Biochemistry Seventh Edition CHAPTER 21 Glygogen Metabolism Copyright © 2012 by W. H. Freeman and Company Berg Tymoczko Stryer

Glycogen is a polymer of glucose consisting of 104 to 105 glucose monomers linked by a(1  4) glycoside bonds, but with frequent branches arising from a(1  6) bonds. In glycogen, about 10% of the glucose units are branched. The molecule has one reducing end (right hand end of chain) but many nonreducing ends (left hand ends) due to the branches. The nonreducing ends are the locations of all glucose additions or removals. Branches are added by branching enzyme, and removed by debranching enzyme.

Degradation of stored glycogen (glycogenolysis) occurs through the action of glycogen phosphorylase. The action of phosphorylase is to phosphorolytically remove single glucose residues from a-(1,4)-linkages within the glycogen molecules. The product of this reaction is glucose-1-phosphate. The advantage of the reaction proceeding through a phosphorolytic step is that: 1.The glucose is removed from glycogen in an activated state, i.e. phosphorylated and this occurs without ATP consumption. 2.The concentration of Pi in the cell is high enough to drive the equilibrium of the reaction the favorable direction since the free energy change of the standard state reaction is positive. Glycogenolysis

Glycogenolysis:degradation of glycogen

The active form of Vitamin B-6 is Pyridoxal-5- phosphate or P5P, this active form allows for the best absorption, because it is ready to go to work immediately.

debranching enzyme (a-(1,6)-glucosidase )

Enzymatic activity of glycogen phosphorylase debranching enzyme (also called glucan transferase) which contains 2 activities: glucotransferase and glucosidase. The transferase activity removes the terminal 3 glucose residues of one branch and attaches them to a free C-4 end of a second branch The glucose in a-(1,6)-linkage at the branch is then removed by the action of glucosidase

Glycogen synthesis A different reaction sequence is required for glycogen synthesis because the glycogen phosphorylase is not easily reversed. A high energy glucose donor is required to make new glycoside bonds in glycogen. This is the compound uridine diphosphate glucose (UDP-Glc), an example of a sugar nucleotide

UDP glucose is made by the action of the enzyme UDP-glucose pyrophosphorylase. The incoming glucose-1-phosphate displaces two units of phosphate from UTP, released as inorganic pyrophosphate, HP 2 O 7 3 –. UDP-glucose pyrophosphorylase

Glycogen synthase uses UDG-glucose as glucose donor Glycogen synthase adds glucose to the non-reducing ends of glycogen chains. The 4α-OH of the non reducing terminal glucose acts as the nucleophile, and displaces UDP from UDP glucose. The added glucose forms a new a(1  4) glycoside bond.

Glycogen synthesis costs ATP energy Since UTP is required at the UDP-glucose pyrophosphorylase step, and UDP is released at the glycogen synthase step, these reactions contribute an energy cost of 1 UTP hydrolysed (equivalent to 1 ATP) for each glucose unit added with glucose-6-phosphate as starting point. An additional ATP is needed when glucose is the starting point. The benefit is that glycogen can be synthesized when cellular energy is in surplus. Glycogen can deliver glucose-6-phosphate to glycolysis without costing ATP, which occurs when energy is in demand

PANCREATIC HORMONES The primary role of the pancreatic hormones is the regulation of whole body energy metabolism, principally by regulating the concentration and activity of numerous enzymes involved in catabolism and anabolism of the major cell energy supplies. The pancreas has exocrine and endocrine functions. Endocrine function involves Islets of Langerhans Four hormones are secreted: HormoneOriginCompositionFunction Insulin β cells (central)disulfide bonded dipeptide of 21 and 30 amino acids increases glucose uptake and utilization, increases lipogenesis, and general anabolic effects.(secreated when blood glucose levels are high) Glucagonα cells (peripheral)polypeptide of 29 amino acids increases glycogenolysis in order to increase blood glucose levels (Secreted when blood glucose levels are low) Pancreatic Polypeptide F cellspolypeptide of 36 amino acids increases glycogenolysis, regulation of gastrointestinal activity Somatostatin  cells 14 amino acid version inhibition of glucagon and somatotropin release

Glucagon is an endocrine hormone that mobilizes the body’s energy stores. It affects liver cells, muscle cells, adipocytes and kidney cells Glucagon has a major role in maintaining normal concentrations of glucose in blood, and is often described as having the opposite effect of insulin. Glucagon is a linear peptide of 29 amino acids. Glucagon is synthesized as proglucagon and proteolytically processed to yield glucagon within  cells of he pancreatic islets.. How does glucagon work?

Physiologic Effects of Glucagon The major effect of glucagon is to stimulate an increase in blood concentration of glucose. The brain in particular has an absolute dependence on glucose as a fuel, because neurons cannot utilize alternative energy sources like fatty acids. When blood levels of glucose begin to fall below the normal range, it is imperative to find and pump additional glucose into blood. Glucagon exerts control over two pivotal metabolic pathways within the liver, leading that organ to dispense glucose to the rest of the body: Glucagon stimulates breakdown of glycogen stored in the liver. Glucagon activates hepatic gluconeogenesis. Glucagon also appears to have a minor effect of enhancing lipolysis of triglyceride It stimulates glycogenolysis, gluconeogenesis, lipolysis, protein degradation, amino acid catabolism and ketogenesis

Regulation of glycogenolysis Glucagon Glucagon is hyperglycemic - promotes mobilization of glucose from glycogen (glycogenolysis) and mobilization of free fatty acids from adipose tissue (lipolysis). It is also gluconeogenic. Actions of Glucagon: 1. Glycogenolysis 2. Lipolysis 3. Gluconeogenesis Secretion from pancreatic alpha cells

Regulation of phosphorylase by glucagon Regulation through beta-adrenergic receptor glucagon Glucagon receptor on the cellular membrane (Glycogne)n (Glycogne)n-1 + Glucose-1-p

Muscle phosphorylase is regulated by phosphorylation

phosphorylase kinase is fully activated upon phosphorylation and calcium binding

glucagon Glucagon receptor on the cellular membrane Regulation of phosphorylase by glucagon Regulation through beta-adrenergic receptor

Protein phosphatase is inactivated during exercise or fasting by Epinephrine or glucagon

Glycogen metabolism in the liver regulates the blood glucose level After meal 1.Blood glucose levels  2.Insulin secretion  3.Uptake of glucose by the liver  4.Glycogen synthase activities  5.Phosphorylase activities  Lagging period of glycogen synthase activation occurs. Activation of synthase takes place only after inactivation of phosphorlase Why?

Suppression of PP1 by liver glycogen phosphorylase a is relieved upon glucose infusion Binding of glucose to phosphorylase a leads phsophorylase a from R (relaxed) to T (Taut) state While phosphorylase a is bound to PP1 and G L, PP1 is inactive and thus nonfunctional. Upon glucose binding, conformation of phosphorylase a is changed to T state. This causes detachment of PP1 and G L from phosphorylase a. Upon conformational change to T state, serine 14 on phosphorylase a is exposed. PP1 dephosphorylase this exposed serine of phosphorylase a. There are about 10 phosphorylase a to 1 PP1. PP1 is not fully functional until all the R phosphorylase a turns into T state. Upon depletion of phosphorylase a (R state), PP1 becomes fully activated and begins to dephosphorylate glycogen synthase b turning it into glycogen synthase a.

Insulin induces dephosphorylation of glycogen synthase via inactivation of glycogen synthase kinase