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Unformatted text preview: Lecture 36-37: Glycolysis Regulation Regulation of the Glycolytic Pathway 1. Regulation of flux through the glycolytic pathway is determined by the activities of several enzymes rather than 1 rate limiting enzyme 2. The relative contribution of an individual enyzme to glycolytic flux varies from tissue to tissue and with changes in nutritional and hormonal state 3. Control strength : relative contribution of a particular enzyme to flux through a pathway under a particular set of conditions a. Inhibition of 10% activity no effect (10/0). Activity of this enzyme does not determine flux under selected conditions b. Inhibition of 10% activity 10% inhibition of flux through a pathway. Control strength = 1.0 c. Inhibition of 10% activity 5% inhibition of flux. Control Strength = 0.5 4. With the caveat that regulation of flux through glycolysis is dependent on the tissue under consideration and the nutritional and hormonal state of the tissue a. Hexokinase b. 6-phosphofructo-1-kinase c. pyruvate kinase i. regulated by allosteric effectors and/or covalent modification Hexokinase and Glucokinase have different properties 1. Different isoenzymes of hexokinase are expressed in different tissues of the body 2. Hexokinase a. In most tissues b. Low Km for glucose (<0.1 mM) (blood 5mM) c. Strong product inhibition by glucose 6-phosphate 3. Glucokinase a. In liver b. S0.5 (substrate concentration that gives enzyme activity of vmax is 7mM much higher than Km of hexokinase c. Not subject to product inhibition by G6P 4. Glucose saturation curve for glucokinase is sigmoidal; cooperativity is observed as a function of glucose concentration and therefore doesnt follow simple Michaelis Menton kinetics Glucokinase 1. Indirect inhibition by fructose-6-phosphate 2. A special glucokinase regulatory protein (GK-RP) is located in nucleus of liver cells and sequesters glucokinase in an inactive complex in the nucleus 3. Fructose 6-phosphate promotes binding of glucokinase to inhibitory protein by an allosteric mechanism a. Inhibits glucokinase b. Fructose 6-phosphate promotes transloation of glucokinase from the cytosol to the nucleus where glucokinase is completely inhibited by the regulatory protein c. This inhibitory effect of F6P on glucokinase is opposed by glucose and can be completely overcome by a large enough increase in glucose concentration Fructose Intolerance 1. Deficient in liver aldolase responsible for splitting fructose 1-phosphate into dihydroxyacetone phosphate and glyceraldehyde 2. Consumption of glucose results in accumulation of F6P and depletion of Pi and ATP in liver 3. Damage results in cells b/c they are incapable of maintaining normal ion gradients by means of the ATP dependent cation pumps 4. Cells swell and eventually lose their internal contents by osmotic lysis 5. Should not be used for parenteral nutrition Fructose 1. component of vegetables, fruit, sweeteners 2. promotes hepatic glucose utilization by indirect mechanism...
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