BIOCHEMISTRY: A TEXTBOOK FOR MEDICAL UNIVERSITIES - E. S. Severin - 2004

SECTION 7. CARBOHYDRATE METABOLISM

VI. Glycogen Metabolism

Many Tissues synthesize Glycogen as a reserve form of glucose. The Synthesis and degradation of glycogen maintain a constant Blood glucose concentration and provide a depot that tissues can draw upon as needed.

A. Structure AND Functions of Glycogen

Glycogen is a branched homopolysaccharide of glucose in which glucose residues are linked by α-1,4-glycosidic bonds in linear segments. At branching points, the monomers are joined by α-1,6-glycosidic bonds. These bonds occur approximately every tenth glucose residue; consequently, branch points in glycogen appear roughly every ten glucose residues. This creates a tree-like structure with a molecular mass of >10⁷ D, corresponding to approximately 50,000 glucose residues (Fig. 7-21). Thus, a glycogen molecule has only one free anomeric OH group and, therefore, only one reducing end.

Class="center">Fig. 7-21. Structure of glycogen. A. STRUCTURE OF THE glycogen molecule: 1 — glucose residues linked by α-1,4-glycosidic bonds; 2 — glucose residues linked by α-1,6-glycosidic bonds; 3 — non-reducing terminal monomers; 4 — reducing terminal monomer. B. Structure of an individual fragment of the glycogen molecule.

In animal Cells, glycogen is the primary reserve polysaccharide. The polymerization of glucose decreases the solubility of the resulting glycogen molecule and, consequently, its effect on the osmotic pressure within The Cell. This explains why cells store glycogen rather than free glucose.

Glycogen is stored in the cell Cytosol as granules with a diameter of 10–40 nm. Certain Enzymes involved in Glycogen METABOLISM are also associated with these granules, facilitating their interaction with the substrate. The branched structure of glycogen provides A large number of terminal monomers, which assists the enzymes that detach or attach monomers during glycogen degradation or synthesis, as these enzymes can work simultaneously on multiple Branches of the molecule. Glycogen is stored predominantly in The Liver and skeletal Muscles.

Following a carbohydrate-rich meal, liver glycogen stores can account for approximately 5% of the liver's mass. Muscles store about 1% glycogen, but due to the significantly greater mass of Muscle tissue, the total amount of glycogen in muscles is twice that in the liver. Glycogen can be synthesized in many

cells, such as Neurons, macrophages, and adipose tissue cells, but its content in these tissues is negligible. The Human Body can contain up to 450 g of glycogen.

The breakdown of liver glycogen serves mainly to maintain blood glucose levels during the postabsorptive period. Therefore, liver glycogen content fluctuates According to the feeding rhythm, dropping almost to zero during prolonged fasting. Muscle glycogen serves as a glucose reserve—an energy source for Muscle contraction. Muscle glycogen is not used to maintain blood glucose levels. As mentioned earlier, muscle cells lack the enzyme glucose-6-phosphatase, making The formation of free glucose impossible. Glycogen consumption in muscles depends primarily on physical exertion (Fig. 7-22).

Fig. 7-22. Functions of glycogen in the liver and muscles.

B. Glycogen Synthesis (Glycogenesis)

Glycogen is synthesized during the absorptive period (1–2 hours after a carbohydrate-rich meal). It should be noted that the Synthesis of glucose into glycogen (Fig. 7-23), like any anabolic process, is endergonic, meaning it requires an energy input.

Fig. 7-23. Glycogen synthesis. 1 — glucokinase or hexokinase; 2 — phosphoglucomutase; 3 — UDP-glucose pyrophosphorylase; 4 — glycogen synthase (glucosyltransferase); 5 — branching enzyme (amylo-1,4 -> 1,6-glucosyltransferase); light and hatched circles represent glucose residues, filled circles represent glucose residues at branch points.

Glucose entering the cell is phosphorylated with the participation of ATP (reaction 1). Glucose-6-phosphate is then converted into glucose-1-phosphate in a reversible reaction (reaction 2) catalyzed by phosphoglucomutase. Thermodynamically, glucose-1-phosphate could serve as a substrate for glycogen synthesis. However, due to the reversibility of the glucose-6-phosphate <-> glucose-1-phosphate reaction, both the synthesis of glycogen from glucose-1-phosphate and its breakdown would also be reversible and therefore uncontrolled. To make glycogen synthesis thermodynamically irreversible, an additional step is required: the formation of uridine diphosphate glucose from UTP and glucose-1-phosphate (reaction 3). The enzyme catalyzing this reaction is named after the reverse reaction: UDP-glucose pyrophosphorylase. However, the reverse reaction does not proceed in the cell because the pyrophosphate formed during the forward reaction is rapidly hydrolyzed by pyrophosphatase into 2 molecules of phosphate (Fig. 7-24).

Fig. 7-24. Formation of UDP-glucose.

The reaction forming UDP-glucose ensures the irreversibility of the entire series of reactions involved in glycogen synthesis. This also explains why glycogen breakdown cannot occur simply by reversing its synthetic pathway.

The resulting UDP-glucose is subsequently used as a glucose residue donor in glycogen synthesis (Fig. 7-23, reaction 4). This reaction is catalyzed by the enzyme glycogen synthase (glucosyltransferase). Because ATP is not consumed in this specific reaction, the enzyme is termed a synthase rather than a synthetase. The nucleotide moiety of UDP-glucose plays a crucial role in the action of glycogen synthase, acting as a "handle" that the enzyme uses to position glucose correctly within the polysaccharide chain. In addition, the nucleotide portion of UDP-glucose is apparently essential for substrate recognition during catalysis.

Since cellular glycogen is never completely degraded, glycogen synthesis proceeds by elongating an existing polysaccharide molecule called a "primer." Glucose molecules are sequentially added to the primer. The structure of the primer essentially predetermines the type of bond formed during the transglycosylation reaction. Thus, a polysaccharide structurally analogous to the primer is synthesized. The primer may include the protein glycogenin, in which an oligosaccharide chain (approximately 8 glucose residues) is attached to the OH group of a Tyrosine residue. Glucose residues are transferred by glycogen synthase to the non-reducing end of the oligosaccharide and linked by α-1,4-glycosidic bonds. Upon completion of synthesis, glycogenin remains incorporated into the glycogen granule.

The branched structure of glycogen is formed with the participation of amylo-1,4 > 1,6-glucosyltransferase, known as the branching enzyme. Once glycogen synthase elongates a linear segment to approximately 11 glucose residues, the branching enzyme transfers its terminal block of 6 to 7 residues to an internal glucose residue of the same or another chain. At the branch point, the terminal glucose residue of the oligosaccharide is linked to the hydroxyl group at the C6 position, forming an α-1,6-glycosidic bond. A new branch point can be formed at a distance of at least 4 residues from any pre-existing one. Thus, as glycogen synthesis proceeds, the number of branches increases manifold. The chain ends serve as growth points for the molecule during its synthesis and as starting points during its degradation.

C. Glycogen degradation (Glycogenolysis)

Glycogen degradation, or mobilization, occurs in response to an increased physiological demand for glucose. Liver glycogen is degraded primarily between meals; moreover, this process in the liver and muscles is accelerated during physical exertion.

Glycogen degradation (Fig. 7-25) proceeds through the sequential Cleavage of glucose residues in the form of glucose-1-phosphate. The glycosidic bond is cleaved utilizing inorganic phosphate, which is why the process is termed phosphorolysis, and the corresponding enzyme is Glycogen phosphorylase.

Fig. 7-25. Glycogen degradation. The inset shows a glycogen fragment with a branch point. The filled circle represents a glucose residue linked by an α-1,6-glycosidic bond; open and hatched circles represent glucose residues in linear segments and side chains linked by α-1,4-glycosidic bonds. 1 — glycogen phosphorylase; 2 — oligosaccharide transferase; 3 — α-1,6-glucosidase.

Much like synthesis, glycogen breakdown begins at the non-reducing end of the polysaccharide chain. The branched structure of glycogen facilitates the rapid release of glucose residues because the more ends a glycogen molecule possesses, the more glycogen phosphorylase molecules can act simultaneously.

Glycogen phosphorylase exclusively cleaves α-1,4-glycosidic bonds (reaction 1). The sequential removal of glucose residues stops when 4 monomers remain before a branch point. This Specificity in glycogen phosphorylase action is dictated by the Size and Structure of its Active Site.

Further glycogen degradation requires the participation of two Other Enzymes. First, the three remaining glucose residues proximal to the branch point are transferred by oligosaccharide transferase (reaction 2) to the non-reducing end of an adjacent chain, lengthening it and thereby enabling phosphorylase action. The glucose residue remaining at the branch point is hydrolytically cleaved by α-1,6-glucosidase as free glucose (reaction 3), after which the unbranched stretch of glycogen can once again be attacked by phosphorylase.

It is believed that The transfer of the three glucose residues and the removal of the monomer from the branch point (reactions 2 and 3) are catalyzed by a single bifunctional enzyme possessing two distinct enzymatic activities: transferase and glucosidase. It is referred to as the debranching enzyme.

The product of glycogen phosphorylase action—glucose-1-phosphate—is subsequently isomerized to glucose-6-phosphate by phosphoglucomutase. Glucose-6-phosphate then enters Catabolic pathways or other metabolic routes. In the liver (but not in muscle), glucose-6-phosphate can be hydrolyzed to yield glucose, which is released into the bloodstream. This reaction is catalyzed by glucose-6-phosphatase. The reaction takes place in the lumen of The Endoplasmic reticulum (ER), where glucose-6-phosphate is transported by a specific carrier protein. The enzyme is localized on the ER membrane with its active site facing the ER lumen. The Hydrolysis products (glucose and inorganic phosphate) are returned to the Cytoplasm likewise via transport systems.

D. Biological Significance of Glycogen metabolism in the liver and muscles

Figure 7-26 illustrates the overall scheme of Glycogen Synthesis and Degradation along with the Hormonal Regulation of these processes.

A comparison of these processes allows for the following Conclusions:

✵ glycogen synthesis and degradation proceed via distinct metabolic pathways;

✵ the liver stores glucose as glycogen not so much for its own needs as to maintain a constant blood glucose concentration, thereby ensuring a continuous supply of glucose to other tissues. The presence of glucose-6-phosphatase in the liver underlies this primary function in glycogen metabolism;

✵ the function of muscle glycogen is to provide glucose-6-phosphate, which is consumed locally within the muscle for oxidation and energy production;

✵ glycogen synthesis is an endergonic process; specifically, the incorporation of a single glucose residue into the polysaccharide chain consumes 1 mol of ATP and 1 mol of UTP;

✵ the breakdown of glycogen to glucose-6-phosphate does not require energy;

✵ the irreversibility of glycogen synthesis and degradation is ensured by their precise regulation.