Bioc 460 - Dr. Miesfeld Spring 2008 1 of 12 pages Figure 2. Figure 1. Carbohydrate Metabolism 2 Supplemental Reading Key Concepts - Overview of glycogen metabolism - Biochemistry and regulation glycogen degradation - Biochemistry and regulation of glycogen synthesis - Control of glycogen metabolism by intracellular signaling - Human glycogen storage diseases Key Question about Glycogen Metabolism: What mechanisms regulate the activity of muscle and liver glycogen phosphorylase? How do insulin and glucagon mediate recipricol reglation of glycogen metabolism? Overview of glycogen metabolism The storage form of glucose in most eukaryotic cells (except plants) is glycogen, a large highly branched polysaccharide consisting of glucose units joined by α-1,4 and α-1,6 glycosidic bonds (figure 1). Both the liver and muscle store glycogen and hence have the necessary anabolic and catabolic enzymes.Glycogen degradation and synthesis occurs in the cytosol and the substrate for these reactions is the free ends of the branched polymer (nonreducing ends). The large number of branch points in glycogen results in the generation of multiple nonreducing ends that provide a highly efficient mechanism to quickly release and store glucose. The three key enzymes required for reversible degradation and synthesis of glycogen are glycogen phosphorylase, glycogen synthase and the branching/debranching enzymes. Glycogen phosphorylase and glycogen synthase modify glycogen at the nonreducing ends, whereas, the branching and debranching enzymes modify glycogen at the α-1,4 and α-1,6 glycosidic bonds (figure 2). Glycogen phosphorylase releases glucose-1-phosphate (glucose-1P) from glycogen in a phosphorolysis reaction involving inorganic phosphate (Pi) and cleavage of the α-1,4 glycosidic bond. The glucose-1P molecules are converted to glucose-6-phosphate (glucose-6P), which is either used for glycolysis in muscle cells, or is dephosphorylated in liver cells so that glucose can be exported to other tissues. Glycogen synthase is responsible for adding glucose to the nonreducing ends in a reaction involving uridine diphosphate glucose (UDP-glucose). Glycogen synthase uses the bond energy available in UDP-glucose to form α-1,4 glycosidic bonds at the growing nonreducing ends. ATP hydrolysis is required to regenerate UTP for subsequent rounds of glucose addition, and therefore, glycogen synthesis requires 1 ATP/glucose residue added. As first presented in lecture 22 in the context of signal transduction, hormone signaling through glucagon, epinephrine andBioc 460 - Dr. Miesfeld Spring 2008 2 of 12 pages Figure 3. insulin results in reversible phosphorylation of glycogen phosphorylase and glycogen synthase. As described later, the activities of glycogen phosphorylase and glycogen synthase can also be controlled by allosteric mechanisms in response to the metabolic state of the cell. Lastly, the glycogen branching and debranching enzymes ensure that glycogen phosphorylase and glycogen synthase have access to the maximum number of non-reducing ends for the cleavage and formation of α-1,4 glycosidic bonds. Although small amounts of glycogen are synthesized in many animal cell types, it is only the liver and skeletal muscle that accumulate large amounts of glycogen. Glycogen core complexes consist of glycogenin protein and ~50,000 glucose molecules with α-1,6 branches about every 10 residues creating ~2,000 nonreducing ends. Twenty to forty glycogen core complexes associate inside liver and muscle cells to form glycogen particles containing over a million glucose molecules. These glycogen particles can be visualized by electron microscopy and account for up to 10% by weight of liver tissue (figure 3). Importantly, the physiological roles of liver and muscle glycogen are quite different. Liver glycogen is used as a source of glucose for export to other tissues when dietary glucose is limiting (between meals), whereas, the sole purpose of glycogen in muscle cells is to generate glucose-6P for use as a chemical energy source in anaerobic and aerobic glycolysis. Since muscle cells do not contain the enzyme glucose-6-phosphatase, all of the glucose-6P that is made available from glycogen degradation stays inside the cell. 1. What purpose does glycogen metabolism serve in animals? • Liver glycogen is used as a short term energy source for the organism by providing a means to store and release glucose in response to blood glucose levels; liver cells do not use this glucose for their own energy needs (fatty acids provide chemical energy to liver cells) • Muscle glycogen provides a readily available source of glucose during exercise to support anaerobic and aerobic energy conversion pathways within muscle cells; muscle cells lack the enzyme glucose-6-phosphatase and therefore cannot release glucose into the blood. 2. What are the net reactions of glycogen degradation and synthesis? Glycogen degradation: Glycogenn units of glucose + Pi --> Glycogenn-1 units of glucose + glucose-6-phosphate Glycogen Synthesis: Glycogenn units of glucose + glucose-6-phosphate + ATP + H2O--> Glycogenn+1 units of glucose + ADP + 2Pi 3. What are the key enzymes in glycogen metabolism? Glycogen phosphorylase – enzyme catalyzing the phosphorolysis reaction that uses Pi to remove one glucose at a time from nonreducing ends of glycogen resulting in the formation of glucose-1P. Liver and muscle glycogen phosphorylase are isozymes (two different genes) that are both activated by phosphorylation but have distinct responses to allosteric effectors. Glycogen synthase - enzyme catalyzing the addition of glucose residues to nonreducing ends of glycogen using UDP-glucose as the glucose donor. Glycogen synthase activity is inhibited by phosphorylation; binding of the allosteric activators glucose or glucose-6P promotes dephosphorylation and enzyme activation.Bioc 460 - Dr. Miesfeld Spring 2008 3 of 12 pages Figure 4. Figure 5. Figure 6 Branching and debranching enzymes - these two enzymes are responsible for adding (branching) and removing (debranching) glucose residues to the glycogen complex through the cleavage and formation of α-1,6 glycosidic bonds. 4. What are examples of glycogen metabolism in real life? The performance of elite endurance athletes can benefit from a diet regimen of carbohydrate "loading" prior to competition. Recent studies indicate that a short period of intense
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