Glycolysis PDF

Glycolysis  Glucose is a central to metabolism Glucose is relatively rich in potential energy - the complete oxidation of glucose to carbon dioxide and water proceeds with a standard free-energy change of −2,840 kJ/mol. Glucose can be stored in large quantities as high m...

Glycolysis  Glucose is a central to metabolism Glucose is relatively rich in potential energy - the complete oxidation of glucose to carbon dioxide and water proceeds with a standard free-energy change of −2,840 kJ/mol. Glucose can be stored in large quantities as high molecular weight polymers such as starch or glycogen while maintaining a relatively low cytosolic osmolarity. Glucose is a versatile precursor, capable of supplying a huge array of metabolic intermediates for biosynthetic reactions.  Glycolysis Glycolysis was the rst metabolic pathway to be elucidated. Greek glykys, “sweet” or “sugar,” and lysis, “splitting”. Glycolysis is an almost universal central pathway of glucose catabolism, the pathway with the largest ux of carbon in most cells. A molecule of glucose is degraded in a series of enzyme- catalyzed reactions to yield two molecules of the three-carbon compound pyruvate. Glycolytic breakdown of glucose is the sole source of metabolic energy in some mammalian tissues and cell types (eg. erythrocytes, renal medulla, brain, and sperm). Some of the free energy released from glucose is conserved in the form of ATP and NADH. fl fi  Glycolysis The breakdown of the six-carbon glucose into two molecules of the three- carbon pyruvate occurs in 10 steps, the rst 5 of which constitute the preparatory phase. I n t h e p re p a r a t o r y p h a s e o f glycolysis the energy of ATP is invested, raising the free-energy content of the intermediates, and the carbon chains of all the metabolized hexoses are converted to a common product, glyceraldehyde 3-phosphate. fi  Phosphorylation of Glucose Because the plasma membrane generally lacks transporters for phosphorylated sugars, the phosphorylated glycolytic intermediates cannot leave the cell. After the initial phosphorylation, no further energy is necessary to retain phosphorylated intermediates in the cell, despite the large di erence in their intracellular and extracellular concentrations. Energy released in the breakage of phosphoanhydride bonds (such as those in ATP) is partially conserved in the formation of phosphate esters such as glucose 6-phosphate. ff Conversion of Glucose 6-Phosphate to Fructose 6- Phosphate  Phosphorylation of Fructose 6-Phosphate to Fructose 1,6-Bisphosphate The PFK-1 reaction is essentially irreversible under cellular conditions, and it is the rst “committed” step in the glycolytic pathway; glucose 6-phosphate and fructose 6- phosphate have other possible fates, but fructose 1,6-bisphosphate is targeted for glycolysis. fi  Cleavage of Fructose1,6-Bisphosphate Reversible aldol condensation reaction Although the aldolase reaction has a strongly positive standard free- energy change in the direction of fructose 1,6-bisphosphate cleavage, at the lower concentrations of reactants present in cells the actual free-energy change is small and the aldolase reaction is readily reversible (gluconeogenesis).  Interconversion of the Triose Phosphates Only one of the two triose phosphates formed by aldolase, glyceraldehyde 3-phosphate, can be directly degraded in the subsequent steps of glycolysis. The other product, dihydroxyacetone phosphate, is rapidly and reversibly converted to glyceraldehyde 3-phosphate.  The energy gain comes in the payo phase of glycolysis. Each molecule of glyceraldehyde 3-phosphate is oxidized and phosphorylated by inorganic phosphate (not by ATP) to form 1,3- bisphosphoglycerate. Energy is then released as the two molecules of 1,3-bisphosphoglycerate are converted to two molecules of pyruvate. Much of this energy is conserved by the coupled phosphorylation of four molecules of ADP to ATP. The net yield is two molecules of ATP per molecule of glucose. Energy is also conserved in the payo phase in the formation of two molecules of the electron carrier NADH per molecule of glucose. ff ff  Oxidation of Glyceraldehyde 3-Phosphate to 1,3- Bisphosphoglycerate This is the rst of the two energy- conserving reactions of glycolysis that eventually lead to the formation of ATP. The aldehyde group of glyceraldehyde 3-phosphate is oxidized, not to a free carboxyl group but to a carboxylic acid anhydride with phosphoric acid. Free energy of oxidation of the aldehyde group of glyceraldehyde 3- phosphate is conserved by the formation of the acyl phosphate group of 1,3-bisphosphoglycerate. fi Phosphoryl Transfer from 1,3-Bisphosphoglycerate to ADP Reverse reaction occurs during gluconeogenesis Conversion of 3-Phosphoglycerate to 2- Phosphoglycerate Dehydration of 2-Phosphoglycerate toPhosphoenolpyruvate  Transfer of the Phosphoryl Group from Phosphoenolpyruvate to ADP Overall Balance Sheet Shows a Net Gain of ATP Three possible catabolic fates of the pyruvate formed in glycolysis.  Pyruvate Is the Terminal Electron Acceptor in Lactic Acid Fermentation The lactate formed by active skeletal muscles (or by erythrocytes) can be recycled; it is carried in the blood to the liver, where it is converted to glucose during the recovery from strenuous muscular activity. Ethanol Is the Reduced Product in Ethanol Fermentation Pyruvate decarboxylase is present in brewer’s and baker’s yeast (Saccharomyces cerevisiae) and in all other organisms that ferment glucose to ethanol, including some plants. The CO produced by pyruvate 2 decarboxylation in brewer’s yeast is responsible for the characteristic carbonation of champagne.  High Rate of Glycolysis in Tumors The anaerobic metabolism of glucose in tumor cells yields far less ATP. Glycolytic enzymes are overproduced in tumors. Hexokinase inhibitors are good anti- cancer drugs. Positron emission tomography (PET) used for Cancer diagnosis use labeled compound is 2- uoro-2-deoxyglucose (FdG), in which the hydroxyl group at the C-2 of glucose is replaced with 18F. fl  Type 1 Diabetes Mellitus Glucose uptake from the blood is mediated by the GLUT family of glucose transporters