Glycogen Synthesis & Breakdown PDF

Formation and Degradation of Glycogen Glycogenesis and Glycogenolysis Glycogen Structure A branched polymer of glucose with no phosphates. Chains are α-1,4 and branch points are α-1,6 glycosidic bonds One reducing end and many non-reducing ends. MW 250000 to > 1000000 Anomeric carbon Reducing end La...

Formation and Degradation of Glycogen Glycogenesis and Glycogenolysis Glycogen Structure A branched polymer of glucose with no phosphates. Chains are α-1,4 and branch points are α-1,6 glycosidic bonds One reducing end and many non-reducing ends. MW 250000 to > 1000000 Anomeric carbon Reducing end Large number of nonreducing ends, which are required as substrates for the enzymes of glycogen metabolism. Glycogen Structure Branch points every 8-10 residues. Glycogen is principally stored in the cytosol granules of – Liver – Muscle Glycogen is present in the cytoplasm in the form of granules ranging in diameter from 10 to 40 nm Can slowly release glucose bloodstream between meals into Good source of fuel for anaerobic activity, does not require O2 for breakdown Why Store Glucose As Glycogen? 1. We do store fat, but fat cannot be mobilized nearly as rapidly in muscle as glycogen 2. Fat cannot be used as a source of energy in the absence of oxygen 3. Fat cannot be converted to glucose to maintain blood glucose levels FUNCTION OF GLYCOGEN IN SKELETAL MUSCLE AND LIVER In skelatal muscle and other cell types - The synthesis and breakdown of glycogen is regulated to meet the energy requirements of the cell. In liver – The synthesis and breakdown of glycogen is regulated to maintain blood glucose levels. Catabolic pathways – from glycogen to glucose-6-phosphate (glycogenolysis) – from glucose-6-phosphate to pyruvate (glycolysis) Anabolic pathways – from pyruvate to glucose (gluconeogenesis) – from glucose to glycogen (glycogenesis) General structure of a glycogen particle Glycogen Synthesis 1. Hexokinase/ Glucokinase 2. Phosphoglucomutase 3. UDP-glucose pyrophosphorylase 4. Glycogen synthase 5. Branching enzyme (glucosyl transferase) De novo synthesis starts a new glycogen molecule and requires the enzyme glycogenin in addition to those above. Especially prominent in the liver and skeletal muscles. Occurs in the cytosol, and requires energy Glucose-6-phosphate Glucose-1-phosphate phosphoglucomutase Glucose-1-phosphate + UTP UDP-glucose + PPi UDP-glucose pyrophosphorylase UDP-Glucose Synthesis UDP-glucose pyrophosphorylase UDP Glucose A high-energy glucose carrier: activated form of glucose Glycogen is synthesized via uridine diphosphate glucose (UDP – glucose). Synthesis: Glycogenn + UDP-glucose → glycogenn+1 + UDP Degradation: Glycogenn+1 + Pi → Glycogenn + glucose 1phosphate. Glycogen is synthesized by glycogen synthase Glycogen synthase catalyzes α-1,4 linkages A primer of a least 4-8 units are required via glycogenin Glucose is added to the nonreducing end. UDP Glycogenin: catalyzes attachment of glucose residues autoglucosylation : glucosyl transferase activity from UDP-glucose : Glycogenin, can serve as an acceptor of glucose residues from UDP-glucose. The OH group of tyrosine serves as the site at which the initial glucosyl unit is attached. The reaction is catalyzed by glycogenin itself via autoglucosylation; thus, glycogenin is an enzyme. Glycogenin then catalyzes the transfer of the next few molecules of glucose from UDP-glucose, producing a short, α(1→4)-linked glucosyl chain. This short chain serves as a primer that is able to be elongated by glycogen synthase Glycogenin Primes the Initial Sugar Residues in Glycogen The first glucose is attached to Tyr and requires UDP-G and tyrosine glucosyl transferase activity. Then glycogenin adds ~7 more residues to form a short a-1,4 chain again using UDP-G as the glucose source. At this point glycogen synthase takes over along. Glycogenin remains permanently attached to the reducing end of the molecule. Synthesis of branches in glycogen 1,6-transglycosylase (glucosyl α-4:6 transferase) needs a strand of ~ 11 residues to act. It transfers ~6-7 residues to another strand to form a branch point and leaves ~4 residues at the cleavage point. Synthase & Branching Enzyme Glycogen synthase requires an a-1,4 chain of at least 4-8 residues to be able to add another glucose. a-1,4 addition continues until enough residues are present to permit branching. Branching facilitates degradation and synthesis by providing substrate sites (non-reducing ends). Branching enzyme forms α-1,6 linkages: Remodeling The enzyme breaks the α-1,4 link and forms a α-1,6 link. A large number of terminal residues are now available for glycogen phosphorylase; degradation. Branching increases solubility of glycogen. the Glycogenolysis Glycogenolysis is a catabolic process; the breakdown of glycogen to glucose units. Glycogenolysis Glycogen breakdown activities: requires different enzyme – to degrade glycogen – to remodel glycogen so that it remains a substrate for degradation – And to convert the product of glycogen breakdown into a form suitable for further metabolism. 1st: Glucose residues are removed from glycogen by glycogen phosphorylase Glycogen phosphorylase, the key enzyme in glycogen breakdown Catalyzes the removal of glucosyl residues from the nonreducing ends of the glycogen molecule A phosphorolysis reaction This process is repetitive; the enzyme removes successive glucose residues until it reaches the fourth glucose unit from a branch point Cleavage & Debranching 1. Phosphorylase cleaves a-1,4. 2. Transferase moves a-1,4 to a-1,4. 3. Glucosidase cleaves a-1,6. This is a glucose not G-1-P Dealing with Branch Points in Glycogen Glycogen phosphorylase works on non-reducing ends until it reaches four residues from an (a1→ 6) branch point Transferase transfers a block of three residues to the non-reducing end of the chain α-1,6-Glucosidase cleaves the single remaining (a1→6)– linked glucose – Transferase and a-1,6-Glucosidase: (debranching enzymes) in eukaryotes the transferase activity and the α-1,6glucosidase activity are within one bifunctional protein. These activities are in two enzymes in prokaryotes The glucose 1-phosphate to converted to glucose 6-phosphate by phosphoglucomutase. A phosphoryl group is transferred from the enzyme to the substrate, and a different phosphoryl group is transferred back to restore the enzyme to its initial state. Glucose-6-phosphate is dephosphorylated in the liver for transport out of the liver The liver contains a hydrolytic enzyme, glucose 6-phosphatase that enables glucose to leave that organ. Muscle does not contain this enzyme.