Glycogen Metabolism.docx

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Biomedical Sciences
Prof.Christina Mitchell

Glycogen Metabolism Glycogen is the polymeric of glucose. The reason this structure exists enables glucose to be stored in the body. It is primary found in 2 stores within the body. These are the liver and skeletal muscle. 10% of the livers weight is this glycogen. 1-2% of the muscle weight is glycogen. It is store in cytosolic granules. It is an important store of energy in the body. In provide a quick source of energy for the energy. This glycogen is a reservoir of energy, especially for neurons. Skeletal muscle glycogen can be used for aerobic and anaerobic glycogen, this last one hour. When glucose levels within the blood falls, glycogenolysis occurs to raise these glucose levels within the blood. Stored in the liver, glycogen is found in a-1,4 glygocidic bond. This is the breakdown of glycogen, to glucose-1- phosphate. This involves many enzymes, in particular glycogen phosphorylase, glycogen debranching enzyme and phosphoglycomutase. Glycogen phospholoase, is a homodimeric enzyme subject to allosteric control. Peridoxal phosphatase serves as a prosthetic group for glycogen phosphorylase. its role is to break down the a-1,4 bonds from the non-reducing end, separating the chained clycogen into separate glucose residues, until it reaches 4 away from a 1,6 glycocidic bond. This is known as the branched portion of glycogen. Glycogen disbranching enzyme results in transferase activity, that is transferring 3 glucose residues to the lower chain enabling glycogen phosphorylase to act. Glycogen debranching enzyme then breaks this a-1,6 bond, freeing the last glucose molecule. Glycogen phosphorylase continues its action. Phosphoglycomutase then acts to convert a glucose-1- phospate into a glucose-6-phosphate, found in the lumen of the liver and kidney. This can enter the glycolytic pathway and glycolysis. This is particularly active in skeletal muscle, supports muscle contraction. However, in the liver, glucose is released in the blood. This enables the use of glucose-6- phosphatase. Normal blood glucose levels range between 60-90mg/100ml, in cases where blood glucose drops, this enzyme is required. It converts glucose-6-phostapte into glucose. Glucose-6-phosphotase In the liver it is converted to glucose, by phosphoglycomutase. It is the main source of energy for the brain and red blood cells. In the muscle in undergoes glycolysis/cac and etc or is stored as glycogen. The Cori Cycle: There is no glucose-6-pohsphatase present in skeletal muscle. ATP is produced by glycolysis (g-1-p converted by phosphoglycomutase into g-6-p which enters glycolysis in the muscle) in this process glycogen is converted into lactate and ATP for rapid contraction. In the skeletal muscle from glucose to pyruvate to lactate. Pyruvate to lactate via lactate dehydrogenase, (NADH2 – NAD) In the liver: lactate to pyruvate to glucose (lactate to pyruvate by ldh) Also alanine cycle from pyruvate by gluatamate (alanine transferase) results with alpha ketoglutarate & alanine, opposite in the liver. Amino acid metabolism in the liver This is the process of deamination and transamination of amino acids, followed by the conversion of the non-nitrogenous parts of those molecules to glucose or lipids. Enzymes include alanine, aspartate aminotransferases, Transport across membranes: plasma membrane – cytosolic different to extracellular side. Glycolipids found on the outside of the cell Mechanisims: osmosis, facilitated transport (down a concretion gradient via a specific transporter), active transport (against concentration gradient, through a specific transporter) facilitated: glucose trasporter: GLUT1-5 Taken into the cell when glucose concentration manner. Intake into brain and rbc = insulin independent. Muscle and adipose tissue, insulin dependent. Different glucose transporter isoforms with variability in their kinetics and mechanisms of action respond to the physiological demands of the body and maintain glucose levels within 4-5mM Liver and pancreas GLUT2: high km for glucose. Therefore when glucose levels within the blood is high, maximal uptake is possible. In pancreatic beta cells, glucose uptake signals that blood glucose is high, this responds with secretion of insulin. When insulin reacts with its receptor, vesicles move to the surface and fuse with the plasma membrane increasing no of glucose transporters in the plasma membrane. When glucose levels drop transporters are removed from the membrane by forming small vesicles. Insulin stimulates glut4 expression on myocytes (synthesising glycogen) and adipocytes (synthesising triacylglycerols). This results in an increase of glucose uptake by 15x or more. Type 1 diabetes, no insulin production, no mobilisation of glut4, high blood glucose. Regulation of Glucose metabolism: After a meal, the liver converts glucose absorbed from the blood into glycogen. Between meals the liver converts glycogen into glucose (glycogenolysis) to maintain a constant blood glucose concentration. How are these two processes regulated? This is done via a process called gluconeogenesis, which runs in parallel with glycolysis. Strategies for metabolic control Why does the body need to regulate pathways, how does the body regulate pathaways. 1. Regulation of enzyme concentration 2. Regulation of enzyme activity Regulation of enzyme concentration (slow) , regulation of enzyme activity (fast) regulation of enzyme concentration in cells and is role in the regulation of cellular metabolism. Enzymes act as catalysts for chemical reactions within an organisms body, thereby dictating the metabolism of an organism. Metabolic regulation is achieved through 2 controls. These are the regulation of enzyme concentration, a slow way to increase or decrease action, or actual control of the enzymes ability for action. This is modulated in two ways, inhibition and stimulation of classical enzymes or modulation of an enzymes active site. This is achieved either be allosteric modulation of activity, or covalent modulation of enzymes. Certain enzymes are not expressed in certain tissues, therefore limiting the movement of various substances in and out of a cell. For example skeletal muscle do not contain glucose-6-phosphotae, and therefore glucose cannot exit the muscle. Concentration of certain enzymes are required to be maintained at constant levels within some tissues to ensure continual function. Mitochondrial enzymes use oxygen to enable constant production of ATP by mitochondria. These enzymes are termed constitutive proteins. The expression of enzymes that are needed under only specific physiological states are regulated by the modulation of their synthesis. In times of need, enzyme concentration can be increased via various cell signals that usually result in gene translation and enzymatic production. Reducible enzymes are termed, due to repression of synthesis, most likely by the end product of a metabolic pathway. In this situation, the product that relied on the enzyme to be produced is not found in high concentrations, causing negative feedback on the enzyme action. kinetic regulation of enzyme activity Enzyme Kinetics is the rate at which enzymes act of their substrate to produce a reaction, Modulation of this results in the regulation of enzyme activity. Classical Michaelis-Menten Kinetics displays a hyperbola rate of enzyme reaction. It shows enzyme rate is proportional to the concentration of substrates, however when enzyme activity approaches a limiting rate when s substrate levels continual increase. This shows that under constant ezyme levels, enzymatic rection increases, but will reach a maximum rate of reaction, regardless if substrate levels continue to increase. Glucokinase is an enzyme that facilitates the conversion of glucose to g-6-p. It acts as a glucose sensor, responding to falling or increasing glucose levels. Glucokinase (liver) had a stong affity for glucose of 12mM and hexokinase (Glucokinase 1) has a lower affinity 0.04mM. Activity of Glucokinase facilitates the conversion of glucose to g-6-p. Within skeletal muscle, catalysis of the reaction occurs efficiently under normal conditions. It acts in combination with GLUT4 to maintain a balance between glucose uptake and glucose phosphorylation. It is also allosterically inhibited by g6p in order to prevent build up of gp6 within a cell. Km refers to the substrate concentration at 50% of enzyme activity. Km of hexokinase 1 = 0.04M. Within the liver however, hexokinase IV has a km of 10mM. Therefore it will only phosphorylate glucose when levels are high, providing g6p for glycogen synthesis. It acts in combination with GLUT2. Glucokinase and glut2 allow intracellular g6p to equal blood glucose concentrations of 5mM, enabling beta cells to respond to elevated blood glucose levels. It is not inhibited be g6p allosterically but by other intermediate metabolites. Therefore after ingestion of carbohydrates, there is an increase of Glucokinase activity and reduction of g6phosotase, favouring g6p production. When blood concentration is 5mM there the no ne flux
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