Glycogen Metabolism PDF

Glycogen Metabolism Asst. Prof. Gökhan BAĞCI Glycogen Higher organisms store carbohydrates as glucose polysaccharides in order to continuously supply glucose. Plants: Starch Humans and animals : Glycogen Glycogen is a broad glucose primary in its main chain linked by α-1,4 glycosidic bonds, with...

Glycogen Metabolism Asst. Prof. Gökhan BAĞCI Glycogen Higher organisms store carbohydrates as glucose polysaccharides in order to continuously supply glucose. Plants: Starch Humans and animals : Glycogen Glycogen is a broad glucose primary in its main chain linked by α-1,4 glycosidic bonds, with glucose units branching by α-1,6 glycosidic bonds every 8-10 units. Glycogen stored in humans is sufficient for 12-18 hours. Glycogen metabolism takes place in the cytosol and its responsible enzymes are located in the cytosol. • Glycogen synthesis occurs in almost all tissues. • However, intense glycogen synthesis occurs in the liver and muscle tissue. • Glycogen is the storage form of glucose in the liver. It is easily converted to blood glucose for distribution to other tissues. • Glucose obtained from the breakdown of glycogen in the muscles is used to provide the necessary ATP for muscle contraction. • UDP-glucose is the substrate of glycogen synthesis. • The synthesis of glycogen starting from a precursor molecule is called glycogenin, the breakdown of glucose units from the non-reduced end of glycogen and the release of free glucose into the circulation is called glycogenolysis. • Glycogen breakdown in muscle and liver is different from each other. • Muscle: Glycogen is broken down to glucose 6phosphate and this product is metabolized for ATP synthesis via glycolysis and the TCA cycle. • Liver: Free glucose, which is the end product of glycogenolysis, is given to the bloodstream, enabling other tissues to use glucose. Fluctuation of glycogen stores • Liver glycogen stores increase during the well-fed state and are depleted during a fast. • Muscle glycogen is not affected by short periods of fasting (a few days) and is only moderately decreased in prolonged fasting (weeks). • Muscle glycogen is synthesized to replenish muscle stores after they have been depleted following strenuous exercise. • [Note: Glycogen synthesis and degradation are cytosolic processes that go on continuously. • The differences between the rates of these two processes determine the levels of stored glycogen during specific physiologic states.] • Sugar nucleotides are involved in most of the transformation or polymerization reactions of hexoses. • In sugar nucleotides, the anomeric carbon atom of the sugar is activated by binding to the nucleotide by a phosphodiester bond. • Sugar nucleotides polymerization of are substrates for monosaccharides the into disaccharides, glycogen, starch, cellulose, and more complex extracellular polysaccharides. • The formation of sugar nucleotides is metabolically irreversible, making the synthesis pathways in which it is an intermediate also irreversible. UDP-Glucose Sugar nucleotide formation: It is formed by a condensation reaction between a nucleoside triphosphate (NTP) and a sugar phosphate. The negatively charged oxygen on the sugar phosphate acts as a nucleophile and attacks the phosphate of the nucleoside triphosphate, displacing the pyrophosphate. The reaction is continued forward by hydrolysis of PPi by inorganic pyrophosphatase. Glycogen Glycogen in its straight chain forming α(1→4) glycosidic bonds and It contains α(1→6) glycosidic bonds at the branching point. • After an average of eight to ten glucosyl residues, there is a branch containing an α(1→6) linkage . • A single molecule of glycogen can have a molecular mass of up to 108 daltons. • These molecules exist in discrete cytoplasmic granules that also contain most of the enzymes necessary for glycogen synthesis and degradation. Glycogen Synthesis ➢ The starting point of glycogen synthesis is glucose-6phosphate. ➢ Glucose 6-phosphate is formed from free glucose by glucokinase (in liver) or hexokinase (in muscle). ➢ The phosphoglucomutase enzyme reversibly converts glucose 6-phosphate to glucose 1-phosphate. ➢ Thus, an intermediate product of glycogen synthesis and degradation occurs. ➢ The liver glucose 6-phosphatase enzyme hydrolyzes glucose 6-phosphate to release glucose into the circulation. ➢ This enzyme is not found in muscle. • Glycogen Synthesis UDP-glucose+ glycogen (n residue)→UDP+Gliycogen (n+1 residue) - Glycogen consists of α-D-glucose units. - Its synthesis takes place in the cytosol with energy from ATP (for the phosphorylation of glucose) and UTP.. - UDP-glucose, the active form of glucose, is synthesized from glucose 1-phosphate and UTP by the enzyme UDPglucose pyrophosphorylase. • UDP-glucose is the glucose donor for glycogen synthesis. • A glycogen moiety in the cell can be the initiator for the initiation of glycogen synthesis. • If glycogen is completely depleted, then a special protein called glycogenin acts as a receptor for glucose residues. • UDP-glucose is the glucose donor in the reaction catalyzed by glycogen synthase. • The glycogen synthase enzyme transfers glucose from UDP-glucose to the non-reducing end of the branched glycogen molecule. This enzyme forms (α1-4) glycosidic bonds but not (α1-6) bonds. • Elongation of the glycogen chain: Chain elongation occurs with the formation of a glycosidic bond between the hydroxyl group of the first carbon (anomeric) of glucose from UDPglucose and the 4th carbon of the acceptor glucose in the chain. • In other words, a glucose from UDP-glucose is added to the chain. • The enzyme that makes α-1,4 glycoside bonds in chain extension reactions is glycogen synthase. • The rate-limiting step in glycogen synthesis is the glycogen synthase step. 15 • Formation of the branching point: After at least 11 glucose units, branching occurs in glycogen. • The enzyme that performs the reactions is glucosyl α-4.6 transferase [amilo (1→4)→(1→6) transglycosylase] known as the branching enzyme. • This enzyme takes a terminal fragment containing six or seven glucose from the non- reducing end of a glycogen branch with at least 11 glucose molecules and transfers it to another place in the chain or to the C-6 hydroxyl group of a glucose molecule located further inside another glycogen molecule. allows to form. • The new bond formed is an α-1,6 glycoside bond. • The newly formed non-reduced end is extended by glycogen synthase like the previous nonreduced end. • When the elongation of the newly formed tips is completed, the last 5-8 residues are separated and new branches are formed. 16 Glycogen Breakdown (Glycogenolysis) Glycogen breakdown (Glycogenolysis) Rate-limiting reaction: Glycogen phosphorylase breaks the α-1,4 glycoside bond at the end of the glycogen chain, allowing glucose to be separated as glucose-1phosphate. Glycogen (n) + Pi  Glycogen (n-1) + Glucose-1-phosphate 20 ⚫ When four glucose units remain at the branching point, glycogen phosphorylase stops. ⚫This final structure formed is called limit dextrin. ⚫Limit dextrin is broken down by the glycogen cleavage enzyme, which shows two different activities. ⚫1) With the 4-glucanotransferase activity, 3 units of glucose are transferred from the branching point to the free 4' end of the chain on the glycogen molecule. 21 2) With the amylo 1,6-glucosidase activity, the α-1,6-glucosidic bond is hydrolyzed to release one unit of glucose into the circulation. This is a hydrolysis reaction and not phosphorylation. Therefore, free glucose is released directly into the circulation. Glucose-1-phosphate is not the product of this reaction. Glucose 22 • In cells, glucose-1-phosphate is rapidly converted to glucose6-phosphate by the enzyme phosphoglucomutase. • In the liver, glucose-6-phosphate is hydrolyzed to free glucose by glucose-6-phosphatase. • Muscle glycogen cannot increase blood sugar levels because there is no glucose 6-phosphatase in the muscles. GLYCOGEN METABOLISM IS REGULATED BY TWO HORMONES Glycogen Synthase When phosphorilated= Inactive When dephosphorilated= Active Glycogen Phosphorilase When phosphorilated= Active When dephosphorilated= Inactive • Glycogen synthesis and glycogen breakdown cannot occur simultaneously. • Therefore Glycogen synthase and glycogen phosphorylase cannot be active at the same time. • Insulin and, according to tissues, glucagon or adrenaline (epinephrine) are effective hormones in this regulation. 24 • Hormones and second messengers regulate the phosphorylation of glycogen synthase and glycogen phosphorylase enzymes. • Insulin, which increases the synthesis of glycogen in the liver and skeletal muscle, enables the storage of excess carbohydrates taken with food as glycogen. • When the blood glucose level decreases in fasting, glucagon increases the blood glucose level by stimulating glycogen breakdown in the liver. 26 Glycogen Storage Diseases • Extraordinary Measures is a 2010 American medical drama film starring Brendan Fraser, Harrison Ford, and Keri Russell. • The film is about parents who form a biotechnology company to develop a drug to save the lives of their children, who have a lifethreatening disease. • The film is based on the true story of John and Aileen Crowley, whose children have Pompe's disease.