GLYCOGEN METABOLISM

GLYCOGEN Found in liver and skeletal muscles. Represents 10% of weight of liver and 1-2% of muscles. Stored in large cytosolic granules. Elementary particles, β-particles consist of 50,000 glucose residues. 20-40 β-particles form α-rosettes. Quick source of energy for either aerobic or anaerobic metabolism. Liver glycogen serves as the reservoir of glucose. Glycogen granules, aggregates of glycogen and enzymes that synthesize it. Mechanism for storage and metabolism is same for liver and muscles.

GLYCOGEN BREAKDOWN Catalyzed by glycogen phosphorylase. Three enzymes : glycogen phosphorylase, glycogen debranching enzyme, and phosphoglucomutase. This phosphorolysis differs from hydrolysis of glycosidic bonds by amylase. Pyridoxal phosphate as a cofactor. Glycogen phosphorylase acts on nonreducing end till its action stops. Further degradation occurs only after the debranching enzyme, oligo(α 1-6) to (α 1-4) glucantransferase, catalyses two successive reactions till the branches are transferred and glucosyl residue at C-6 is hydrolyzed, glycogen phosphorylase activity can continue.

Phosphoglucomutase Glucose-1-phosphate is converted into glucose-6-phosphate by phosphoglucomutase, which catalyzes the reversible reaction. Initially phosphorylated at a Ser residue, the enzyme donates a phosphoryl group to C-6 of the substrate, then accepts a phosphoryl group from C-1. Glucose-6-phosphate in skeletal muscles serves as the energy source for muscle contraction. In liver, the glucose is released in the blood when the glucose level drops, it requires glucose-6-phosphatse.

Glucose-6-phosphatase Integral membrane protein of endoplasmic reticulum, contains nine transmembrane helices, active site on the lumenal side of the ER. Glucose-6-phosphate formed in the cytosol is transported into the ER lumen by a specific transporter(T1) and hydrolyzed by glucose-6-phosphatase. The iP and glucose are carried back into the cytosol by two different tranporters (T2 and T3), and the glucose leaves the hepatocyte via another transporter in the plasma membrane(GLUT2). By having the active site of glucose-6-phosphatase inside the ER lumen, the cell seperates this reaction from the process of glycolysis. Genetic defects in either glucose-6-phosphatase or T1 lead to serious derangement of glycogen metabolism, resulting in type 1a glycogen storage disease.

UDP-Glucose The sugar nucleotide UDP-Glucose donates glucose for glycogen synthesis. Sugar nucleotides are the substrates for polymerization of monosaccharides into disaccharides, glycogen, starch, cellulose, and more complex extracellular polysaccharides. The role of sugar nucleotides in the biosynthesis of glycogen and many other carbohydrate derivatives was first discovered by Luis Leloir.

Glycogen synthesis Takes place in all animal tissues but especially prominent in the liver and skeletal muscles. The starting point for synthesis of glycogen is glucose-6-phosphate which can be derived from the free glucose in a reaction catalyzed by the isozymes hexokinase I and hexokinase II in muscles and hexokinase IV (glucokinase) in liver. The glucose-6-phosphate is converted to glucose-1-phosphate in the phosphoglucomutase reaction, then converted into UDP-Glucose by the action of UDP-glucose phosphorylase. The (α 1-6) bonds are formed by the glycogen-branching enzyme, also called amylo (1-4) to (1-6) transglycosylase or glycosyl-(4-6)-transferase. The biological effect of branching is to make the glycogen molecule more soluble and to increase the number of nonreducing ends.

Glycogenin Glycogen synthase cannot initiate a new glycogen chain de novo. It requires a primer, usually a preformed (α 1-4) polyglucose chain or branch having at least eight glucose residues. The intriguing protein glycogenin is both the primer on which new chains are assembled and the enzyme that catalyzes their assembly. The first step is the transfer of a glucose residue from UDP-glucose to the hydroxyl group of Tyr^194 of glycogenin, catalyzed by the protein’s intrinsic glucosyltransferase activity. The reactions are catalyzed by the chain-extending activity of glycogenin and glycogen synthase further extends the glycogen chain. Glycogenin remains buried within the particle, covalently attached to the single reducing end of the glycogen molecule.

Thanks