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Bavidra kulendrarajah Compare metabolism of Glucose in the liver and in type 2 skeletal muscle fibres Glucose is metabolised in both the liver and type 2 skeletal muscle but in both of these tissues the glucose is used for different reasons. In type 2 skeletal muscle fibre the glucose is used to provide ATP for muscle contraction whereas in the liver glucose metabolism is controlled to regulate the blood glucose concentrations. In both tissues the glucose enters by facilitated diffusion through specific transport proteins where it is either oxidised or stored as glycogen according to demands of the tissue. A key difference is that only the liver tissue is able to synthesise glucose. Transport of glucose Glucose from the blood plasma originates from the breakdown of starch and a small amount of glycogen in the small intestine. The glucose then moves into cells by facilitated diffusion via specific glucose transport proteins. There are 5 different types of glucose transporters and each of these have a distinct structure and function. GLUT 1 and GLUT 3 which are found in all cells have a low Km for glucose (1mM) and this means the glucose strongly binds to its binding site. In the case of the muscle and liver this property allows for the basal glucose uptake into the cells of the muscle and liver. GLUT 2 is only present in the liver and has a very high Km for glucose (15-20mM) and this means glucose only enters the liver when there are very high blood glucose concentrations which means that glucose only enters liver cells when there is a surplus of glucose. In contrast to this muscle cells have GLUT 4 which has a lower Km (5mM) than liver's glucose transport protein. This property results in glucose binding to the transport protein at lower concentrations and allows a greater uptake of glucose. In both liver and skeletal muscle the number of glucose transporter proteins at the surface of the cell can be increased either in the presence of insulin or through exercise. Once the glucose is taken up into the liver or the skeletal muscle it can be broken down by glycolysis or stored as glycogen. Glycolysis Glycolysis is a common metabolic pathway that occurs in the cytoplasm of both the skeletal muscle and the liver where glucose is converted into pyruvate and the free energy released is used to form high energy compounds ATP and reduced NADH. The first step in the reaction involves the enzyme hexokinase which phosphorylates glucose to form glucose-6-phosphate by using the inorganic phosphate derived from the hydrolysis of ATP. This is an essential reaction as it ensures that the glucose is trapped in the cell as it can't diffuse back out of the cell. Following this the glucose6-phosphate (aldose) is converted into ketose-6-phosphate (ketose) by an isomerisation reaction that is catalysed by phosphoglucose isomerase. Fructose 1,6, phosphate is then formed by the phosphorylation of ketose-6-phosphate, which is the committed step, and this molecule is cleaved into a three carbon compound glyceraldehyde-3-phosphate. Glyceraldehyde is oxidised and phosphorylated to
Bavidra kulendrarajah form 1,3 biphosphoglycerate which is a high phosphyrl transfer potential compound and is coupled with ADP to form ATP and 3-phosphoglycerate, another high phosphyrl transfer potential compound. A phosphate is cleaved from the 3 phosphglycerate to form pyruvate and an ATP. The formation of ATP occurs by substrate level phosphorylation. In summary the process of glycolysis forms 2 ATP molecules, 2 NADH and 2 pyruvate molecules from one molecule of glucose. Control of glycolysis in skeletal muscle Glycolysis is very important in type 2 skeletal muscle fibres because they have a low capacity for oxidative phosphorylation and no triglyceride stores. They are fast twitch, white fibres whose main function is to generate high intensity bursts of power for short periods of time. These fibres have a low content of myoglobin, few mitochondria, small amount of blood capillaries and as they require a fast production of ATP they rely on glycolysis which can generates ATP in the absence of oxygen. Oxygen often becomes the limiting during vigorous exercise but glycolysis ensures ATP is constantly produced which allows muscle contraction to continue. However due to the muscle's dependence on glycolytic pathways it results in the muscles easily becoming fatigued when ATP is the limiting factor. In order for glycolysis to continue in the abscence of oxygen the NAD has to be regenerated. The enzyme lactate dehydrogenase reduces excess pyruvate to lactate and this regenerates NAD. The lactate produced leaves the muscle cell and enters the blood stream where it is either used as an energy source for cardiac muscle or it enters the liver where it is converted back into glucose via the gluconeogenic pathway. In the type 2 muscle fibres glycolysis is regulated to meet the demand of ATP which is needed for muscle contraction. This is done by three key enzymes in the metabolic pathway that are sensitive to the ratio of ATP/AMP. The key enzyme that is controlled is phosphofructokinase which catalyses the committed step of glycolysis, phosphorylation of fructose-6-phosphate into fructose 1,6 phosphate. The presence of ATP allosterically inhibits the enzyme and prevents it from binding to fructose-6-phosphate. This in turn leads to an increase in the concentration of glucose-6-phosphate which inhibits the first enzyme hexokinase and glucose remains in the blood. The inhibition of hexokinase is important as it prevents cellular depletion of Pi. This occurs when ATP/ADP ration is high and there is sufficient ATP molecules present for muscle contraction. On the other hand AMP, which acts as a signal for the utilisation of ATP, activates phosphofructokinase and leads to glycolysis being stimulated. The enzyme is also regulated by a decrease in pH which occurs if lactic acid produced by extreme exercise accumulates. The increase in hydrogen ion concentration inhibits its action by increasing the effect of ATP. This control mechanism is advantageous to the skeletal muscle as it prevents the accumulation of lactic acid produced in anaerobic respiration which damages the cells. Control of glycolysis in the liver
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