Glycogen Metabolism BC 340 lecture 9
Structure of glycogen Glycogen is homopolysaccharide formed of branched D-glucose units The primary glycosidic bond is 1-4-linkage Each branch is made of 6-12 glucose units. At the branching point, the chain is attached by 1-6 linkage
Location of glycogen Glucose is stored as glycogen predominantly in liver muscle cells. Liver glycogen is about 120 grams (about 6 % of weight). and liver Muscle glycogen is about 350 grams (about 1 % of total muscles weight).
Functions of glycogen Liver glycogen: It maintains normal blood glucose concentration especially during the early stage of fast (between meals). After 12-18 hours fasting, liver glycogen is depleted. Muscle glycogen: It acts as a source of energy within the muscle itself especially during muscle contractions.
Glycogenesis: It is the formation of glycogen in liver and muscles Substrates for glycogen synthesis: 1. In liver: o Blood glucose o ther hexoses: fructose and galactose o Non-carbohydrate sources: (gluconeogenesis) e.g. lactic acid, glycerol and lactate. These are converted first to glucose, then to glycogen 2. In muscles: o Blood glucose only
C 2 P glucose-1-phosphate UDP-Glucose Pyrophosphorylase + P PP i P P UTP N N C 2 C 2 N N P P C 2 UDP-glucose Uridine diphosphate glucose (UDP-glucose) is the immediate precursor for glycogen synthesis
C 2 P glucose-1-phosphate UDP-Glucose Pyrophosphorylase + P PP i P P UTP N N C 2 C 2 N N P P C 2 UDP-glucose UDP-glucose is formed from glucose-1-phosphate: glucose-1-phosphate + UTP UDP-glucose + 2 Pi Cleavage of PPi is the only energy cost for glycogen synthesis
Glycogenin (dimer) initiates glycogen synthesis Glycogenin is an enzyme that catalyzes attachment of a glucose molecule to one of its own tyrosine residues. 4 6 5 C 2 3 2 1 UDP-glucose P P Uridine tyrosine residue of Glycogenin C 2 C C N -linked glucose residue 4 6 5 C 2 3 2 1 C 2 C C N + UDP C 2 C 2 UDP is released as a product C 2 C C N
-linked glucose residue 4 UDP-glucose 6 5 C 2 3 2 1 C 2 C C N + UDP C 2 C 2 (1 4) linkage C 2 C C N + UDP Glycogenin then catalyzes glucosylation at C4 of the attached glucose (UDP-glucose again the donor), to yield an -linked disaccharide with α(1 4) glycosidic linkage This is repeated until a short linear glucose polymer (glycogen primer) with α(1 4) glycosidic linkages is built up on Glycogenin
Glycogen Synthase then catalyzes elongation of glycogen chains initiated by Glycogenin.
By the action of Glycogen Synthase (key enzyme of glycogenesis) UDP-G molecules are added to glycogen primer causing elongation of the α1-4, branches up to 11 glucose units. glycogen (n residues) + UDP-glucose glycogen (n +1 residues) + UDP
A branching enzyme transfers a segment (minimum 6 Glc residues) from the end of a glycogen chain to the C6 hydroxyl of a glucose residue of glycogen to yield a branch with an α(1 6) linkage. The new branches are elongated by the glycogen synthase and the process is repeated.
Glycogen catabolism It is the breakdown of glycogen into glucose (in liver) and lactic acid (in muscles)
Two major enzymes participate in all glycogen degradation: Glycogen phosphorylase and Glycogen debranching enzyme
Glycogen Phosphorylase (the key enzyme of glycogenolysis) catalyzes phosphorolytic cleavage (addition of Pi) of the α(1 4) glycosidic linkages of glycogen, releasing glucose-1-phosphate as reaction product glycogen (n residues) + P i glycogen (n 1 residues) + glucose-1-phosphate Always acts at nonreducing end, stops at fourth glucose from α 1,6 branch point
Debranching enzyme has 2 independent active sites, consisting of residues in different segments of a single polypeptide chain: 1. The transferase 2. The α (1 6) glucosidase
The transferase transfers 3 glucose residues from a 4-residue limit branch to the end of another branch, diminishing the limit branch to a single glucose residue.
The α(1 6) glucosidase moiety of the debranching enzyme then catalyzes hydrolysis of the α(1 6) Linkage by adding 2, yielding free glucose This is a minor fraction of glucose released from glycogen The major product of glycogen breakdown is glucose-1-phosphate, from Phosphorylase activity.
Glucose-1-P formed by phosphorolytic cleavage of glycogen is converted into glucose-6-p by Phosphoglucomutase (catalyzes the reversible reaction): glucose-1-phosphate glucose-6-phosphate
Glucose 6-phosphate derived from glycogen can be: o used as a fuel for anaerobic or aerobic metabolism as in, for instance, muscle; o converted into free glucose in the liver and subsequently released into the blood to maintain a relatively level of blood glucose; o processed by the pentose phosphate pathway to generate NADP or ribose in a variety of tissues
Regulation of Glycogen Metabolism Glycogen reserves are the most immediately available large source of metabolic energy for mammals Storage and utilization are under dietary and hormonal control Glycogen synthase and glycogen phosphorylase are the targets of allosteric modulators and of covalent, reversible modification (phosphorylation)
Allosteric regulation of phosphorylase activity
Glycogen Phosphorylase in muscle is subject to allosteric regulation by AMP, ATP, and glucose-6-phosphate. A separate isozyme of Phosphorylase expressed in liver is less sensitive to these allosteric controls o AMP (present significantly when ATP is depleted) activates Phosphorylase o ATP & glucose-6-phosphate inhibit Phosphorylase Thus glycogen breakdown is inhibited when ATP and glucose-6-phosphate are plentiful
Glycogen Synthase is allosterically activated by glucose- 6-phosphate (opposite of the effect on Phosphorylase) Thus, glycogen synthesis is activated when glucose-6-phosphate is plentiful These controls benefit the cell because it is more useful to a cell to store glucose as glycogen when the input to Glycolysis (glucose-6-p), and the main product of Glycolysis (ATP), are adequate.
Regulation by covalent modification Primary hormones : 1. epinephrine (adrenaline) 2. glucagon 3. insulin (phosphorylation) The actions of these hormones on glycogen phosphorylase and glycogen synthase are indirect
Glucagon Low levels of glucose induce release of glucagon Acts primarily on liver cells. Detected by receptors on surface of liver cells. Stimulates glycogen breakdown & inhibits glycogenesis. Glucagon also blocks glycolysis & stimulates gluconeogenesis.
Epinephrine Low levels of glucose induce release of Epinephrine Acts primarily on skeletal muscle. Detected by receptors at surface of cells. Stimulates glycogen breakdown & inhibits glycogenesis. Glucagon and epinephrine both stimulate intracellular pathway via increasing levels of camp
Insulin igh levels of glucose induce release of insulin from β- cells of islets of Langerhan in the pancreas. Detected by receptors at surface of muscle and liver cells. Increases glycogenesis in muscle. Intracellular signal pathway involves complex sequential phosphorylations and dephosphorylations
ow is Glycogenesis Inhibited? Epinephrine and glucagon inhibit glycogen synthesis 1. protein kinase A phosphorylates glycogen synthase, decreasing its activity. 2. also phosphorylase kinase can phosphorylate glycogen synthase, inactivating it.
ow is Glycogenesis Activated? Complex process stimulated by Insulin dephosphorylation is the major pathway for stimulation of glycogenesis in liver and resting muscles Insulin indirectly activates a phosphoprotein phosphatase: glycogen synthase b glycogen synthase a phosphorylated dephosphorylated less active active
Differences between liver glycogen and muscle glycogen Source Amount Concentration Functions End product Effect of hormones 1. Insulin 2. Epinephrine 3. Glucagon Liver glycogen 1. Blood glucose: 2. ther hexoses 3. Non-C sources 120 grams maximum 6% General store of glucose for all body cells Glucose Stimulate glycogenesis Stimulate glycogenolysis Stimulate glycogenolysis Muscle glycogen Blood glucose only 400 grams maximum 1% Private source of energy for muscles only Lactate (due to the absence of G6Pase) Same Same No effect