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Storage Mechanisms and Control in Carbohydrate Metabolism

Storage Mechanisms and Control in Carbohydrate Metabolism. Chapter 18. Dr. M. khalifeh. Glycogen Metabolism. When digest a meal high in CHO  supply of glucose exceeds immediate needs  store glucose as a polymer of glycogen.

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Storage Mechanisms and Control in Carbohydrate Metabolism

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  1. Storage Mechanisms and Control in Carbohydrate Metabolism Chapter 18 Dr. M. khalifeh

  2. Glycogen Metabolism • When digest a meal high in CHO  supply of glucose exceeds immediate needs  store glucose as a polymer of glycogen. • In the degradation of glycogen, several glucose residues can be released at one time •  one from each end of a branch  this feature is useful to provide energy as quickly as possible. • Glucose reserves are like ready cash, whereas lipid reserves are like a fat savings account. • It is only after glycogen supplies are depleted the fat burning becomes important. • The body use glycogen for energy storage, than fat due to:- • Muscle cannot mobilize fat as rapidly as they can glycogen Dr. M. khalifeh

  3. Breakdown of Glycogen • Glycogen is primarily found in liver and muscle. • Release of glycogen in liver is triggered by •  low level of glucose in blood. • Glycogen degradation consists of 3 steps:- • The release of glucose 1-phosphate from glycogen • The remodeling of glycogen substrate to permit further degradation • The conversion of glucose 1-phosphate into glucose 6-phosphate for further metabolism

  4. Glycogen Breakdown: Glucose-1-phosphate Glycogen is cleaved by phosphate to give Glucose-1-phosphate Cleavage reaction is phosphorolysis not hydrolysis No ATP is involved in reaction Reaction is catalyzed by glycogen phosphorylase Dr. M. khalifeh

  5. glycogen phosphorylase • This enzyme will only release a glucose unit that is at least 5 units from a branch point • Leave 4 glucose attached to the branch Dr. M. khalifeh

  6. Debranching Glycogen: remodeling Complete breakdown requires debranching enzymes to degrade the a(1-6) linkage Glycogen debranching enzyme (transferase) shift a block of 3 residues from one outer branch to the other the residue remaining at the branch point is hydrolyzed by further action of debranching enzyme to yield free glucose. The new elongated branched is subject to degradation by glycogen phosphorylase Dr. M. khalifeh

  7. Glycogen Breakdown In the second reaction, glucose-1-phosphate is isomerized to Glucose-6-phosphate Save ATP ! Glucose-6-phosphate is formed in the first step of glycolysis through the action of either hexokinase or glucokinase Require ATP This reaction is catalyzed by phosphoglucomutase G6P enter into glycolysis in muscle hydrolysis to glucose in liver and transfer to blood stream

  8. Glycogen Synthesis • Glycogen biosynthesis and breakdown must occur by separate pathways. • The formation of glycogen from glucose is not the exact reversal of the breakdown of glycogen to glucose. • The enzymes catalyzing the 3 steps involved in the glycogen synthesis pathways are:- • UDP-glucose pyrophosphorylase • Glycogen synthase • Glycogen branching enzyme Dr. M. khalifeh

  9. Formation of glycogen from glucose • The synthesis of glycogen requires energy, which is provided by the hydrolysis of UTP. • Glucose-1-phosphate reacts with UTP to make UDPG • UDPG is then added to a growing chain of glycogen, catalyzed by glycogen UDPG pyrophosphorylase • G1P + UTP  UDP-glucose (UDPG) + PPi • (by UDPG pyrophosphorylase). • Pyrophosphate is also formed Dr. M. khalifeh

  10. How is Glycogen formed from Glucose? • Coupling of UDPG formation with hydrolysis of Pyrophosphate drives formation of UDPG to completion Dr. M. khalifeh

  11. UDPG – glucose pyrophosphatase • Phosphoryl oxygen of G1P attacks the alpha phosphorus atom of UTP to from UDPG and release PPi. • The PPi is rapidly hydrolyzed by inorganic pyrophosphatase Dr. M. khalifeh

  12. The key regulatory enzyme in glycogen synthesis The glycosyl unit of UDPG is transferred to the C4 – OH group on one of glycogen’s nonreducing ends to form a alpha (14) glycosidic bond The glycosyl synthase is thought to involve a glycosyl oxonium ion intermediate Reaction Catalyzed by Glycogen Synthase Dr. M. khalifeh

  13. Glycogen Synthase • Glycogen synthase can only extend an already existing alpha (14) glycosidic bond. • Glycogen synthase cannot simply link together 2 glucose residues • So that first step in glycogen synthesis is the self-catalyzed attachment of a glucose residue to the Tyr 194OH groupof a protein named “Glycogenin” (a primer) • Glycogenin initiates glycogen synthesis. • Glycogenin is an enzyme that considered as glucose acceptor. • Act as catalyst for Glucose addition until 8 units • Glycogen synthase take over Dr. M. khalifeh

  14. Glycogen Branching • Branches are created by the transfer of terminal chain segments consisting of ~7 glucosyl residues to C6 – OH group of glucose residues on the same or another glycogen chain • Each transferred segment must come from a chain of at least 11 residues, and new branch point must be at least 4 residues away from the other branch point • Debranching involves breaking alpha(1—6) and reforming alpha(14) glycosidic bonds • Branchinginvolves breaking alpha(14) glycosidic bonds and reforming alpha(16) linkages. Dr. M. khalifeh

  15. Glycogen Metabolism

  16. Phosphorylase is regulated by allosteric interactions and reversible phosphorylation • Glycogen metabolism is precisely controlled by multiple interlocking mechanisms, and focus on glycogen phosphorylase. • Phosphorylase is regulated by several allosteric effectors that • signal the energy state of the cell • responsive to hormones:- insulin, glucagon and epinephrine

  17. Phosphorylase a convert to phosphorylase b by phosphorylase kinase The T-state is less active because the catalytic site is partial blocked. It easily accept Phosphate In R-state, the catalytic site is more accessible In muscle, phosphorylase bis active only in the presence of high [AMP] (in R-state). ATP & G6Pacts as a negative allosteric effector by competing with AMP and so favors the T-state

  18. Under physiological condition, phosphorylase b is inactive due to the inhibitory effects of ATP and G6P In contrast,phosphorylase a is fully active, regardless of the level of AMP, ATP and G6P In resting muscle, nearly all enzymes are in the inactive b form When exercise, the elevated level of AMP leads to the activation of phosphorylase b Exposed to the action of phosphotase

  19. Regulation of liver glycogen phosphorylase differs markedly from that of muscle. Liver phosphorylasea but not bexhibit the most responsive T-to-R transition The binding of glucose shifts the allosteric equilibrium of the a form from R to the T state, deactivating the enzyme. Liver phosphorylase in insensitive to regulation by AMP, due to liver does not undergo the dramaticchanges in energy charge seen in a contracting muscle

  20. Dr. M. khalifeh

  21. Control of Glycogen Metabolism • When cAMP decrease, phosphorylation rate decrease, dephosphorylation increase and the fraction of enzymes in their dephosphorylated form increase • The resultant activation of glycogen synthase, and the inhibition of glycogen phosphorylasecause a change in the flux direction toward net glycogen synthesis Dr. M. khalifeh

  22. Control of Glycogen Metabolism (Cont’d) • The covalent modification is under hormonal control • Hormonal signals (glucagon or epinephrine) stimulate glycogen synthase phosphorylation • After phosphorylation, glycogen synthase becomes inactive at the same time the same hormonal signal is activating phosphorylase • Glycogen synthase can be phosphorylated by several other enzymes including phosphorylase kinase • Dephosphorylation is by phosphoprotein phosphatase Dr. M. khalifeh

  23. Gluconeogenesis Gluconeogenesis: pyruvate → glucose Gluconeogenesis is not exact reversal of glycolysis; that is, pyruvate to glucose does not occur by reversing the steps of glucose to pyruvate Three Glycolysis reactions have such a large negative DG that they are essentially irreversible. Hexokinase(Glucose to glucose-6-phosphate) Phosphofructokinase(Fructose-6-phosphate to fructose-1,6-bisphosphate) Pyruvate Kinase(Phosphoenolpyruvate to pyruvate + ATP) Net result of gluconeogenesis is reversal of these three steps, but by different pathways and using different enzymes Dr. M. khalifeh

  24. Oxaloacetate is an Intermediate • In first step, pyruvate is carboxylated to oxaloacetate • Requires Biotin (CO2 carrier) • Requires ATP • Pyruvate carboxylase (mitochodria) is subject to allosteric control; it is activated by Acetyl CoA Dr. M. khalifeh

  25. Pyruvate Carboxlyase Reaction Mean that CO2 is accumlated Dr. M. khalifeh

  26. Fate of Oxaloacetate • Oxaloacetate formed in mitochondria (trapped) • must leave because all the rest of the gluconeogenesis enzymes are in the cytosol • malate dehydrogenase a mitochondrial enzyme change Oxaloacetate to malate • Oxaloacetate + NADH + H+ malate (mitochondria) + NAD+ • malatecan be transported through the mitochondrial membrane • malate dehydrogenasecytosolic enzyme • malate + NAD+  oxaloacetate + NADH + H+ Dr. M. khalifeh

  27. Fate of Oxaloacetate • The GTP-dependent decarboxylation of oxaloacetate • Enzyme = PEP carboxykinase is a cytosolic and mitochodriaenzyme • Oxaloacetate continue to form PEP (in cytoplasm or mitochodria) • PEP leaves mitochondria to continue the Gluconeogenesis in cytoplasm Dr. M. khalifeh

  28. Gluconeogenesis (Cont’d) • Next, decarboxylation of oxaloacetate is coupled with phosphorylation by Carboxikinase to give PEP • The net reaction of carboxylation/decarboxylation is at equilibrium as small amount accumulated will drive the rxn • Low of mass action (relates concentration of R and P in equ Pyruvate + ATP +GTP → Phosphenolpyruvate + ADP + GDP + Pi Dr. M. khalifeh

  29. Role of Sugar Phosphates • Other different reactions in gluconeogenesis relative to glycolysis involve phosphate-ester bonds bound to sugar-hydroxyl groups being hydrolyzed • G° = -16.7•kJ mol-1 • Fructose-1,6-bisphosphatase is an allosteric enzyme, inhibited by AMP and activated by ATP Dr. M. khalifeh

  30. Role of Sugar Phosphates (Cont’d) • Another reaction is the hydrolysis of glucose-6-phosphate to glucose and phosphate ion • Takes place in ER • Reaction also spontaneous (G°’ = -13.8 kJ mol-1) • Reaction catalyzed by glucose-6-phosphatase Dr. M. khalifeh

  31. Why is phosphofructokinase, rather than hexokinase, the key control point of glycolysis? • Because glucose-6-phosphate is not only an intermediate in glycolysis. It is also involved in glycogen synthesis and the pentose phosphate pathway. • PFK catalyzes the first unique and irreversible reaction in glycolysis. Dr. M. khalifeh

  32. PFK-2 F-6-P F-2,6-P2 PFK-1 + F-1,6-P2 glycolysis Phosphofructokinase (PFK-1) as a regulator of glycolysis • PFK-1 activated by: • Fructose-2,6-bisphosphate (F-2,6-P2) • Activates PFK-1 by increasing its affinity for fructose-6-phosphate and diminishing the inhibitory effect of ATP. F-2,6-P2 Dr. M. khalifeh

  33. kinase ATP ADP fructose-2,6-bisphosphate fructose-6-phosphate Pi phosphatase Phosphofructokinase-2 (PFK-2) is also a phosphatase (bifunctional enzyme) • Bifunctional enzyme has two activities: • Phosphofructokinase-2 (PFK2) activity • decreased by phosphorylation • 2,6-Fructose bisphosphatase(FBPase) activity • increased by phosphorylation Dr. M. khalifeh

  34. Control of Carbohydrate Metabolism • High concentration of F2,6P stimulates glycolysis • Low concentration stimulates Gluconeogenesis • Concentration of F2,6P in a cell depends on the balance between • synthesis (catalyzed by phosphofructokinase-2) • breakdown (catalyzed by fructose bisphosphatase-2) Dr. M. khalifeh

  35. Mechanisms of Metabolic Control • Substrate cycling • opposing reactions can be catalyzed by different enzymes and each opposing enzyme or set of enzymes can be independently regulated Dr. M. khalifeh

  36. Organs Share Carbohydrate Metabolism The Cori cycle • Under vigorous exercise, glycolysis in muscle tissue converts glucose to pyruvate; NAD+ shortage, NAD+ is regenerated by reduction of pyruvate to lactate • Lactate from muscle is transported to the liver, reoxidized to pyruvate, and converted to glucose • The liver shares the stress of vigorous exercise Dr. M. khalifeh

  37. The Cori Cycle Dr. M. khalifeh

  38. Control Points in Carbohydrate Metabolism First and last steps in glycolysis are major control points in glucose metabolism Hexokinase Inhibited by high levels of glucose 6-phosphate When glycolysis is inhibited through phosphofructokinase, glucose 6-phosphate builds up, shutting down hexokinase Glucokinase in liver is activated by high glucose in liver Glucose ---- G6P This will activate glucogenesis (glycogen formation not needed for energy release) Dr. M. khalifeh

  39. Control Points in Carbohydrate Metabolism • First and last steps in glycolysis are major control points in glucose metabolism • Pyruvate kinase (PK) is an allosteric enzyme • Inhibited by ATP and alanine (a.a. version of pyruvate) • Activated by fructose-1,6-bisphosphate • Pyruvate kinase have 3 different subunits • Native PK is a tetramer • Liver isoenzymes are subject to covalent modification • phosphorolyation make PK less active Dr. M. khalifeh

  40. Glycogen metabolism • The glucose 6-phosphate derived from glycogen breakdown has 3 fates:- • It is the initial substrate for glycolysis • It can be processed by the pentose phosphate pathway to yield NADPH and ribose phosphate • It can be converted into free glucose for release into the blood stream (mainly in the liver, lesser extent in intestine and kidney) Dr. M. khalifeh

  41. Pentose Phosphate Pathway • Consist of two irreversible oxidative rxn and a series of reversible sugar phosphate inter-conversion • CO2 is released +2 NADPH • Other names: Phosphogluconate Pathway Hexose Monophosphate Shunt Dr. M. khalifeh

  42. The Pentose Phosphate Pathway Dr. M. khalifeh

  43. Glucose-6-phosphate Dehydrogenase catalyzes oxidation of G6P NADP+ serves as electron acceptor. NADPH/NADP+ ratio control the Enz activity Dr. M. khalifeh

  44. Phosphogluconate Dehydrogenase catalyzes oxidative decarboxylation of 6-phosphogluconate, to yield the 5-C ketose ribulose-5-phosphate. This promotes loss of the carboxyl at C1 as CO2. NADP+ serves as oxidant. Dr. M. khalifeh

  45. NAD+ serves as electron acceptor in catabolic pathways, in which metabolites are oxidized. The resultant NADH is reoxidized by the respiratory chain, producing ATP. • NADPH, a product of the Pentose Phosphate Pathway, functions as a reductant in anabolic (synthetic) pathways, e.g., fatty acid synthesis. • (instead of transfering electron to oxgyen as in NADH the energy is used in biosynthesis) Reduction of NADP+ (as with NAD+) involves transfer of 2e- and 1H+ to the nicotinamide moiety. Dr. M. khalifeh

  46. Reversible rxns Catalyze sugar interconversion Epimerase inter-converts stereoisomers ribulose-5-P and xylulose-5-P. Isomerase converts the ketose ribulose-5-P to the aldose ribose-5-P. Dr. M. khalifeh

  47. Transketolase transfers a 2-C fragment from xylulose-5-phosphate to either ribose-5-phosphate or erythrose-4-phosphate. Dr. M. khalifeh

  48. Transaldolase catalyzes transfer of a 3-C fragments, from sedoheptulose-7-phosphate to glyceraldehyde-3-phosphate. Dr. M. khalifeh

  49. Depending on needs of a cell for ribose-5-phosphate, NADPH, and ATP, the Pentose Phosphate Pathway can operate in various modes, to maximize different products. There are two major scenarios: Ribulose-5-P may be converted to ribose-5-phosphate, a substrate for synthesis of nucleotides and nucleic acids. The pathway also produces some NADPH. Dr. M. khalifeh

  50. Glyceraldehyde-3-P and fructose-6-P, formed from 5-C sugar phosphates, may enter Glycolysis for synthesis of ATP. The pathway also produces some NADPH. Dr. M. khalifeh

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