Glucose Metabolism

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Biochemistry & Molecular Bio.
David Gross

Chapter 13: Glucose Metabolism • glucose is stored in polymeric form as starch in plants & glycogen in animals • glycolysis is the breaking of 6-C glucose into 3-C pyruvate • glycolysis (& other metabolic pathways) have the following properties: o each step of pathway catalyzed by distinct enzyme o free nrg consumed or released in some rxns transferred by molecules likeATP & NADH o rate of pathway can b controlled by altering individual enzyme activity • glucose combustion requires many steps so that the cell can recover its free nrg in smaller, more useful quantities 13-1 Glycolysis • overall rxn is a 2-C glucose molec. broken down into 2 3-C pyruvate molecs. • reactions 1-5 are nrg-investment phase of glycolysis 1. hexokinase  hexokinase transfers phosphoryl group fromATP to C6 OH group of glucose, forms glucose-6-phosphate  kinase is an enzyme that transfers phosphoryl group fromATP to substrate °  ∆G =−16.7 , metabolically irreversible rxn, prevents glucose from backing out of glycolysis  many pathways have similar irreversible step near start, commits metabolite to proceed through pathway 2. phosphoglucose isomerase  isomerization rxn, glucose-6-phosphate converted to fructose-6-phosphate  fructose forms 5-member ring °  ∆G =2.2 , but ∆G=−1.4 , freely reversible b/c excess of products can easy drive rxn in reverse 3. phosphogructokinase  second ATP molecule consumed, fructose-6-phosphate yields fructose-1,6- bisphosphate °  ∆G =−17.2 rxn irreversible  regulated allosterically • ADP binds & promotes fructose-6-phosphate binding, increasing catalysis ofATP • phophoenolpyruvate binds & destabilizes fructose-6-phosphate binding, decreasing catalysis ofATP • most potent activator is fructose-2,6-bisphosphate, synthesized by phosphogructokinase-2 from fructose-6-phosphate o regulated by hormones when blood glucose levels high, runs glucose through glycolysis  primary control for glycolysis: • slowest rxn • rate determines the flux 4. Aldolase  converts fructose-1,6-bisphosphate to 2 3-C molecules, each w/ P group • glyceraldehyde-3-phosphate • dihydroxyacetone phosphate ' ∆G =22.8  rxn unfavorable under standard conditions, in vivo ∆G<0 • b/c products are quickly taken away by next rxn 5. triose phosphate isomerase  dihydroxyacetone phosphate converted to glyceraldehyde-3-phosphate  rate of enzyme only limited by rate @ which substrates can diffuse to active site  protein loop closes over active site, low-barrier H-bonds stabilize transition state ∆G =7.9 ∆G=4.4  & , but rxn proceeds quickly b/c products rapidly consumed • Rxn’s 6-10 are nrg payoff phase of glycolysis 6. glyceraldehyde-3-phosphate dehydrogenase  glyceraldehyde-3-phosphate(G3P) is oxidized & phosphorylated to form 1,3-bisphosphoglycerate  inorganic P is added, not P fromATP  aldehyde group of G3P oxidized & cofactor NAD+ reduced to NADH • NADH can be re-oxidized & free nrg harvested to generateATP  enzyme can b inhibited by arsenate through competitive inhibition 7. phosphoglycerate kinase  1,3-BPG (product of #6) is an acyl phosphate  removal of phosphoryl group releases large amount of free nrg b/c products more stable • used to driveATP synthesis, 1,3-BPG donates phosphoryl group to ADP  result is 3-phosphoglycerate (3-PG) ∆G 6.7 ∆G=−18.8  , but so rxn proceeds exergonicly 8. phosphoglycerate mutase  3-phosphoglycerate converted to 2-phosphoglycerate (2-PG)  rxn site requires phosphorylated His res. • transfers phosphoryl group to 3-PG to make 2,3-PG • phosphoryl group transferred back to His, leaving 2-PG  rxn freely reversible 9. enolase  catalyzes dehydration rxn of 2-PG to phosphoenolpyruvate (PEP)  active site contains Mg2+ ion, coordinates w/ OH group, makes it better leaving group 10. pyruvate kinase  transfers phosphoryl group from PEP toADP producing pyruvate &ATP  rxn occurs in 2 parts: • ADP attacks phosphoryl group, formsATP & enolpyruvate • tautomerization (isomerization through shift of an H atom) of enolpyruvate to pyruvate  ∆G=−61.9 for overall rxn, drives ATP synthesis  can be subject to feed-forward activation from fructose-1,6-bisphosphate to ensure rapid flux 13.2 Gluconeogenesis • pathway operates when liver’s supply of glycogen is exhausted • contains several unique enzymes that bypass the 3 irreversible steps of glycolysis, those catalyzed by pyruvate kinase, phosphofructokinase, and hexokinase • 4 gluconeogenic enzymes plus some glycolytic enzymes convert pyruvate to glucose o p
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