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GLYCOLYSIS Prof. S. Kajuna Catabolism Central Role of Glucose Overview of glycolysis Two phases of glycolysis Two phases of glycolysis Preparatory Phase Reaction 1: phosphorylation pg 526 Reaction 1: phosphorylation Hexokinase vs. glucokinase Tissue-specific isozymes. Reaction 2: isomerization aldose ketose Reaction 2: isomerization Reaction 3: phosphorylation Reaction 3: phosphorylation Reaction 4: cleavage Reaction 4: cleavage Reaction 5: isomerization Reaction 5: isomerization Keeping Track of Carbons G3P glucose Reaction 6: oxidation Reaction 6: oxidation Reaction 7: substrate level phosphorylation Reaction 8: shift of phosphoryl group Reaction 8: shift of phosphoryl group ~Fig 14-8 Reaction 9: dehydration Reaction 10: substrate level phosphorylation Summary Energy investment Cleavage Energy Harvest https://www.youtube.com/watch?v=EfGlznwfu9U Efficiency Feeder Pathways All carbohydrate s enter glycolysis In muscle, often via hexokinase glycerol Glycerol 3-P Fig 14-9 Fructose intolerance Hereditary fructose intolerance results from a defect in fructose breakdown in the liver, usually in aldolase. Glycogen Breakdown Glycogen Breakdown Glycogen phoshorylase catalyzes the simultaneous phosphorylation and cleavage of an a-1,4 linked glucose from a non-reducing end of glycogen. This reaction is called “phosphorolysis.” Glycogen Phosphorylase Glycogen Fig 15-12 Breakdown Step 1. Glycogen Phosphorylase Pyridoxal phosphate Fig 14-12 Glycogen Fig 15-12 Breakdown Phosphoglucomutase Fig 15-29 G6P fate depends on tissue. In muscle, G6P proceeds through glycolysis. In liver, G6P is converted to glucose. Limit Dextrins Glycogen Breakdown Debranching enzyme Fig 15-28 Glycogen storage diseases Fate of the products, pyruvate and NADH Fig 143 Fig 143 Fermentation in Animals Fermentation in Animals • Lactic acid from skeletal muscle is sent into the bloodstream. • Lactate threshold occurs when production exceeds clearance. Glycolysis cannot continue. Cori Cycle Fermentation in Yeast Fermentation in Yeast Pyruvate decarboxylase reaction Alcohol dehydrogenase reaction Regulation of glycolysis Irreversible steps are regulated: Hexokinase/Glucokinas e Phosphofructokinase I Pyruvate Kinase Control of Hexokinase Glucose + ATP G6P + ADP Feedback inhibition by G6P. Tissue-specific isozymes. Control of PFK-1 Many allosteric effectors; e.g., ATP. H+, Control of PFK-1 ATP is an allosteric inhibitor of PFK1. Two binding sites: substrate and allosteric site. Control of pyruvate kinase PEP + ADP pyruvate + ATP Control of pyruvate kinase Fig 15-19 Control of glycogen phosphorylase phosphorylation phosphorylase b (inactive) phosphorylase a (active) glycogen breakdown Glycogen phosphorylase is activated upon phosphorylation by phosphorylase kinase. Glycogen phosphorylase is activated upon phosphorylation by phosphorylase kinase. Phosphorylase kinase is activated upon phosphorylation by protein kinase A (PKA). Glycogen phosphorylase is activated upon phosphorylation by phosphorylase kinase. Phosphorylase kinase is activated upon phosphorylation by protein kinase A (PKA). PKA is activated by cyclic AMP, which is produced by a G-protein in response to epinephrine/glucagon. Fig 14-1 NADPH is necessary to protect against reactive oxygen species Transketolase requires thiamine pyrophospate (TPP) as a coenzyme Ribose 5-P is necessary in rapidly dividing cells Oxidative phase •Rxns 1 and 3 produce NADPH •Rxn 4 produces ribose-5phosphate Glucose 6-P + 2 NADP+ + H2O Ribose 5-P + 2 NADPH + 2 H+ + CO2 From C1 Key Enzyme: G6P Dehydrogenase Case Study Omar’s mother noticed that every time she served falafel, her son complained of feeling tired, hot, headachy, and sick to his stomach. At first she thought he was just being fussy, but sometimes he would actually look yellow. Medical testing confirmed hemolytic anemia. What’s up with Omar? Divicine leads to reactive oxygen species Favism! A deficiency in G6PDH is the most common human enzyme defect, affecting more than 400 million people worldwide. Protective against malaria. Case Study Omar’s mother noticed that every time she served falafel, her son complained of feeling tired, hot, headachy, and sick to his stomach. At first she thought he was just being fussy, but sometimes he would actually look yellow. Medical testing confirmed hemolytic anemia. What’s up with Omar? X Regulation G6P dehydrogenase is allosterically inhibited by NADPH; activated by NADP+ Oxidative Phase Glucose 6-P + 2 NADP+ + H2O Ribose 5-P + 2 NADPH + 2 H+ + CO2 Some cells need NADPH but not ribose 5-P Ribose 5-P can be recycled in the nonoxidative phase Pentose Phosphate Pathway: Nonoxidative Phase Fig 14-22 Fig 14-23 Ribose 5-phosphate Carbon Shuffling Reactions Glucose 6-phosphate Fig 14-23