2 22 15 Biochemistry 401 Lecture 23 Beginning Glycogen Metabolism Glycogen Degradation Mobilization of glucose Glycogen synthesis Formation of the glucose storage unit Glycogen is a highly branched polymer of glucose 1 Straight chains 1 4 linkage 2 Branch points 1 6 linkage every 10 units 3 Initiator primer molecule glycogenin G Non reducing ends Primary storage sites are skeletal muscle and liver Skeletal muscle cells contain glycogen for their own needs 2 by wt Liver cells contain glycogen primarily for the needs of the body as a whole 10 by wt Glycogen is stored as dense granules in the cytoplasm Why glycogen Why not Fatty Acids Glucose is sole RBC and primary Brain fuel Utilization of glucose can proceed under anaerobic conditions Glycolysis Glycogen has many branch points for rapid regulated mobilization 1 2 22 15 Linear 1 4 linkage Branch points 1 6 linkage Straight Chain Phosphorolysis Glycogen free ends are broken down releasing Glucose1 P Enzyme Glycogen phosphorylase Glucose 1 P is transformed to glycolytically usable glucose 6 P Enzyme Phosphoglucomutase Three fates of Glucose 6 P 1 Glycolysis 2 Free glucose Liver kidneys 3 Pentose phosphate pathway to make NADPH Fate depends on cell type current metabolic needs 2 2 22 15 Glycogen Phosphorylase Cleaves glucose through addition of inorganic phosphate Can catalyze phosphorolysis of the straight chain to within 4 glucosyl units of a branch point Yields Glucose 1 P monomers Energetically favorable Released glucose is phosphorylated Also favorable because this intermediate cannot diffuse out of cell Glycogen Phosphorylase overview Dimeric enzyme that cleaves 1 4 glycosidic bond between C1 and the glycosidic oxygen through phosphate addition Cofactor Pyridoxal Phosphate It is important to make sure that this is a phosphorylytic not a hydrolytic reaction A loss of the phosphate must not occur Must exclude water from this reaction 3 2 22 15 Glycogen Phosphorylase Allosterically regulated homodimer One subunit is shown in yellow and the other is in white Pyridoxal Phosphate is shown with Pi and glycogen in the active site Excludes water The enzyme is processive and can cleave many residues without leaving the substrate Glycogen Phosphorylase mechanism Pyridoxal Phosphate a B vitamin derivative is a cofactor that is covalently linked to a lysine in the enzyme through Schiff base linkage This cofactor acts as an acid base catalyst Acid donor Base acceptor Two step reaction keeps the alpha configuration Donation of a proton Attack of Pi on the to C4 Oxygen carbocation Acid Proton Donor Base Proton Acceptor Inorganic phosphate donates a proton to the C4 oxygen while accepting a proton from PLP Pi attacks the carbocation and donates a proton back to PLP 4 2 22 15 Phosphoglucomutase catalyzes the transformation of glucose 1 P to glucose 6 P for use in glycolysis In muscle cells Phosphate keeps glucose in the cell for the muscle s own energy needs In Liver and Kidney cells The phosphate is removed from C6 by hydrolysis in a reaction catalyzed by Glucose 6 phosphatase This enzyme also functions during gluconeogenesis and is found in the ER Free glucose is released to meet the metabolic needs of other tissues The Problem of Branches Glycogen phosphorylase cannot catalyze the breakdown of 1 6 linked glucose at the branch points or any of the four 1 4 glucose units terminal to the 1 6 glycosidic bond Two additional enzyme functions transferase and 1 6 glucosidase are supplied by the Debranching enzyme to release these monomers Hexokinase in muscles phosphorylates free glucose P hexokinse Debranching Enzyme P hexokinse 5 2 22 15 1 6 Glucosidase hydrolyses the 1 6 glycosidic bond to release free glucose Glycogen Synthesis Activated glucose UDP G Glycogen UDP Glucose Glycogenn 1 UDP Activating Glucose UDP Glucose Pyrophosphorylase This reaction is driven forward by the hydrolysis of PPi 6 2 22 15 Glycogen Synthesis Activated glucose UDP G Glycogen UDP Glucose Glycogenn 1 UDP Adding Activated Glucose Glycogen synthase Glycosyl unit of UDP glucose is transferred to C4 of the growing chain must have at least 4 residues already there A primer is needed to start a new molecule Glycogenin a dimeric protein with 1 4 linked oligosaccharides is used as a primer to initiate synthesis of a new glycogen molecule 7 2 22 15 Branching Enzyme Why branching Increases free ends Increases solubility Forms 1 6 linkages 1 Breaking an 1 4 linkage 2 Formation of an 1 6 linkage A block of 7 residues usually is transferred to a more interior location The block is transferred to a branch containing 3 or more residues This is the end of Lecture 23 Have a great day 8
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