glycogen

 A constant source of blood glucose is an absolute requirement for human life. Glucose is the greatly preferred energy source for the brain, and the required energy source for cells with few or no mitochondria, such as mature erythrocytes. Glucose is also essential as an energy source for exercising muscle, where it is the substrate for anaerobic glycolysis. Blood glucose can be obtained from three primary sources: the diet, degradation of glycogen, and gluconeogenesis. Dietary intake of glucose and glucose precursors, such as starch, monosaccharides, and disaccharides, is sporadic and, depending on the diet, is not always a reliable source of blood glucose. In contrast, gluconeogenesis (see p. 117) can provide sustained synthesis of glucose, but it is somewhat slow in responding to a falling blood glucose level. Therefore, the body has developed mechanisms for storing a supply of glucose in a rapidly mobilizable form, namely, glycogen. In the absence of a dietary source of glucose, this sugar is rapidly released from liver and kidney glycogen. Similarly, muscle glycogen is extensively degraded in exercising muscle to provide that tissue with an important energy source. When glycogen stores are depleted, specific tissues synthesize glucose de novo, using amino acids from the body’s proteins as a primary source of carbons for the gluconeogenic pathway. Figure 11.1 shows the reactions of glycogen synthesis and degradation as part of the essential pathways of energy metabolism. II. STRUCTURE AND FUNCTION OF GLYCOGEN The main stores of glycogen in the body are found in skeletal muscle and liver, although most other cells store small amounts of glycogen for their own use. The function of muscle glycogen is to serve as a fuel reserve for the synthesis of adenosine triphosphate (ATP) during muscle contraction. That of liver glycogen is to maintain the blood glucose concentration, particularly during the early stages of a fast (Figure 11.2, and see p. 329). A. Amounts of liver and muscle glycogen Approximately 400 g of glycogen make up 1–2% of the fresh weight of resting muscle, and approximately 100 g of glycogen make up to 10% of the fresh weight of a well-fed adult liver. What limits the production of glycogen at these levels is not clear. However, in some Figure 11.1 Glycogen synthesis and degradation shown as a part of the essential reactions of energy metabolism (see Figure 8.2, p. 92, for a more detailed view of the overall reactions of metabolism). UDP-Glucose Glycogen Glucose 1-P Glucose 6-P UDP-Glucose Galactose 1-P Glycogen Galactose Ribose 5-P Glucose 1-P UDP-Galactose Glucose 6-P Glucose Fructose 6-P Fructose 1,6-bis-P Glyceraldehyde 3-P 1,3-bis-Phosphoglycerate 3-Phosphoglycerate 2-Phosphoglycerate Phosphoenolpyruvate Pyruvate Acetyl-CoA Glyceraldehyde 3-P Glyceraldehyde Fructose Fructose 1-P Dihydroxyacetone-P Glycerol-P Glycerol Triacylglycerol Fatty acyl CoA Fatty acid Malonyl CoA Acetoacetate Leu Phe Tyr Trp Lys CO2 β-Hydroxybutyrate Citrate Isocitrate α-Ketoglutarate Gln Glu Pro His Arg Methylmalonyl CoA Propionyl CoA Acetyl CoA Fatty acyl CoA (odd-number carbons) Succinate Succincyl CoA Lactate Oxaloacetate Malate Fumarate Asn Citrulline Aspartate Argininosuccinate Arginine Phe Tyr NH3 Carbamoyl-P Ornithine Urea Xylulose 5-P Ribulose 5-P 6-P Gluconate 6-P Gluconolactone Erythrose 4-P Sedoheptulose 7-P CO2 CO2 CO2 CO2 Ile Met Val Thr Glucose Ala Cys Gly Ser Thr Try 125 168397_P125-136.qxd7.0:11 Glycogen 10-11-05 2010.4.4 3:12 PM Page 125 glycogen storage diseases (see Figure 11.8), the amount of glycogen in the liver and/or muscle can be significantly higher. B. Structure of glycogen Glycogen is a branched-chain polysaccharide made exclusively from α-D-glucose. The primary glycosidic bond is an α(1→4) linkage. After an average of eight to ten glucosyl residues, there is a branch containing an α(1→6) linkage (Figure 11.3). A single molecule of glycogen can have a molecular mass of up to 108 daltons. These molecules exist in discrete cytoplasmic granules that also contain most of the enzymes necessary for glycogen synthesis and degradation. C. Fluctuation of glycogen stores Liver glycogen stores increase during the well-fed state (see p. 323), and are depleted during a fast (see p. 329). Muscle glycogen is not affected by short periods of fasting (a few days) and is only moderately decreased in prolonged fasting (weeks). Muscle glycogen is synthesized to replenish muscle stores after they have been depleted following strenuous exercise. [Note: Glycogen synthe sis and degradation are cytosolic processes that go on continuously. The differences between the rates of these two processes determine the levels of stored glycogen during specific physiologic states.] III. SYNTHESIS OF GLYCOGEN (GLYCOGENESIS) Glycogen is synthesized from molecules of α-D-glucose. The process occurs in the cytosol, and requires energy supplied by ATP (for the phosphorylation of glucose) and uridine triphosphate (UTP). A. Synthesis of UDP-glucose α-D-Glucose attached to uridine diphosphate (UDP) is the source of all the glucosyl residues that are added to the growing glycogen molecule. UDP-glucose (Figure 11.4) is synthesized from glucose 1-phosphate and UTP by UDP-glucose pyrophosphorylase (Figure 11.5). The high-energy bond in pyrophosphate (PPi), the second product of the reaction, is hydrolyzed to two inorganic phosphates (Pi) by pyrophosphatase, which ensures that the UDP-glucose pyro - phosphorylase reaction proceeds in the direction of UDP-glucose production. [Note: Glucose 6-phosphate is converted to glucose 1- phosphate by phosphoglucomutase. Glucose 1,6-bis phosphate is an obligatory intermediate in this reaction (Figure 11.6).] B. Synthesis of a primer to initiate glycogen synthesis Glycogen synthase is responsible for making the α(1→4) linkages in glycogen. This enzyme cannot initiate chain synthesis using free glucose as an acceptor of a molecule of glucose from UDP-glucose. Instead, it can only elongate already existing chains of glucose. Therefore, a fragment of glycogen can serve as a primer in cells whose glycogen stores are not totally depleted. In the absence of a Glucose Glycogen Glucose 6-P Pi Glucose 6-P Glycogen Figure 11.2 Functions of muscle and liver glycogen. ENERGY MUSCLE LIVER BLOOD GLUCOSE 126 11. Glycogen Metabolism O OH OH OH OH OH OH CH2OH CH2 CH2OH O OH OH OH CH2OH CH2OH OH α(1→6) glycosidic bond α(1→4) glycosidic bonds Figure 11.3 Branched structure of glycogen, showing α(1→ 4) and α(1→ 6) glycosidic bonds. O O O O O O O O O 168397_P125-136.qxd7.0:11 Glycogen 10-11-05 2010.4.4 3:12 PM Page 126 glycogen fragment, a protein, called glycogenin, can serve as an acceptor of glucose residues from UDP-glucose (see Figure 11.5). The side chain hydroxyl group of a specific 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 as described below [Note: Glycogenin stays associated with and forms the core of a glycogen granule.] C. Elongation of glycogen chains by glycogen synthase Elongation of a glycogen chain involves the transfer of glucose from UDP-glucose to the nonreducing end of the growing chain, forming a new glycosidic bond between the anomeric hydroxyl of carbon 1 of the activated glucose and carbon 4 of the accepting glucosyl residue (see Figure 11.5). [Note: The nonreducing end of a carbohydrate chain is one in which the anomeric carbon of the terminal sugar is linked by a glycosidic bond to another compound, making the terminal sugar nonreducing (see p. 84).] The enzyme responsible for making the α(1→4) linkages in glycogen is glycogen synthase. [Note: The UDP released when the new α(1→4) glycosidic bond is made can be phosphorylated to UTP by nucleoside diphosphate kinase (UDP + ATP UTP + ADP, see p. 296).]