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5 Glycogen metabolism- glycogenesis and glycogenolysis

Detail description of synthesis and catabolism of glycogen. The significance and applied importance. Glycogen metabolism in sportperson and clinical significance.

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Glycogen metabolism PROF DR VIYATPRAJNA ACHARYA MD, PHD MEDICAL BIOCHEMISTRY
The learner will be able to: • Why glycogen?? • Synthesis and degradation of glycogen • Regulation of glycogen metabolism and role of cyclic AMP • Major glycogen storage diseases and their salient features Specific Learning Objectives
 Glycogen is the polymeric storage form of glucose in animals– Animal Starch.  Ready source of glucose to supply brain and skeletal mm.  Fat stores 100 times more energy than carbohydrates but it can’t generate glucose  Glycogen is highly branched- make glucose and glucose phosphate monomers readily available  This branched structure doesn’t raise osmolarity of the cytosol and more suitable storage form  Glycogen storage disorders Why Glycogen???
 The major sites of storage are liver and muscle.  The glycogen content of liver (10 gm/100 gm tissue) is more than in the skeletal muscle (1–2 gm/100 gm).  But the total quantity of muscle glycogen is more than liver glycogen because of the larger muscle mass.  When blood glucose level falls, liver glycogen is broken down and helps to maintain blood glucose level- GLYCOGENOLYSIS  After taking food, blood glucose tends to rise, which causes glycogen deposition in liver- GLYCOGENESIS
 Up to 5 hours of food intake blood glucose is maintained by the same  Glycogen takes over  After about 18 hours fasting, most of the liver glycogen is depleted, when depot fats are hydrolyzed and energy requirement is met by fatty acid oxidation.  The function of muscle glycogen is to act as reserve fuel for muscle contraction.  All the enzymes related to glycogen metabolism are cytoplasmic.  Liver glycogen- Maintains blood glucose for different organs  Muscle glycogen- Glucose-1-P formed; Pyruvate formed can give rise to lactate or transaminated to glucogenic AA and taken by liver for gluconeogenesis How long it sustains??
1. Glycogen Phosphorylase • Glycogen phosphorylase removes glucose as glucose-1-phosphate from glycogen (phosphorolysis). • It contains Pyridoxal phosphate (PLP) as a prosthetic group. • The alpha-1,4 linkages in the glycogen are cleaved. • It removes glucose units one at a time. • Enzyme sequentially hydrolyses alpha-1,4 glycosidic linkages, till it reaches a glucose residue, 3-4 glucose units away from a branch point. • It cannot attack the 1,6 linkage at branch point. • If glycogen phosphorylase alone acts on a glycogen molecule, the final product is a highly branched molecule; it is called limit dextrin. Degradation of Glycogen (Glycogenolysis)
2. Debranching by bifunctional (two) Enzymes • Then a block of 3 glucose residues (trisaccharide unit) are transferred from the branching point to another branch. • This enzyme is alpha-1,4 →alpha-1,4 glucan transferase. • Alpha- 1,6- glucosidase (debranching enzyme)- hydrolyses remaining glucosyl unit held in alpha-1,6 linkage at the branch point- free glucose • At this stage, the ratio of glucose-1- phosphate to free glucose is about 8:1!! • Now, phosphorylase can proceed with its action. • Both activities by same enzyme
3. Phosphogluco mutase  Phosphorylase reaction produces glucose-1- phosphate while debranching enzyme releases glucose.  The glucose-1-phosphate is converted to glucose-6-phosphate by phosphoglucomutase
4. Glucose-6-phosphatase in Liver  Hepatic glucose-6-phosphatase hydrolyses glucose-6- phosphate to glucose.  The free glucose is released to the blood stream.  Muscle will not release glucose to the blood stream, because muscle tissue does not contain glucose-6- phosphatase--glucose-6-phosphate undergoes glycolysis to produce ATP for muscle contraction.
 In muscle, the energy yield from one glucose residue derived from glycogen is 3 ATP molecules, because no ATP is required for initial phosphorylation of glucose (step 1 of glycolysis).  If glycolysis starts from free glucose only 2 ATPs are produced. Bioenergetics
Glycogenesis
Glycogen Synthesis (Glycogenesis)- a distinct pathway, not the reversal of Glycogenolysis  Site- Muscle and liver  Involves UDP-glucose  1st step- Activation of Glucose UDP-glucose pyrophosphorylase Glucose-1-P +UTP ———————® UDP-glucose + PPi
 The glucose moiety from UDP-glucose is transferred to a glycogen primer (glycogenin) molecule.  Glycogenin is glycosylated at a specific Tyr residue by UDP-glucose  The primer accepts 7 such glycosyl unit.  Primer - protein-carbohydrate complex.  This facilitates action of glycogen synthase  Up to 30k residues are attached on this primer 2. Glycogen Synthase
Glycogenin  37KDa protein  It is an enzyme- Glycosyltransferase  It is self-glucosylating  2 isoforms  Glycogenin-1 in muscle- coded by GYG-1 gene  Glycogenin-2 in cardiac mm and liver- GYG-2 gene  Genetic defect- glycogen storage hampered- muscle weakness and cardiac disease  Why only 7 glucose residues??
UDP-glucose donates glucose ↓ Glycogenin transfers the first glucose to a specific tyrosine residue (Tyr-194) on itself ↓ Glycogenin elongates the chain to about 8–10 glucose residues via α-1,4 linkages ↓ Once this short chain is formed: Glycogen synthase takes over → chain elongation; Glycosidic bond between C1 of UDPGlu and C4 of terminal residue on glycogen ↓ Branching enzyme(amylo-[1,4]®[1,6]-transglucosidase ) introduces α-1,6 branches after it becomes ~11 residues long, detaching at least 6 residue long chain  The glucose unit is added to the nonreducing (outer) end of the glycogen primer to form an alpha- 1,4 glycosidic linkage and UDP is liberated  Up to 30k glucose units added  Glycogenin remains in the center
 The synthetic and degradative pathways are reciprocally regulated to prevent futile cycles.  The phosphorylated form of glycogen phosphorylase is active; but glycogen synthase becomes inactive on phosphorylation.  The covalently modified phosphorylase is active even without AMP.  The covalent modification of glycogen phosphorylase and synthase is by a cyclic AMP mediated cascade.  Specific protein kinases bring about phosphorylation and protein phosphatases cause dephosphorylation. Regulation of Glycogen Metabolism
 Both liver and muscle phosphorylases are activated by a cyclic AMP mediated activation cascade triggered by the hormonal signal.  The hormones epinephrine and glucagon can activate liver glycogen phosphorylase but glucagon has no effect on the muscle.  When the hormone binds to a specific receptor on the plasma membrane, the enzyme adenyl cyclase is activated which converts ATP to cyclic AMP (cAMP).  When level of cyclic AMP rises, it will activate a protein kinase.  The protein kinase is inactive when the catalytic (C) and regulatory (R) subunits are associated with each other. Generation of Cyclic AMP (cAMP)
1. Liver: The liver phosphorylase-b is the inactive form. • It becomes active on phosphorylation. • Active enzyme is phosphorylase-a. • Inhibited by ATP and glucose-6-phosphate Glycogen Phosphorylase in Liver and Muscle
2. Muscle: Skeletal muscle glycogen is degraded only when the demand for ATP is high.  The regulation of glycogenolysis in skeletal muscle is by epinephrine.  Glucagon has no effect on muscle glycogenolysis.  AMP formed by degradation of ATP during muscle contraction is an allosteric activator of phosphorylase b.
 Glycogen synthase and phosphorylase activities are reciprocally regulated.  The same protein kinase, which phosphorylates the phosphorylase kinase would also phosphorylate glycogen synthase.  The activity of the glycogen synthase is markedly decreased on phosphorylation.  Insulin promotes glycogen synthesis by favoring dephosphorylation.  The reciprocal regulation of glycogenolysis and glycogenesis is by covalent modification (phosphorylation and dephosphorylation).  Insulin and glucagon are the major regulatory hormones, although epinephrine has stimulatory effect on glycogenolysis in both liver and muscle. Glycogen Synthase
Effects of Hormones on Glycogen
Regulators of glycogen metabolism Effectors Glycogen phosphorylase- Liver Glycogen synthase- Liver Glycogen Phospho- rylase- Muscle Glycogen synthase- Muscle ATP Inhibition Inhibition Inhibition Inhibition AMP Activation Activation Inhibition Glucose- 6Phosphate Inhibition Activation Inhibition Activation Ca++ Activation Activation
 The key enzyme for glycogenolysis is phosphorylase, which is activated by glucagon and adrenaline, under the stimulus of hypoglycemia.  The key enzyme for glycogen synthesis is glycogen synthase, the activity of which is decreased by adrenaline but is enhanced by insulin, under the stimulus of hyperglycemia.  Glycogen metabolism is regulated by coordinated regulation of glycogen synthase and glycogen phosphorylase.  The regulatory mechanisms include allosteric control as well as hormonal control by covalent modification of enzymes.  The allosteric effectors are ATP, glucose-6-phosphate and AMP. Summary of Regulation
Glycogen Storage Diseases Sir Archibald Garrod
Von Gierke’s disease  Glycogen Storage Disease Type-I  Most common type of glycogen storage disease is type I.  Incidence is 1 in 100,000 live births.  Glucose-6-phosphatase is deficient. Type Defect Site GSD Ia Glucose-6- phosphatase deficiency Liver, kidney, intestine GSD Ib G6P translocase deficiency ER membrane Clinical Features 🔹 Severe fasting hypoglycemia (infancy) 🔹 Hepatomegaly, protuberant abdomen 🔹 Doll-like facies 🔹 Failure to thrive, growth retardation 🔹 Lactic acidosis 🔹 Hyperuricemia → gout (later) 🔹 Hyperlipidemia Additional feature in 🔸Additional feature in GSD Ib- Neutropenia and recurrent infections Neutropenia and recurrent infections
Biochemical basis of the symptoms- Tell me why?? •Excess G6P is diverted into: •Glycolysis → ↑ lactate → lactic acidosis •Pentose phosphate pathway → ↑ uric acid •Lipogenesis → hypertriglyceridemia •Glycogen accumulates in liver & kidney → hepatomegaly, renomegaly •G6P cannot be converted to glucose → severe fasting hypoglycemia Management • Frequent feeding • Uncooked cornstarch (slow glucose release) • Avoid fructose & galactose (they enter as G6P) • Allopurinol (for hyperuricemia) • Lipid-lowering therapy if needed
Type Name Enzyme Clinical features Ia Von Gierke’s disease Glucose 6 phosphatase Fasting hypoglycemia, hepatomegaly II Pompe’s disease Lysosomal maltase Glycogen accumulates in liver, muscle and heart. Death by 2 yrs III Limit dextrinosis, Cori’s disease Debranching enzyme Fasting hypoglycemia, hepatomegaly IV Amylopectinosis, Anderson’s disease Branching enzyme Mild hypoglycemia, hepatosplenomegaly V McArdle’s disease Muscle phosphorylase Exercise intolerance VI Hers’ disease Liver phosphorylase Mild hypoglycemia, hepatomegaly, better prognosis VII Tarui’s disease Muscle PFK Exercise intolerance, hemolytic anemia
 Types VIII, IX and X – Are due to deficiencies of phosphorylase kinase of liver, muscle and protein kinase A deficiency respectively.  Mild hypoglycemia, exercise intolerance and hepatomegaly are seen.  They have better prognosis.
Endurance athletes build glycogen store  Marathon runners, Long-distance cyclists, Triathletes, Cross- country skiers, Long-distance swimmers •Exercise duration: Long (minutes to hours) •Intensity: Low to moderate (below anaerobic threshold for most of the activity)  They practice Carbohydrate loading  Exercise to exhaustion – When after exercise glycogen is exhausted, carbohydrate meal is loaded ↓ Faster glycogen synthesis, less branch points and larger storage  This spares muscle glycogen exhaustion
Dieting mass! Do not get enthralled by initial weight loss For each gm Glycogen, there’s 3gm water Early rapid weight loss during dieting or switching to low calorie diet is due to water loss and not due to fat loss !!! Supplements and diet advisors take advantage of this fact
Brain too have stores of glycogen!!  Astrocytes, non-neuronal cells that support neighbouring neurons  Explains the neurological symptoms in GSD
For more PPT on medical Biochemistry www.drvpacharya.com