MHS_GLYCOGEN SYNTHESIS & BREAKDOWN_Nayyar.pdf

Glycogen: Synthesis & Breakdown Tultul Nayyar, Ph.D., MSCI Associate Professor and Director Master of Health Sciences Program West Basic Science, Room 3210 Phone: 615-327-6898 (O) 615.944.0824 (C) email: [email protected] Glycogen *  Glucose is stored as:  glycogen (animals)  starch (plants) ...

Glycogen: Synthesis & Breakdown Tultul Nayyar, Ph.D., MSCI Associate Professor and Director Master of Health Sciences Program West Basic Science, Room 3210 Phone: 615-327-6898 (O) 615.944.0824 (C) email: [email protected] Glycogen *  Glucose is stored as:  glycogen (animals)  starch (plants)  Glycogen storage: predominantly in the cytosol of liver and muscle cells  Glycogen is a polymer of glucose residues linked by  α(14) glycosidic bonds (OH group of anomeric C of one glucose with the OH of C-4 of another glucose molecule),  α(16) glycosidic bonds, at branch points CH2OH CH2OH H O H OH H H CH 2OH H OH OH CH 2OH O H OH H H H OH H O H OH O OH H H OH H H O H OH H O H OH H H O 4 H 1 O 6 CH2 5 H OH 3 H CH 2OH CH2OH O H 2 OH H H 1 O H 4 OH H O H OH H H O H OH H O H H OH OH Glycogen Functions * In liver – • to maintain blood glucose levels Glycogen breaks down when blood glucose level is low  Glycogen synthesis occurs when blood glucose level is high In muscle – • to meet the energy requirements of the muscle cells (i.e., glycolysis) • Does not yield free glucose Glycogenesis: The Synthesis of Glycogen An Energy Consuming Pathway Reaction step 1 Glucose + ATP  Glucose-6-P + ADP by Hexokinase (or Glucokinase) * [Glucokinase, isoenzyme of hexokinase, present in liver] Fate of Glucose-6-phosphate:  Glycolysis OR Pentose pathway OR  dephosphorylated by Glucose-6-phosphatase to release into blood as glucose (mainly in liver) OR  Converted to Glucose-1-P for glycogen synthesis Glycogen Glucose-1-P Pentose Pathway . Glucose Hexokinase or Glucokinase Glucose-6-Phosphatase Glucose-6-P Glucose + Pi Glycolysis Pathway Pyruvate Reaction step 2 * • Glucose-6-P  Glucose-1-P by phosphoglucomutase Reaction step 3 • Glucose-1-phosphate + UTP  UDP-glucose (UDPG) + PPi catalyzed by UDPG pyrophosphorylase [UTP has the role as source of energy like that of ATP, but more specific for this enzyme]  Uridine diphosphate glucose (UDPG) is the immediate precursor for glycogen synthesis O UDP-Glucose Pyrophosphorylase CH2OH HN O H H OH H O H H O− P O OH O OH − + O − P O O O P − O − O CH2OH H OH HN H O OH H OH O P O O O O H O − UDP-glucose P O O CH2 − H N O H H OH H OH CH2 − UTP PPi O P O glucose-1-phosphate H O O O O H N O H H OH H OH 6 CH H 4 OH 2OH 5 O H OH H 3 H 1 2 H O O P O O 6 CH O H OH C H2 HO CH NH H 3 H 1 2 O C O C H2 OH + UDP CH NH 6 CH 2OH O-linked glucose H residue 4 5 O H OH OH UDP-glucose H 3 H 1 2 H C C H2 O OH O CH + UDP NH CH2OH CH2OH O H H H H OH O H O OH H Uridine O 2OH H H OH O O− 5 OH C P O− OH O-linked glucose H residue 4 H tyrosine residue of Glycogenin UDP-glucose OH α(1 4) linkage H OH H C O C H2 CH NH O + UDP Reaction step 4 Glycogen Synthase catalyzes elongation of glycogen chains α(1-4) linkage is formed between C4 of terminal residue of glycogen chain (non-reducing end) and C1 of UDPG by Glycogen Synthase glycogen(n residues) + UDP-glucose  glycogen(n +1 residues) + UDP  A branching enzyme transfers a segment from the glycogen chain (about 6 glucose residues) to a neighboring chain to form the α (1-6) linkage to yield a branch Deficiency in glycogen branching enzyme, would be likely to cause all of the following effects EXCEPT: Decreased glycogen solubility in human cells Less storage of glucose in the body Glycogen devoid of alpha-1-4 linkages Slower action of glycogen phosphorylase Glycogen is less branched than normal, thereby inducing lower solubility of glycogen. Branches reduce the interactions between adjacent chains of glycogen and encourage interactions with the aqueous environment. The smaller number of branches means that glycogen phosphorylase has fewer terminal glucose monomers on which to act, making enzyme activity slower than normal overall. Finally, without branches, the density of glucose monomers cannot be as high; therefore, the total glucose stored is lower than normal. Glycogen synthase is still functioning normally, so we would expect normal α-1,4 linkages in the glycogen of an individual with Andersen’s disease but few (if any) α-1,6 linkages. The α-1,4-linkage predominates Synthesis requires the addition of glucose to the nonreducing ends of glycogen via UDP-glucose * Glycogenolysis: It is NOT the reverse of glycogenesis Reaction step 1 * Glycogen Phosphorylase catalyzes phosphorolytic cleavage of the α (14) linkages of glycogen, releasing glucose-1phosphate as reaction product glycogen(n residues) + Pi  glycogen (n–1 residues) + glucose-1-phosphate Pyridoxal phosphate, a derivative of vitamin B6, serves as coenzyme for Glycogen Phosphorylase Reaction step 2 * The terminal glucose residues are removed sequentially until 4 residues remain on either side of the a(16) branch Debranching enzyme has 2 catalytic sites : The transferase part transfers 3 glucose residues from the 4-residue limit branch to the end of another branch, diminishing the limit branch to a single glucose residue  The glucosidase part then catalyzes hydrolysis of the a (16) linkage, yielding free glucose. This is a minor fraction of glucose released from glycogen Limit Bra nch (4 residu es) α-(1—>4) tra nsgly cosyl ase (g ro up transfer reaction) α-(1—>6) glu cosid ase Gluc ose A biopsy is done on a child with an enlarged liver and shows accumulation of glycogen granules with single glucose residues remaining at the branch points near the periphery of the granule. The most likely genetic defect is in the gene encoding: α-1,4 phosphorylase (glycogen phosphorylase), α-1,4:α-1,6 transferase (branching enzyme), α-1,4:α-1,4 transferase (part of debranching enzyme complex) or α-1,6 glucosidase (part of debranching enzyme complex) * Reaction step 3 • Glucose 1-P  Glucose-6-P by phosphoglucomutase • Glucose-6-P  glucose by phosphatase in liver but not in muscle The liver releases glucose to the blood to be taken up by brain and active muscle. The liver regulates blood glucose levels The muscle retains glucose 6-phosphate to be used for energy. Phosphorylated glucose is not transported out of muscle cells * Regulation of glycogen metabolism (glycogenesis and * glycogenolysis) Glycogen synthase and glycogen phosphorylase are the principal controlling enzymes   Glycogen synthase activity Phosphorylation decreases the enzyme activity Dephosphorylation increases the enzyme activity Glycogen phosphorylase activity Phosphorylation increases the enzyme activity Dephosphorylation decreases the enzyme activity * In short: • The active form of phosphorylase enzyme is phosphorylated form • Whereas, the active form of synthase enzyme is dephosphorylated form Cyclic AMP (cAMP) increases phosphorylation of these two enzymes (phosphorylase and synthase) cAMP formation is increased by glucagon, epinephrine, norepinephrine and thus stimulates glycogenolysis (because phosphorylase activity increases) inhibits glycogenesis ( because synthase activity decreases) Blood sugar level increases  Hydrolysis of cAMP is increased by insulin (liver) and thus decreases the levels of cAMP, which in turn • stimulates glycogenesis and • inhibits glycogenolysis Blood sugar level decreases * • Liver provides glucose for export whereas muscle provides * glu-6-P for glycolysis to yield ATP • Phosphorylase enz is activated by phosphorylation, catalyzed by kinase to make phosphorylase a (active form of phosphorylase, PR-a) • Phosphorylase is inactivated by dephosphorylation, catalyzed by phosphatase to make phosphorylase b (inactive form of phosphorylase, PR-b) • Insulin causes activation of phosphatase • Thus, results in formation of phosphorylase b (inactive form) • Glycogenolysis inhibition occurs • Leads to reduce blood glucose level PR-b Kinase PR-a (glycogenolysis) Glucagon PR-a Phosphatase PR-b (glycogensynthesis) Insulin • Phosphorylase a is allosterically inhibited by • ATP, glu-6-P in muscle and liver • Free glucose in liver only * Glycogen synthesis and breakdown are reciprocally regulated Red=inactive forms, green = active forms. Active Inactive Protein phosphatase 1 (PP1) regulates glycogen metabolism A Take Home Lesson! • Glucagon = starved state; stimulates glycogen breakdown, inhibits glycogen synthesis • High blood glucose levels = fed state; insulin stimulates glycogen synthesis and inhibits glycogen breakdown A genetic defect in the isoform of an enzyme expressed in liver causes the following symptoms:  After eating a CHO meal, elevated blood levels of glucose, lactate, & lipids.  During fasting, low blood glucose & high ketone bodies. Which liver enzyme is defective? Glycogen Synthase Explain Symptoms:  After eating, blood glucose is high because liver cannot store it as glycogen. Some excess glucose is processed via Glycolysis to produce lactate & fatty acid precursors.  During fasting, glucose is low because the liver lacks glycogen stores for generation of glucose. Ketone bodies are produced as an alternative fuel. How would you nutritionally treat deficiency of liver Glycogen Synthase?  Frequent meals of complex carbohydrates (avoiding simple sugars that would lead to a rapid rise in blood glucose)  Meals high in protein to provide substrates for gluconeogenesis Glycogen Storage Diseases are genetic enzyme deficiencies associated with excessive glycogen accumulation within cells Symptoms in addition to excess glycogen storage: When a genetic defect affects an enzyme expressed in liver, a common symptom is hypoglycemia: relating to impaired mobilization of glucose for release to the blood during fasting When the defect is in muscle tissue, weakness & difficulty with exercise result from inability to increase glucose entry into Glycolysis during exercise Additional symptoms depend on the particular enzyme that is deficient Defects in glycogen metabolism Name Tissues Type Enzyme Deficiency Chiefly Affected Clinical Consequences Severly enlarged liver, severe hypoglycemia, Liver, kidney lactic acidosis, ketosis, hyperuricemia, hyperlipemia Von Gierke's Disease I Glucose 6phosphatase Pompe's Disease II 1,4-D-Glucosidase (lysosomal) Liver, heart, Cardiac failure in infancy muscle Cori's Disease III Amylo-1,6glucosidase ("Debranching" enzyme) Liver, muscle Similar to Type I, but milder Andersen's Disease IV "Branching" enzyme Liver Liver cirrhosis, death usually before 24 months McArdle's Disease V Phosphorylase Muscle Muscle cramps, easily fatigued Hers' Disease VI Phosphorylase Liver Similar to Type I, but milder Tarui's Disease VII Phosphofructokinas Muscle e Similar to Type V VIII Phosphorylase kinase Enlarged liver, hypoglycemia IX Glycogen synthase Liver Liver