Glycogen Metabolism PDF

Glycogen Metabolism Prof. Dr. MAHA SMAISM Introduction to Glycogen Metabolism Glycogen metabolism refers to the processes involved in the synthesis and breakdown of glycogen, a highly branched glucose polymer that serves as a key energy storage molecule in animals. Glycogen is stored primarily...

Glycogen Metabolism Prof. Dr. MAHA SMAISM Introduction to Glycogen Metabolism Glycogen metabolism refers to the processes involved in the synthesis and breakdown of glycogen, a highly branched glucose polymer that serves as a key energy storage molecule in animals. Glycogen is stored primarily in the liver and skeletal muscles. The liver regulates blood glucose levels by storing and releasing glucose, while muscle glycogen provides energy for muscle contraction during exercise. Glycogen metabolism involves two main processes: 1.Glycogenesis: The synthesis of glycogen from glucose. 2.Glycogenolysis: The breakdown of glycogen to release glucose.  Glycogenesis (Glycogen Synthesis) Glycogenesis is the process of converting glucose into glycogen for storage, mainly in the liver and skeletal muscles. This process occurs when there is an excess of glucose in the bloodstream, typically after a meal. Steps of Glycogenesis: Glucose Uptake: o Liver and muscle cells take up glucose from the blood. This process is facilitated by insulin. o In muscles, GLUT4 transporters, stimulated by insulin, move glucose into the cells. Conversion of Glucose to Glucose-6-phosphate: o Enzyme: Hexokinase (in muscles) or Glucokinase (in the liver). o Glucose is phosphorylated to form glucose-6-phosphate (G6P). o Reaction: Glucose+ATP→Glucose-6-phosphate+ADP 3.Conversion of Glucose-6-phosphate to Glucose-1-phosphate: o Enzyme: Phosphoglucomutase. o Glucose-6-phosphate is isomerized to form glucose-1-phosphate (G1P). o Reaction: Glucose-6-phosphate→Glucose-1-phosphate 4.Activation of Glucose-1-phosphate to UDP-Glucose: o Enzyme: UDP-glucose pyrophosphorylase. o Glucose-1-phosphate reacts with UTP (uridine triphosphate) to form UDP-glucose (activated glucose). Reaction: Glucose-1-phosphate+UTP→UDP-glucose+PPi Uridine diphosphate glucose (UDP-glucose) is the immediate precursor for glycogen synthesis 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  5.Elongation of Glycogen Chain: o Enzyme: Glycogen Synthase. o UDP-glucose is added to a growing chain of glycogen. o Glycogen synthase catalyzes the formation of α-1,4-glycosidic bonds between glucose units. o Reaction: UDP-glucose + Glycogen (n) → Glycogen (n+1)+UDP Branching of Glycogen: o Enzyme: Branching Enzyme (glycosyl-4:6 transferase). o Branching enzyme introduces α-1,6-glycosidic bonds to create branches in the glycogen molecule, making it more soluble and easier to degrade when needed. Reaction: Linear Glycogen → Branched Glycogen Glycogenin then catalyzes glucosylation at C4 of the attached glucose (UDP-glucose again the donor), to yield an O-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 Branching enzyme deficiency Type IV: (Andersen’s Disease): Presence of unbranched long chains of glycogen, which become insoluble particles, causing sever liver malfunction. The abnormal size particle may leads to immune response that causes liver damage and death of the patients within 4 yr of age. Glycogenolysis Phosphorylase is specific for the α-1,4 linkage and stops at fourth glucose from α1,6 branch point Transferase Shifts 3 glycosyl units to the core. Hydrolyzes the single 1,6 glucose unit to free glucose.  Glucose 6- Phosphoglucomutase phosphatase Glucose 6-p Glucose Type I: Glucose 6-Phosphatase deficiency (von Gierke’s Disease): This enzyme catalyses' step which leads to the delivery of glucose in blood stream from l i v e r. I n t h e a b s e n c e o f t h i s enzyme, liver is unable to release glucose in blood, leading to hypoglycemia. Their is build up of G6P in the liver which activates glycogen synthase leading to glycogen accumulation and hepatomegaly Type V: Muscle phosphorylase deficiency (McArdle’s Disease): Cause severe muscle cramps after exercise. Blood glucose remain unaffected. Type VI: Liver phosphorylase deficiency (Her’s Disease): Patients unable to use liver glycogen. Symptoms are similar to type I disease. Type II:(Pompes Disease) lysosomal maltase deficiency accumulation of glycogen in lysosomes of liver, heart and muscle; death before 2 years. Type III :(Coris Disease) Debranching enzyme deficiency cause hepatomegaly and cirrhosis.  Glycogenolysis 1. Removal of Glucose-1-P Units from glycogen: Enzyme: Glycogen Phosphorylase. Glycogen phosphorylase removes glucose units from the non-reducing ends of glycogen by breaking the α-1,4-glycosidic bonds but its stop at fourth glucose from α 1,6 branch point, The glucose is released as glucose-1-phosphate (G1P). Reaction: Glycogen (n) + Pi → Glycogen (n-1) + Glucose-1-phosphate 2.Conversion of Glucose-1-phosphate to Glucose-6-phosphate: o Enzyme: Phosphoglucomutase. o Glucose-1-phosphate is isomerized to form glucose-6-phosphate (G6P). Reaction: Glucose-1-phosphate→ Glucose-6-phosphate 3. Converting Glucose-6-phosphate into free glucose Glucose 6-phosphatase (G6Pase) is an enzyme primarily found in the liver and kidneys that plays a critical role in glucose homeostasis. It is catalyzes the final step in both gluconeogenesis and glycogenolysis—the process of converting glucose-6- phosphate into free glucose and inorganic phosphate. This free glucose is then released into the bloodstream, helping to maintain normal blood sugar levels, especially during fasting or in between meals. Absent in muscle cells, which is why muscle cells do not release glucose into the bloodstream. Enzyme Function: Glucose-6-phosphate + H2O ⟶ Glucose + Pi  4.Debranching of Glycogen: A. Enzyme: Transferase: It transfers an alfa (1-4)-linked trisaccharide unit from the limit branch to the nonreducing end of another branch. B.Enzyme: (1—6) glucosidase activity: It hydrolyses the remaining glucose of the branch liked by alfa(1-6) link releasing free glucose. Reactions: Glycogen → Free Glucose + Linear Glycogen Approximately 10% of the total glucose residues generated from glycogen breakdown are as free glucose and 90% as G1P. Glucose 6-phosphate has 3 fates.