Branches are removed by the two enzymic activities of a single bifunctional protein, the debranching enzyme (see Fig. 11.8). First, oligoα(1→4)→α(1→4)-glucantransferase activity removes the outer three of the four glucosyl residues remaining at a branch. It next transfers them to the nonreducing end of another chain, lengthening it accordingly. Thus, an α(1→4) bond is broken and an α(1→4) bond is made, and the enzyme functions as a 4:4 transferase. Next, the remaining glucose residue attached in an α(1→6) linkage is removed hydrolytically by amylo-α(1→6)glucosidase activity, releasing free (nonphosphorylated) glucose. The glucosyl chain is now available again for degradation by glycogen phosphorylase until four glucosyl units in the next branch are reached.
C. Glucose 1-phosphate isomerization to glucose 6phosphate
Glucose 1-phosphate, produced by glycogen phosphorylase, is isomerized in the cytosol to glucose 6-phosphate by phosphoglucomutase (see Fig. 11.6). In the liver, glucose 6-phosphate is transported into the endoplasmic reticulum (ER) by glucose 6-phosphate translocase. There, it is dephosphorylated to glucose by glucose 6-phosphatase (the same enzyme used in the last step of gluconeogenesis; see p. 121). The glucose is then transported from the ER to the cytosol. Hepatocytes release glycogen-derived glucose into the blood to help maintain blood glucose levels until the gluconeogenic pathway is actively producing glucose. [Note: Muscle lacks glucose 6-phosphatase. Consequently, glucose 6-phosphate cannot be dephosphorylated and sent into the blood. Instead, it enters glycolysis, providing energy needed for muscle contraction.]
D. Lysosomal degradation
A small amount (1%–3%) of glycogen is degraded by the lysosomal enzyme, acid α(1→4)-glucosidase (acid maltase). The purpose of this autophagic pathway is unknown. However, a deficiency of this enzyme causes accumulation of glycogen in vacuoles in the lysosomes, resulting in the serious GSD type II: Pompe disease (see Fig. 11.8). [Note: Pompe disease is the only GSD that is a lysosomal storage disease.]
Lysosomal storage diseases are genetic disorders characterized by the accumulation of abnormal amounts of carbohydrates or lipids primarily due to their decreased lysosomal degradation resulting from decreased activity or amount of lysosomal acid hydrolases.
V. GLYCOGENESIS AND GLYCOGENOLYSIS REGULATION
Because of the importance of maintaining blood glucose levels, the synthesis and degradation of its glycogen storage form are tightly regulated. In the liver, glycogenesis accelerates during periods when the body has been well fed, whereas glycogenolysis accelerates during periods of fasting. In skeletal muscle, glycogenolysis occurs during active exercise, and glycogenesis begins as soon as the muscle is again at rest. Regulation of synthesis and degradation is accomplished on two levels. First, glycogen synthase and glycogen phosphorylase are hormonally regulated (by covalent phosphorylation/dephosphorylation) to meet the needs of the body as a whole. Second, these same enzymes are allosterically regulated (by effector molecules) to meet the needs of a particular tissue.
A. Covalent activation of glycogenolysis