BIOCHEMISTRY - L. Stryer - 1984

VOLUME 2

PART II GENERATION AND STORAGE OF METABOLIC ENERGY

CHAPTER 16. GLYCOGEN AND DISACCHARIDE METABOLISM

Glycogen is a readily mobilized storage form of glucose. It is a very large, branched polymer consisting of glucose residues (Fig. 16.1). Most of the glucose residues in glycogen are linked by α-1,4-glycosidic bonds. Branching is introduced by α-1,6-glycosidic bonds; roughly one such bond occurs for every ten residues.

Class="center">Fig. 16.1. Structure of two outer branches of a glycogen particle. Residues at the nonreducing ends are shown in red, and the residues from which branches originate are in blue. The rest of the glycogen molecule is designated by the symbol R

The presence of glycogen greatly increases The amount of glucose readily available for use by the Organism between meals or during periods of muscular activity. The energy content of glucose in the Body Fluids of a 70-kg average human is only 40 kcal, whereas the total body glycogen exceeds 600 kcal, even after an overnight fast. In the body, glycogen is stored mainly in The Liver and skeletal Muscles. The concentration of glycogen is higher in the liver than in muscles, but due to the much greater mass of skeletal muscles, their total glycogen reserves exceed those of the liver. Glycogen is present in the Cytosol in the form of granules ranging from 100 to 400 Å in diameter. This variation in granule size is due to differences in glycogen molecule size; the distribution maximum typically corresponds to a mass of several thousand kilodaltons. In electron micrographs, glycogen granules appear dense (Fig. 16.3). They contain Enzymes that catalyze the Synthesis and degradation of glycogen, as well as some enzymes that regulate these processes. However, glycogen granules differ from multienzyme complexes (such as the Pyruvate dehydrogenase complex) in lacking defined stoichiometric ratios of the associated enzymes. Furthermore, the degree of structural Organization in glycogen granules is lower than in multienzyme complexes.

Fig. 16.2. Schematic cross-section of a glycogen molecule. Terminal residues are shown in red, and the residues from which branches originate are in green

Fig. 16.3. Electron micrograph of a liver Cell. The dense particles in the Cytoplasm represent glycogen granules

The synthesis and degradation of glycogen are discussed here in detail for several reasons. First, these processes are of great importance in regulating Blood glucose levels and providing a glucose reserve for intense muscular activity. Second, glycogen Synthesis and Breakdown proceed via different metabolic pathways, illustrating a fundamental principle of biochemistry. Third, the hormonal Regulation of Glycogen METABOLISM is mediated by mechanisms of general significance. The Role of cyclic adenosine monophosphate (cyclic AMP) in the coordinated control of Glycogen Synthesis and Degradation has been thoroughly elucidated. This provides insight into the Mechanism of hormone Action in various other systems. Fourth, several inherited enzyme defects leading to impaired glycogen metabolism have been characterized. Some of these Glycogen Storage Diseases are fatal in early childhood, whereas others have a relatively benign clinical course. The final part of this chapter is devoted to the metabolism of common Disaccharides: lactose, maltose, and sucrose.

16.1. Phosphorylase Catalyzes the Phosphorolytic Cleavage of Glycogen to Glucose-1-Phosphate

The pathway of glycogen breakdown was elucidated through the elegant studies of Carl Cori and Gerty Cori. They demonstrated that glycogen is cleaved by orthophosphate to yield a new type of phosphorylated sugar, which they identified as glucose-1-phosphate. The Coris also isolated and crystallized Glycogen phosphorylase, the enzyme that catalyzes this reaction.

Glycogen + P¡ ⇄ Glucose-1-phosphate + Glycogen.

(n residues) (n-1 residues)

Phosphorylase catalyzes the sequential removal of glycosyl residues from the nonreducing end of the glycogen molecule. Orthophosphate cleaves the glycosidic bond between C-1 of the terminal residue and C-4 of the adjacent residue. It specifically breaks the bond between carbon atom C-1 and the glycosidic oxygen while retaining the α-configuration at C-1.

This reaction likely proceeds via a carbonium ion intermediate. The Cleavage of the bond between C-1 and O, the retention of configuration at C-1, and the putative involvement of a carbonium ion intermediate are reminiscent of The breakdown of Chitin catalyzed by Lysozyme.

The reaction catalyzed by phosphorylase is readily reversible in vitro. At pH 6.8, the equilibrium ratio of orthophosphate to glucose-1-phosphate is 3.6. ∆G⁰ for this reaction is small because the glycosidic bond is replaced by a phosphoester bond, which has nearly the same transfer potential. In vivo, however, phosphorolysis strongly favors glycogen breakdown because the [Pj]/[Glucose-1-phosphate] ratio typically exceeds 100.

The phosphorolytic cleavage of glycogen is energetically advantageous because the released sugar is already phosphorylated. In contrast, hydrolytic cleavage would yield free glucose, which would have to be phosphorylated at the expense of ATP to enter The Glycolytic Pathway. An additional advantage of phosphorolytic degradation is that glucose-1-phosphate, unlike glucose, cannot diffuse out of The Cell. We will see shortly The Significance of the Muscle's ability to retain phosphorylated sugar.