP.
Uncoupling proteins eg UCP1 -thermogenin are involved in non-shivering thermogenesis. They are present in brown tissue which is found in newborns especially around vital organs ( and in hibernating animals to maintain heat). In cold environments, noradrenalin ( norepinephrine) is released from adrenal medulla and stimulates: 1. Lipase to breakdown TAG into fatty acids which are then beta oxidised to produce NADH & FAD2H which are oxidised in the electron transport chain. 2. UCP1 (thermogenin) is a special proton conductance protein which, increases the permeability of the inner mitochondrial membrane to H+ ions as the movement of H+ ions back into the matrix is no longer restricted to ATPase, therefore ETC continues to pump H+ ions across membrane but they can simply diffuse down electrochemical gradient without using ATPase. Therefore uncoupling ATP synthesis from ETC and p.m.f is used for heat production instead. |
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Compare the processes of oxidative phosphorylation and substrate level phosphorylation.
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Oxidative: requires membrane associate complexes. Substrate: requires soluble enzymes eg cytoplasmic and matrix.
Oxidative: indirect energy coupling between ETC and ATP synthesis by the production and subsequent utilisation of the proton motive force. Substate: direct energy coupling of catabolic and anabolic reactions by formation of high energy of hydrolysis bond -phosphoryl group transfer. Oxidative: cannot occur anaerobicaly. Substrate: can occur anaerobically. Oxidative: major process of ATP synthesis in cells that require a lot of energy. Substrate: Minor process in cells that require lots of energy, major in cells with out mitochondria. |
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Explain the P/O ratio using NADH and FAD2H.
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P/O ratio is ATP generated divided by oxidation of no of moles of hydrogen carrier.
NADH has more energy and so uses 3 proton translocator complexes whereas FAD2H uses 2. The greater the proton motive force the greater the ATP synthesis. 5 ATP generated/ 2 moles of NADH = P/O= 2.5 3 ATP generated/ 2 moles of FAD2H =P/O=1.5 |
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Describe the major energy stores in a 70kg man and when are they used
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Adipose tissue: triacylglycerols - 15kg -> 600,000kj - largest energy store.
Muscle: muscle protein - 6kg, -> 100,000kj - needed for prolonged starvation glucagon 0.3kg ( store only for muscle) Liver: glucagon 0.1kg ( store for whole body, glucose-6-phosphatase) glucagon collectively 0.4kg -> 4000kj - vital for glucose dependant respiring tissue Brain, heart and lungs can't store energy. Glycogen is used during the overnight fast and part of the response to stress and exercise. Triacylglycerols are used in starvation, in response to stress during third trimester of pregnancy, during lactation, during prolonged exercise ( eg marathon). activated by glucagon, adrenaline, cortisol, growth hormone, thyroxine. Muscle protein is only used in an emergency due to starvation. |
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Describe, in outline, the reactions involved in glycogen synthesis and breakdown.
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Glycogen synthesis:
Glucose -> glucose 1 phosphate by hexokinase (glucokinase) -> glucose 6 phosphate by phosphoglucomutase -> UDP glucose ( activated)-> glycogen by glycogen synthase ( alpha 1-4 links) and branching enzyme ( alpha 1-6 links). Glycogenolysis. Glycogen -> glucose 1-phosphate by glycogen phophorylase (alpha 1-6 bonds) and debranching enzyme ( alpha 1-4)-> glucose 6-phosphate by phosphoglucomutase. MUSCLES: glucose 6-phosphate enters glycolysis to provide energy for exercising muscle. LIVER: has glucose 6-phosphatase enzyme which is absent in muscle and converts glucose 6-phosphate into glucose which is released into blood and available to all tissues of the body. Therefore muscle glycogen = energy store for muscle, responds to exercis. liver glycogen = energy store for whole body, responds to fasting. |
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Explain the clinical consequences of glycogen storage diseases.
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Defect in gene coding for enzyme in glycogen synthesis. This can lead to abnormal glycogen formation. Too much glycogen production can cause tissue dammage where as too little glycogen formed can cause fasting hypoglycaemia and poor tolerance for exercise. The disease can be in the liver and or muscle.
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How is glycogen metabolism regulated.
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Enzymes controlled are glycogen synthase and glycogen phosphorylase.
Glycogen synthase is activated by covalent modification - dephosphorylation by phosphatases Glycogen phosphorylase is activated by phosphorylation by kinases. Glucagon and adrenalin promote phosphorylation( glycogenolysis) and insulin promotes dephosphorylation ( glycogen synthesis). Allosteric control by energy signals also takes place. |
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Explain oxidative stress.
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During oxidative phosphorylation, ROS- reactive oxygen species may be produced: superoxide radical (O2- dot at top), peroxide ( O2 2-) and hydroxyl radicals ( OH dot at top). These oxidants can attack cell membrane producing free lipid radicals. Attack certain proteins causing aggregation( heinz bodies) or degradation. Attack DNA sugar phosphate backbone causing base deletion.
ROS contribute to many diseases: diabetes, multiple sclerosis, alzheimers and atherogenesis. Antioxidants deactivate ROS: NADPH, glutathione, vitamins C & E. Neutrophils release ROS to destroy nearby bacteria. |
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Describe the various classes of lipids.
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Fatty acid derivatives:
1. fatty acids - fuel molecules 2. TAG - fuel storage and insulation and protection in adipose tissue 3 . phospholipids - plasma membrane and plasma lipoproteins 4. eicosanoid - local mediators Hydroxyl-methyl-glutaryl coA derivatives: 1. Ketone bodies - fuel molecule used by CNS 2. Cholesterol - Membranes an steroid hormone synthesis 3. cholesterol esters - cholesterol storage 4. bile acids and salts - emulsify lipids for digestion in GI Vitamins: A,D,E & K |
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Explain why triacylglycerols can be used as efficient energy storage molecules in adipose tissue.
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Hydrophobic and so stored in anhydrous form in specialised storage cells - adipocyte. Undergo esterification store energy ( glycerol phosphate + fatty acid -> TAG) and lipolysis - release energy ( TAG -> glycerol phosphate( from dihydroxyacetone phosphate in glycolysis) + fatty acid)
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Describe how dietary triacylglycerols are processed for storage or to produce energy.
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Dietary triacylglycerols are hydrolysed into glycerol and fatty acids ( ester bond is broken- lipolysis) by pancreatic lipases in the small intestine, using bile salts and a protein factor - colipase.
chylomicrons transport the TAG to the liver, adipocytes, heart and skeletal muscle. Glycerol then enters the blood stream where it is transported to the liver to be metabolised. Glycerol is phosphorylated by glycerol kinase to glycerol phosphate where it either enters triacyclglycerol synthesis or enters glycolysis ( via dihydroxyacetone phosphate (3c intermediate) to produce energy. Fatty acids are transported to tissues via the blood stream bound non-covalently to albumin. They are oxidised to release energy by beta oxidation in mitochondria, therefore cells such as RBCs which don't have mitochondria can't oxidise fatty acids. The CNS - brain and spinal cord also can't use fatty acids because fatty acids do not readily cross the blood brain barrier. |
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Compare fatty acid oxidation to fatty acid synthesis.
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Both processes involve increasing or decreasing the fatty acid carbon chain by C2 per turn of the cycle. Otherwise they are 2 totally different processes ( not the reverse of one another)
FATTY ACID OXIDATION: - remove C2 per turn FA SYNTHEISIS: - add C2 each turn in cycle of reactions FA OX: C2 atoms removed as acetyl coA. FA SY: C2 atoms added as malonyl coA FA OX: produces acetyl coA FA SY: Consumes acetyl coA FA OX: occurs in mitochondria FA SY: occurs in cytoplasm FA OX: enzymes seperate in mitochondrial matrix FA SY: multi-enzyme complex in cytoplam FA OX: Oxidative - produces NADH and FAD2H FA SY: reductive- requires NADPH FA OX: small amount of ATP required to activate the fatty acid FA SY: large amount of ATP required to drive the process FA OX: intermediates are linked to coA FA SY: Intermediates are linked to fatty acid synthase by carrier protein FA OX: Regulated indirectly by availability of fatty acids in mitochondria FA SY:Regulated directly by activity of acetyl-coA carboxylase FA OX: Glucagon and adrenaline stimulate, insulin inhibits FA SY: Glucagon and adrenalin inhibit, insulin stimulates |
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Describe fatty acid degradation.
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TAG in adipose tissue are hydrolysed by hormone sensitive lipase into fatty acids and glycerol ( lipolyis) during stress situations ( starvation, aerobic respiration, lactase)
Beta oxidation of fatty acids to release energy takes place in mitochondria. First fatty acids must be activated in the cytoplasm, by linking to coA ( forming a high energy of hydrolysis bond with the free -SH group on coA). This requires ATP and is catalysed by fatty acyl coA synthase. Activated fatty acids do not readily cross the inner mitochondrial membrane so carnitine is used, a special transport system. The rate of fatty acid oxidation is regulated by controlling their entry into mitochondria. Transport is inhibited by malonyl CoA( intermediate of fatty acid synthesis) which prevents fatty acids that have just been synthesised from being oxidised. A defective fatty acid transport system causes poor exercise tolerance and large amounts of TAG in muscle cells. Beta oxidation pathway- C2 as acetyl CoA is removed per turn until only 2 carbon atoms remain of the fatty acid. This pathway uses NAD+ & FAD+ and requires oxygen to reoxidise hydrogen carriers. Acetyl coA can be oxidised by stage 3 of catabolism ( krebs cycle) and is an organic precursor for sugars, amino acids, alcohol. It is an important intermediate in lipid synthesis, major site liver, some in adipose tissue. |
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Describe fatty acid synthesis.
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Many unsaturated ( double bonds) fatty acids are essential in the diet as they can't be made in the body.
Fatty acids are synthesised from acetyl coA from the catabolism of carbohydrates and amino acids. It takes place in the cytoplasm and requires a large amount of ATP and NADPH. Citrate from mitochondria is cleaved in cytoplasm to release oxloacetate and acetyl coA. Fatty acids are formed from adding C2 ( malonyl coA (C3) and loosing CO2) per turn of the cycle to acetyl coA catalysed by the multi-enzyme complex , the fatty acid synthase complex. ( malonyl coA is made form acetyl coa + co2 + ATP catalysed by acetyl-coA carboxylase) Acetyl coA carboxylase is controlled by allosteric regulation - citrate activates and AMP inhibits and covalent modification. Insulin acitvates the enzyme by promoting dephosphorylation, glucagon and adrenaline inhibit enzyme by promoting its phosphorylation. |
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Why is it beneficial that some degradative and biosynthetic pathways occur by partially different routes and other by totally different routes?
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Partially different routes: glycolysis/glucogenesis
Totally different routes: Fatty acid oxidation/fatty acid synthesis It allows: greater flexibility as substrates and intermediates can be different, better contol - independantly or co-ordinately, thermodynamically irreversible steps can be by passed. |
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Describe the central role of acetyl coA.
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Acetyl CoA is produced by the catabolism of fatty acids, sugars, alcohol and certain amino acids.
It can be oxidised via the TCA cycle. It is an important intermediate of lipid synthesis ( citrate cleaved -> oxyloacetate and acetyl coA. C2 atoms are added to Acetyl coA to build up fatty acid). Acetyl coA is used to make malonyl-CoA by acetyl coA carboxylase using CO2 and ATP. Acetyl coA -> Fatty acids -> TAG or phospholipids Acetyl coA -> hydroxymethyl glutaryl coA -> ketone bodies or cholesterol ( -> steroid hormones) |
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Describe the key features of electron transport and explain how the proton motive force (p.m.f) is produced.
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Electrons and protons are released from NADH and FAD2H. The electrons move down a series of electron carriers terminating with molecular oxygen. As the electrons move down the chain they release energy, of which 30% is used to actively pump H+ ions across the inner mitochondrial membrane and into inter membranal space. The high [H+] in the inter membranal space compared to the matrix, forms an electrochemical gradient- the proton motive force.
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Explain why cyanide is toxic to cells.
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Cyanide prevents oxidation of NADH and FAD2H by inhibiting the respiratory chain at cytochrome oxidase. Therefore no p.m.f is generated and hence ATP is not synthesised or heat generated. This causes rapid irreversible cell damage -( cell function and structure) and leads to cell death.
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What symptoms would you expect to see in a patient who has had contact with an aromatic weak acid such as dinitrocresol, used in pesticides, and why?
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Aromatic weak acids such as dinitrocresol can penetrate the inner mitochondrial membrane and function as uncouplers to increase the permeability of the inner membrane to H+ ions, uncoupling ETC to ATP synthesis so that heat is generated instead. This uncontrolled respiration would cause high levels of metabolic substrate to be used eg fatty acids from adipose tissue so subcutaneous layer would decrease. It would also increase oxygen requirement leading to hypoxia if pulmonary activity does not increase. Although he would not be producing much ATP by oxidative phosphorylation, he would be producing a lot of heat, increasing body temperature and when sweating fails to reduce the heat enough he will be comatose and eventually die.
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Compare and contrast triacylglycerols and glycogen as energy storage materials in man.
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TAGs and glycogen are both forms of energy storage. TAGs are stored in specialised tissues( adipose tissue) whereas glycogen does not have a specialised storage cell and is stored in the liver and muscle which have other important functions. TAG is the main energy storage material storing 15kg in a 70Kg male, wheras glycogen stores would only be 0.4kg. Triacylglycerols are more efficient forms of storage as they are hydrophobic and stored anhydrously whereas glycogen is hydrophillic and stored with water. In addition TAGs are more reduced than glucose and so contain more energy per C atom than glycogen.
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Explain why the process of fatty acid synthesis(lipogenesis) is not simply the reversal of the process pf fatty acid degradation.
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Fatty acid degradation is an exergonic process that involves reactions which are not freely reversible in the cell, thus the process cannot be easily reversed. Fatty acid synthesis therefore uses different reactions:
This allows greater flexibilty ( different substrates and intermediates) and better control. |
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Explain how when and why ketone bodies are formed.
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There are 3 ketone bodies: acetoacetate, acetone, beta- hydroxbutyrate.
HOW:Acetyl CoA in the liver is converted to hydroxymethyl glutaryl CoA by synthase. HMG-CoA is converted to mevalonate by reductase which then forms cholesterol or HMG-CoA is converted to ketone bodies, acetoacetate by lyase. Acetoacetate then forms beta hydroxybutyrate. Acetone is made from acetoacetate by spontaneous non enzymatic decarboxylation. WHEN: when insulin levels drop, and glucagon levels rise lyase is activated to produce ketone bodies, when insulin is high lyase is inhibited and reductase is activated to produce cholesterol. WHY: ketone bodies are fuel molecules that can be metabolised in all tissues containing mitochondria including CNS - they are converted to acetyl coA and oxidised via TCA cycle. The rate of utilisation is proportional to plasma concentration. |
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Explain how when and why ketone bodies are formed.
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There are 3 ketone bodies: acetoacetate, beta- hydroxbutyrate ( acidic - ketoacidosis - excreted in urine - ketonuria) and acetone ( made from acetoacetate, volatile - excreted via lungs - nail varnish breath)
Ketone bodies are water soluble fuel molecules that can be metabolised by all cells including CNS. The rate of utilisation is proportional to plasma concentration. They are converted to acetyl coA and then enter stage 3 metabolism. Ketone bodies are made from Acetyl CoA in the liver by a pathway that produces hydroxymethyl glutaryl CoA by synthase. This is converted into ketone bodies, acetoacetate by lyase. Acetoacetate then forms beta hydroxybutyrate. Acetone is made from acetoacetate by spontaneous non enzymatic decarboxylation. Lyase activity is regulated by insulin/glucagon ratio, when ratio is lowerd lyase is activated. Ketone synthesis requires both of the following to occure: - fatty acids to be available for oxidation in the liver following intense lipolysis of adipose tissues ( hormone sensitve lipase) - low insulin/glucagon ratio. The 2 conditions normally only occur in starvation but can occur in untreated diabetes mellitus 1 |
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Describe how lipids are transported in the blood.
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TAGs, fatty acids, cholesterol, cholesterol esters and phospholipids are insoluble in water and so are carried in plasma in association with proteins.
98% of lipids carried as lipoprotein particles - micelles ( hydrophbic core of TAG and cholesterol esters surrounded by polar molecules such as apoproteins, phospholipids, cholesterol) Lipoproteins vary in size, function, density, composition of lipids and proteins, and surface charge. Each class of lipoproteins has a specific set of apoproteins. Apoproteins may also be involved in the activation of enzymes or recognition of cell surface receptors. 2% of lipids, mainly fatty acids are bound non-covalently to albumin - released from adipose tissue and transported to tissue eg muscle for fuel. ( hormone sensitve lipase activated by stress, lactation, prolonged exerices, starvation, third trimester of pregnancy) |
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Explain how tissues obtain the lipids they require from lipoproteins.
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Transfer of cholesterol from LDL:
- Cells have LDL receptors on surface - Complex proteins bind LDL (at Apo b-100) - Endocytosis of receptor/LDL complex occurs - Lysosome digests particle. - Cholesterol esters in hydrophobic core are converted to cholesterol which is stored or used in the cell. REGULATION OF LDL RECEPTORS - by cholesterol concentration in cell, uptake stimulated if needed. Transfer of TAGs from Chylomicrons and VLDL: - Endothelial cells of capillaries have lipase on outside membrane - Lipase binds to chylomicron & VLDL - Cleavage of TAGs to glycerol( remains in circulation) & fatty acids ( enter tissue for metabolism) - VLDL remnants removed by liver or converted to other types of lipoprotein particles ( eg HDLs) |
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What are the different classes of lipoproteins.
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There are 4 lipoprotein clases based on their distinct transport function determined largely by its apoprotein composititon and density ( chylomicrons lowest density -> HDLs highest density). Lipids are less dense than proteins so removal of lipid, increases density of lipoprotein.
Lipoprotein classes can be seperated from each other by electrophoresis or by ultracentrifugation. CHYLOMICRONS: - transport dietary TAGs from intestine to tissues eg adipose tissue - TAGs are hydrolysed by pancreatic lipases in the small intestine ( using bile salts) into FA and glycerol. - FA enter epithelial cells of small intestine and are re-esterified by glycerol phosphate from glycolysis - TAGs packaged with other dietary lipids: cholesterol, fat soluble vitamins and specific apoproteins to form chylomicrons. - Normally only present in blood 4-6hrs after a meal - Chylomicrons are absorbed the lacteal ( lymphatic capillary in villus of intestine) -> lymphatic system -> thoracic duct -> left subclavian vein. - The cream of tomato soup appearance of blood - high conc. of chylomicrons. VLDL: - Formed in liver - Combine TAGs synthesised in liver with specific apoproteins - transport of TAGs from liver to adipose tissue for storage LDL: - formed in liver - combine cholesterol with specific apoproteins ( ApoB100) - Transport of cholesterol from liver to tissues - Increase in LDLs increases risk of atheroscleosis HDL: - Some HDL formed as shells in liver, others formed from VLDL remnants - HDL shells are matured into HDL particles when combinded with cholesterol from capillaries. - Transport of excess tissue cholesterol to the liver for disposal as bile salts |
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What is the structure of lipoproteins.
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Mature lipoproteins:
- spherical particles - surface coat( shell): phopholipids, apoproteins and cholesterol. Many are free to transfer to different particles and cell membranes. - hydrophobic core: triacylglycerols and cholesterol esters. can only be removed by special proteins, lipases are transfer proteins. Lipoproteins are only stable if they maintain their spherical shape which is dependant on the ratio of core to surface lipids. |
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Explain how disturbances to the transport of lipids can lead to clinical problems
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Hyperlipoproteinaemias:
- over production of lipoproteins - under removal of lipoproteins Increase in LDLs ( ie increased cholesterol) increases the risk of atherosclerosis. Atheroma formation = oxidised LDLs ( by ROS)-> macrophages phagocytosise LDLs -> form foam cells which accumulate in intima of blood vessel wall -> fatty streak -> atheroma. Increased fat stores -> obesity Under production: cells recieving too little lipid/ cholesterol - no regulated fluidity of cells - No energy store when glucose levels low, poor exercise tolerance -Thermoregulation - Painful joints - no shock absorber - less cholesterol to make steroid hormones ( although cholesterol can also come from food and be made in nearly every cell but prefers liver cholesterol) |
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Analyse simple problems that involve disturabances to lipid transport.
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Primary: genetic defects
Secondary: due to diet Receptor defect: - in LDL receptor -> increased LDLs and cholesterol in plasma -> increased risk of atherosclerosis Apoprotein defects (apoB100) Enzyme defects: - lipase - removes core TAG from chylomicrons and VLDLs and hydrolyses them to FA + glycerol ( to liver). Increased synthesis by insulin - Lecithin cholesterol acyltransferase (LCAT) Converts cholesterol into cholesterol ester ( fatty acid derived from lecithin) to stabilise ratio of surface to core lipids and maintain structure. Without LCAT lipid deposits occur in many tissues and increases risk of atheroscleosis. Base mutation -> wrong primary sequence -> defect protein folding -> active site is denatured, not complimentary. - reduced activity or - hyperlipoproteinaemia ( raised level of one of more classes) |
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読んで。
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よんで
To Read |
yonde
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Describe how amino acids are catabolised in the human body.
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Amino acids derive from proteins which are catabolised in the GI tract by proteases and peptidases to release free amino acids.
All 20 amino acids have different metabolic pathways due to the nature of their R group - however they share common features. 1. removal of NH2 (amino group) by transamination, transfer to other molecules, or deamination, remove amino group as free ammonia -> converted to urea -> excreted by kidneys 2. C atoms converted to intermediates of carbohydrate and or lipid metabolism - glucogenic amino acids - converted to pyruvate, alpha- ketoglutarate, oxyloacetate, succinate, fumareate - can be used to synthesis glucose or glycogen - Ketogenic amino acids - converted to acetyl coA, acetoacetyl coA - can be used to make ketone bodie or fatty acids. |
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Explain transamination and deamination including all the enzymes involved.
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Transamination is the transfer of the amino group to a keto acid, usually alpha ketoglutarate or oxyloacetate or pyruvate.
alanine + alpha ketoglutarate <-> pyruvate + glutamate catalysed by alanine aminotransferase aspartate + alpha ketoglutarate <> oxyloacetate + glutatmate catalysed by aspartate aminotransferase Transaminases(eg alanine aminotransferase and aspartate aminotransferase) - catalyse transamination - very active in liver - released into blood when liver damaged - diagnostic test!!!! - Cortisol stimulates transaminases synthesis in liver!! Deamination: amino group released as NH3 and reacts with water to form NH4+ + OH- - Enzymes found in liver and kidney - L & D-amino acid oxidases: amino acid --> keto acid + NH3 ( High activity of D amino acid oxidase as D amino acids(plants and bacteria) must not be used for protein synthesis - stereoisomer, proteins would be structurally abnormal and non functional. - Glutaminase: glutamine -> glutamate + NH3 - glutamate dehydrogenase: glutamate + NAD+ + H20 <-> alpha- ketoglutarate + NH4+ + NADH + H+. Important in AA metabolism as disposes of AAs and synthesises AAs too. Controlled by relative concentrations of substrates and products. |
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Explain the clinical consequences of a defect in phenylalanine metabolism.
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Phenylketonuria.The most common defect in phenylalanine metabolism is caused by an inherited gene defect coding for the enzyme phenyalanine hydroxylase which oxidises phenylalanine into tyrosine. Without this enzyme, phenylalanine accumulates in the blood and tissues and is broken down into phenylpyruvate by transamination. This molecule is toxic, especially to the CNS where is inhibits pyruvate from entering mitochondria and so reduces ATP synthesis from glucose, resulting in a lack of energy to the cells. This impairs developments and functioning of the CNS causing mental retardation.
All newborns are screened for PKU- phenylketones in urine, as if diagnosed early in life, irreversible damage can be prevented. Treatment: Modify diet, low in phenylalanine as phenylalanine is an essential amino acid and so can't be removed entirely from diet. |
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Explain the clinical relevance of measuring creatinine in blood and urine.
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Creatinine is the non-enzymatic break down product of creatine and creatine phosphate in muscle cells. It has no function in the body and is quickly removed by the kidneys in urine. The rate of creatinine production is proportional to the concentration of creatine in muscle and this is related to skeletal muscle mass.
Daily concentration of creatinine in urine is an indication of muscle mass. A drop in urine concentration may be an indication of muscle wasting or pregnancy or if coupled with a high blood creatinine concentration, this may show renal dysfunction. |
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Explain the autosomal recessive defect, homocystinuria.
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Deficiency in cystathionine Beta-synthase (CBS) enzyme which normally converts homocysteine to cystathionine which is further converted to cysteine. Homocysteine accumulates in the blood and some of it is converted to methionine.
Test for homocystinuria: - elevated plasma levels of homocysteine and methionine - homocystine ( oxidised form of homocysteine) in urine. Symptoms: Chronic elevated plasma levels of homocysteine cause disorders of connective tissue, muscle, cardovacular system and CNS. The symptoms are very similar to marfans syndrome ( disorder of fibrillin gene) in children, misdiagnosed. CBS enzyme also metabolises cysteine to produce hydrogen sulphide, which like nitric oxide from argenine, are important signalling molecules. |
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What are the functions of amino acid?
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- protein synthesis ( requires all 20 amino acids)
- synthesis of other N compounds such as purines, pyrimidines, hormones, neurotransmitters, porphyrin, creatine, carnitine ( specific amino acids) - Excess amino acids are broken down into intermediates found in carbohydrate and or lipid metabolism - signalling molecules - nitric oxide is synthesised from arginine and hydrogen sulphide is syntheised form cysteine ( using CBS- Cystathionine beta synthase). |
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Describe how ammonia is metabolised in the body.
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Ammonia in the body is mainly in the form of the ammonium ion NH4+.
Ammonia is produced during amino acid degradation but is toxic so Hyperammonaemia: - reduces TCA cycle activity by reaction with alpha ketoglutarate to produce glutamate via glutamate dehydrogenase, so energy suply to the cell is disrupted. - increases pH - affects neurotransmitter synthesis and release - blurred vision, tremors, slurred speech, coma and eventually death Therfore ammonia blood conc is kept very low ( 25-40micromoles) and is rapidly detoxified by: - IN CELLS: combined with glutamate to make glutamine via glutamine synthase using ATP - IN LIVER & KIDNEY: glutamine hydrolysed to release ammonia by glutaminase and excreted in urine in kidney or converted to urea in liver. Glutamine is most abundant amino acid in the blood. Urea is a water soluble, non toxic, inert molecule ( can't be broken down by human enzymes) Synthesis of urea in liver - urea cycle - 5 enzymes NH4+ + HCO3- + asparate + 3ATP -> urea ( CO(NH2)2) + fumarate + 2ADP + AMP + 4Pi -asparate is made from oxyloacetate by transamination. |
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How is the urea cycle regulated and what are affects of inherited diseases of the urea cycle.
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Urea cycle can't be regulated by feedback inhibition because urea, the product, is removed in urine.
The 5 enzymzyes are inducible - a high protein diet induces the enzymes whereas a low protein diet or starvation represses the enzymes. Therefore in diseases such as kwashiokor- protein energy deficieny, where the patient will have a very low activity of the enzymes, gradual re-introduction of protein has to take place to prevent hyperammoniaemia as excess amino acids are degraded. Defect in one of the urea synthesis enzymes would cause: Complete loss - fatal Partial loss - hyperammoniaemia - accumulation and or excretion of particular urea cycle intermediates - lethargy, vomiting, mental retardation, Treatment of hyperammoniaemia: low protein diets, keto acids of essential amino acids. Keto acids are converted to amino acids, using some of the NH4+ thereby lowering its concentration in the tissues. |
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Apart from a defect in enzymes of the urea cycle or a protein energy deficieny, what else could cause hyperammoniaemia?
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Hyperammoniaemia is the secondary consequence of liver disease eg cirrhosis where the liver can't remove NH4+ from the portal blood. This NH4+ is produced by a small amount of urea diffusing across the intestinal wall and into the intestine where bacteria break it down ( can't be broken down by human enzymes) to release NH4+.
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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?
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All mature lipoproteins found in normal human plasma are spherical particles that consist of a surface coat and a hydrophobic core. 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 (phophatidylcholine). 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. |
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The patient was a 7-month old baby boy. He had developed normally until he was weaned at 6 months. Following the introduction of a high protein diet he had become irritable, lethargic and less alert and had begun to vomit. He was admitted to hospital where he had episodes of screaming, listlessness and ataxia (uncontrolled limb movements) especially after a protein rich meal. His urine was persistently alkaline and contained a lower urea concentration than normal. His blood NH4+ and glutamine concentrations were increased but fell to normal when his protein intake was reduced. He was put on a special low-protein diet and his subsequent development was normal. Explain the biochemical basis of this patient’s signs and symptoms.
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The signs and symptoms developed when a high protein diet was given and went away when a low protein diet was given. This coupled with the high NH4+ and glutamine levels in blood show a potential enzyme deffect in the urea cycle is the cause. As high protein diet is given this causes hyperammoniaemia as all proteins are degraded to ammonia which isn't detoxified due to low activity of enzymes. Complete failure of an enzyme would be fatal.
Ammonia is toxic and disrupts the metabolism of glucose to provide energy, especially in the CNS, by reacting with alpha ketoglycerate to produce glutamate by glutamate dehydrogenase. The effects are irritability, lethargy, vomiting, ataxia etc. |
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What is the normal range of temperature and what is the most common method of measuring core temperature clinically?
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The normal range of core temperature is 36.1 -37.8 degrees celcius.
The most common method of measuring core temperature is infrared measurement of tympanic ( ear) membrane temp. |
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Define hyper- and hypo- thermia and describe the pros and cons.
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Hypothermia is a core temperature below 35 degrees celcius.
- the low temperature decreases metabolic rate and oxygen demands of tissues - artificially induced hypothermia used in treatment of stroke, traumatic head injury, preturn infant and during brain and cardiac surgery as reduces tissue damage. Hyperthermia is a core temperature above 38 degrees celcius. - temperatures above 40 are life threatening, above 50- rigidity in the muscles and certain immediate death - malignant hyperthermia - rare complication of anasthesia triggered by anaesthetic agents - artificially induced hyperthermia is used in the treatment of some cancers- radiotherapy and chemotherapy more effective at higher temp. |
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Describe pyrexia.
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Pyrexia (fever) is the normal response to infection. Raised temperature increases metabolic rate and so increases production of immune cells to combat infections. It is caused by an inflammatory mediator: prostaglandin E2 which acts on the thermoregulatory centre in the hypothalamus.
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what is the usual treatment for pyrexia and explain how it works.
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Antipyretics such as paracetamol and ibuprofen reduce core temperature by inhibits production of prostaglandins. This is because high degrees of fever can be life threatening above 40!
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