Lecture 15 Chapt 16 Glycolysis Living organisms like machines conform to the law of conserva on of energy and must pay for all their ac vi es in the currency of catabolism Ernest Baldwin Dynamic Aspects of Biochemistry Louie Pasteur s scien c inves ga ons into fermenta on of grape sugar were pioneering studies of glycolysis 1 OUTLINE v Glycolysis First phase Reac ons 1 5 no ATP generated Second Phase Reac ons 6 10 genera on of ATP v Feeder pathway to glycolysis other sugars can also enter the glycoly c pathway v Regula on of glycolysis v Glucose transporters v Fate of pyruvate under anaerobic condi ons In yeast Alcohol fermenta on In other microorganisms and exercising muscle Lac c acid fermenta on v Hypoxia Inducible Factor 2 Metabolic pathways are compartmentalized within cells Glycolysis pathway common to both prokaryotes and eukaryotes In eukaryotes glycolysis takes place in cytoplasm Phase 1 Phase 2 25 ATP 3 1st Stage of Glycolysis Uses 2 molecules of ATP glucose but makes no ATP Traps and prepares glucose for following oxida on steps Glucose is converted to glyceraldehyde 3 phosphate GAP 5 steps 1 Phosphoryla on of glucose 2 Isomeriza on 3 Second phosphoryla on of Fructose 6P 4 Cleavage into two 3 carbon molecules 5 Isomeriza on of DHAP to GAP 4 Glycolysis Reac on 1 Phosphoryla on Mg ATP H2O ADP Pi G reac on 1 30 5 kJ mol glucose Pi G 6 P H2O G reac on 2 14 kJ mol glucose ATP G 6 P ADP G overall 16 5 kJ mol 5 Glucose is kept in the cell by phosphoryla on to glucose 6 phosphate 6 Hexokinase 7 Glycolysis Reac on 2 Isomeriza on by phosphoglucose isomerase 8 Glycolysis Reac on 3 Second Phosphoryla on Phosphofructokinase PFK PFK1 9 Glycolysis Reac ons 4 Cleavage of one 6 carbon to two 3 carbon molecules 10 Glycolysis Reac ons 5 end of 1st phase of glycolysis 11 Second Stage of Glycolysis The three carbon units are oxidized to pyruvate genera ng 4 molecules of ATP glucose and 2 NADH glucose GAP is converted to pyruvate 5 steps 6 Oxida on of GAP to 1 3BPG 7 Phosphoryla on of ADP 8 Mutase 9 Dehydra on by Enolase 10 Phosphoryla on of ADP giving pyruvate 12 Glycolysis Reac on 6 GAP is oxidized to 1 3 BPG 13 Uncoupled Oxida on and Phosphoryla on Reac ons G 50 kJ mol 1 G 56 kJ mol 1 14 Coupling of the two processes by one enzyme allows the conserva on of energy released by oxida on G 6 3 kJ mol 15 Molecules with High Phosphoryl Group Transfer Poten al 16 Glycolysis Reac on 7 ATP producing reac on 2X glucose 2X glucose 2 ATP consumed in the 1st phase of glycolysis Reac ons 1 and 3 are paid o in the this step of the 2nd phase of glycolysis 17 Thermodynamically favorable Reac ons 7 drives the less favorable Reac on 6 Preparative step for ATP production in the following step GAP Step 6 G 6 3 kJ mol 1 3 BPG Compound with High Phosphoryl Group Transfer Poten al G 49 6 kJ mol Actual ATP production Step 7 ATP 18 9 kJ mol 30 5 kJ mol 3 PG The forma on of the high phosphoryl group transfe rpoten al compound 1 3 BPG in step 6 is essen al as a prepara on for the ATP produc on in step 7 18 Glycolysis Reac on 8 Phosphoglycerate Mutase Note The term Mutase is applied to those enzymes that catalyze migra on of func onal groups from one posi on to another on the same substrate molecule 19 Glycolysis Reac on 9 Dehydra on of 2 PG G 1 8 kJ mol 20 Molecules with High Phosphoryl Group Transfer Poten al 21 Glycolysis Reac on 10 ATP synthesizing reac on Regulated step Pyruvate kinase Ketone form G 31 7 kJ mol after removing the energy used to phosphorylate ADP 22 Pyruvate kinase G PFK hexokinase The free energies of the reac ons of glycolysis under standard state condi ons 23 The free energies of the reac ons of glycolysis under actual intracellular condi ons in erythrocytes PFK hexokinase G Pyruvate kinase G 96 kJ mol 1 24 The net reac on for glycolysis is G 96 kJ mol 1 25 Entry points in glycolysis for galactose and fructose 26 Fructose enters the glycoly c pathway in the liver through the fructose 1 phosphate pathway 27 Fructose can be converted to F 6P by hexokinase hexokinase 28 Galactose enters the glycoly c pathway in the liver through the glucose 6 phosphate pathway 29 Glycosyltransferase Reac on phosphoglucomutase G 6P glycolysis 30 Regula on of Glycolysis is Cell Type Dependent Liver uses glucose to maintain blood sugar level Muscles use glucose for fuel ATP to power muscle contrac on 31 Regula on of Glycolysis hexokinase phosphofructokinase pyruvate kinase Enzymes catalyzing irreversible reac on in metabolic pathways are poten al control sites 32 Hexokinase versus Glucokinase Muscle contains Hexokinase I while liver contains Hexokinase IV Glucokinase This is to adapt to the di erent roles of muscle and liver Vmax 2 Km hexokinase 0 03 mM Km glucokinase 10 mM X normal blood sugar X 33 Regula on of Glycolysis Hexokinase Phosphofructokinase PFK PFK 1 Pyruvate kinase Enzymes catalyzing irreversible reac on in metabolic pathways are poten al control sites 34 Glucose 6 P is common to several metabolic pathways Hexokinase PFK 35 Regula on of Allosteric Enzymes by feedback Mechanism Nega ve Feedback Inhibi on X e1 e2 e3 e4 e5 W X Y Z A B C D E F Posi ve Feed Feedback forward ac va on Commimed step 36 Regula on of Phosphofructokinase In muscles PFK PFK1 37 Allosteric Regula on of Phosphofructokinase High AMP Low AMP ATP is an allosteric inhibitor of PFK AMP competes o ATP inhibi on of PFK 38 Regula on of Phosphofructokinase PFK PFK1 In muscles PFK In liver 39 Fructose 2 6 bisphosphate Under hormonal I G regula on 40 The ac va on of phosphofructokinase by fructose 2 6 bisphosphate 41 PFK 42 Regula on of Glycolysis hexokinase phosphofructokinase pyruvate kinase Enzymes catalyzing irreversible reac on in metabolic pathways are poten al control sites 43 Regulatory mechanisms of pyruvate kinase In muscles M form and liver L form ATP In liver only L Protein Kinase A PKA AcetylCoA ATP Alanine 44 The control of the cataly c ac vity of liver L form pyruvate kinase Covalent modi ca on cAMP dependent protein kinase A PKA PEP 45 The regula on of glycolysis in the liver corresponds to the biochemical versa lity of the liver Regulates blood sugar levels PFK and PK Uses glycoly c intermediates as substrates in other pathways PFK and PK In muscle glycolysis is regulated to meet the energy needs of contrac on 46 In muscle glycolysis is regulated to meet the energy needs of contrac on 47 2 1 48 1 2 49 Normal serum glucose concentra on is 4 8 mM 50 Glycolysis helps pancrea c cells sense glucose Lowers blood sugar levels
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