1726380153915-Glycogen_2024[1].pdf

Glycogen Metabolism Prof. Dr. Shereen El Tarhouny  HOCH2 O -1,6 linkage between two...

Glycogen Metabolism Prof. Dr. Shereen El Tarhouny  HOCH2 O -1,6 linkage between two glucose units O O R CH2 HOCH2 O O O R O -1,4 linkage Nonreducing ends between two Glucose residue linked by -1,4 glucose units Glucose residue linked by -1,6 R Reducing end attached to glycogenin  Glycogenesis Occurs mainly in the cytosol of liver cells and muscles. Requires: – a primer. – UDP-Glc units. – two enzymes: glycogen synthase and branching enzyme.  A primer R Glycogen synthase cannot initiate chain synthesis using free glucose. It can elongate already existing chains of more than 4 residues of glucose (primer). This primer is either : A fragment of glycogen in cells whose glycogen is not totally depleted. In the absence of glycogen fragment, a protein called glycogenin can serve as acceptor of glucose residues. Glycogenin is a small protein Tyrosin (replaces glycogen primer), it is Glycogenin −OH auto-glycosylated at a specific UDP- glucose tyrosine residue by UDP-Glc, then Auto- glycosylated UDP successive glucose residues are added from UDP-Glc by glycogen Glycogenin −O− glucose synthase. Sometimes, it remains in the center of glycogen molecules.  Synthesis of uridine R diphosphoglucose (UDP-Glc) Glucokinase (liver) Glucose + ATP Glucose 6- P + ADP Hexokinase (peripheral tissue) Phosphoglucomutase Glucose 6- P Glucose 1- P UDP- Glucose pyrophosphorylase Glucose 1- P + UTP UDP-glucose + PPi This reaction generates an activated glucosyl residue which can be used to build the glycogen molecule. The reaction is irreversible by the subsequent hydrolysis of pyrophosphate Pyrophosphatase PPi + H2O 2 Pi  Glycogen synthase Catalyzes only the synthesis of -1,4 linkage This is the key enzyme for glycogen synthesis. It catalyzes the transfer of the glucosyl group of UDPGlc to the non-reducing ends of glycogen primer. This produces elongation of the branches of glycogen primer up to a minimum of 11 glucose residues.  Branching enzyme R When a growing chain of glycogen becomes at least II glucose residues long the branching enzyme, comes into action. It transfers a block of at least 6 glucose residues from the end of this chain to one of the glucose resides in the middle of an adjacent chain, and connects it in -1,6-linkage. This results in the formation of a new branch and permits the glycogen synthase to function again. The new branch-point is at least 4 glucose units away from the nearest branch point.  UDP-Glc UDP Glycogen synthase Branching R enzyme Glycogen primer R R Elongated branch Formation of of glycogen new branches  UDP-Glc UDP Glycogen synthase Branching R enzyme Glycogen primer R R Elongated branch Formation of of glycogen new branches  UDP-Glc UDP Glycogen synthase Branching R enzyme Glycogen primer R R Elongated branch Formation of of glycogen new branches  Glycogenolysis It is the breakdown of glycogen to form glucose-1-phosphate, which is converted to glucose-6- phosphate. Glycogenolysis is not a reversal of glycogenesis, a separate set of cytosolic enzymes is required. Glycogenolysis is catalyzed by two enzymes, glycogen phosphorylase and debranching enzyme.  Glycogen phosphorylase It catalyzes removal of glucose residues from the non-reducing ends on the outer branches of glycogen by adding inorganic phosphate and producing glucose-l-phosphate. The action of the enzyme stops when there is only four glucose residues on each side of the branching point.  Glycogen phosphorylase R Remaining glycogen Glycogen chain H O- P Glucose 1-P Cleavage of an  (1,4) glycidic bond  Glycogen chain P Glycogen phosphorylase O- PO3 Glucose 1-P Remaining glycogen Cleavage of an  (1,4) glycidic bond Debranching enzyme Glucosyl transferase activity of debranching enzyme It catalyzes transfer of the outer three residues of glucose at a branching point to the near non- reducing end of the glycogen molecule, leaving only one glucose residue at the branching point. Glucosidase activity of debranching enzyme It catalyzes the removal of the last glucose residue at the branching point by adding water and producing free glucose, leaving a chain that is further hydrolyzed by the phosphorylase enzyme.  Phosphorylase Pi  Debranching Phosphorylase enzyme (Glucosyl- Pi Glucose 1-P Transferase)  Debranching Phosphorylase enzyme (Glucosyl- H2O Pi Glucose 1-P Transferase) Glucosidase Glucose  Debranching Phosphorylase enzyme (Glucosyl- H2O Pi Glucose 1-P Transferase) Glycogen Glucosidase Glucose Pi Phosphoglucomutase Glucose 6-P Glucose 1-P Phosphorylase Muscle Glucose 6-phosphatase Liver Glycolysis Glucose  Function of liver glycogen Glucose-6-phosphate is mainly converted to glucose due to the presence of G-6- phosphatase. Free glucose is released to the blood, as the main function of liver glycogen is to maintain the blood glucose level especially during fasting or carbohydrate deficiency.  Function of muscle glycogen Glucose-6-phosphate is oxidized by glycolysis to provide energy. G-6-P cannot be converted to free glucose due to deficiency of G-6-Phosphatase. However, it may indirectly give blood glucose through the “Cori’s cycle”.  Hormonal regulation of glycogenesis Glucagon Adrenaline Insulin + H2O ? + PPi Adenylyl cyclase Phosphodiesterase ATP cAMP 5’- AMP + P ATP ADP Glycogen synthase a Protein kinase Glycogen synthase b (active) (inactive) − Protein phosphatase-l + Pi − + H2O Glycogen Glucose 6-P cAMP Insulin  Glucagon Adrenaline Insulin + H2O ? + PPi Adenylyl cyclase Phosphodiesterase ATP cAMP 5’- AMP P ATP ADP Ca2+ P ATP ADP phosphorylase kinase a Glycogen phosphorylase b Glycogen phosphorylase a (inactive) (active) Protein phosphatase-l + − Pi − + H2O Muscle ▪ATP & glucose 6-P AMP cAMP Insulin in liver and muscle ▪Glucose in liver  Allosteric regulation The inactive glycogen synthase b is allosterically activated by glucose 6-phosphate. Thus, when glucose is available glucose 6-phosphate increases, stimulating glycogenesis. The active glycogen synthase a is inhibited by glycogen. Thus, when glycogen stores are full glycogenesis is stopped.  The active glycogen phosphorylase a is allosterically inhibited by glucose 6-phosphate and by ATP. Liver glycogen phosphorylase a is also inhibited by glucose. AMP activates glycogen phosphorylase b in muscles.  Glycogen storage diseases (glycogenosis) These are inherited metabolic disorders that are characterized by deposition of abnormal quantities or types of glycogen. There are many types, the most important are the following: Type I (VonGierke's disease): Defective enzyme: glucose 6-phosphatase. Organ affected: liver and kidney. Glycogen in the affected organ: increased amount, normal structure. Clinical features: massive enlargement of the liver. Failure to thrive. Sever hypoglycemia, ketosis, hyperuricemia, hyperlipidemia. The blood glucose level does not rise on administration of epinephrine or glucagon  Type I (VonGierke's disease) (cont.) Glucose Severe hypoglycemia Glucose 6-phosphatase between meals Glucose 6- P Glucose 1-P 6 phosphogluconate Fructose 1,6- P UDP glucose Ribose 5- P Pyruvate Lactate Liver glycogen is Glycogen  Uric acid normal structure but present in large amounts Fatty acids Acetyl CoA Ketone bodies Cholesterol Hyperlipidemia Increase lipolysis in adipose tissue  Type V (McAardle’s syndrome) It is due to genetic deficiency of muscle phosphorylase resulting in accumulation of glycogen in muscles, painful muscle cramps and increased serum levels of muscle enzymes e.g. creatine kinase (CK) and lactate dehydrogenase (LDH).