The Metabolism of Glycogen in Animals: -The Sugar Nucleotide UDP-Glucose Donates Glucose for Glycogen Synthesis
Many of the reactions in which hexoses are transformed or polymerized involve sugar nucleotides, compounds in which the anomeric carbon of a sugar is activated by attachment to a nucleotide through a phosphate ester linkage. Sugar nucleotides are the substrates for poly merization of monosaccharides into disaccharides, glycogen, starch, cellulose, and more complex extracellular polysaccharides. They are also key intermediates in the production of the aminohexoses and deoxyhexoses found in some of these polysaccharides, and in the synthesis of vitamin C (L-ascorbic acid). The role of sugar nucleotides in the biosynthesis of glycogen and many other carbohydrate derivatives was first discovered by the Argentine biochemist Luis Leloir.
The suitability of sugar nucleotides for biosynthetic reactions stems from several properties:
1. Their formation is metabolically irreversible, con tributing to the irreversibility of the synthetic pathways in which they are intermediates. The condensation of a nucleoside triphosphate with a hexose 1-phosphate to form a sugar nucleotide has a small positive free-energy change, but the reaction releases PPi, which is rapidly hydrolyzed by inorganic pyrophosphatase in a reaction that is strongly exergonic (ΔG0=-19.2 kJ/mol; Fig. 15–7). This keeps the cellular concentration of PPi low, ensuring that the actual free-energy change in the cell is favorable. In effect, rapid removal of the product, driven by the large, negative free-energy change of PPi hydrolysis, pulls the synthetic reaction forward, a common strategy in biological polymerization reactions.
FIGURE 15–7 Formation of a sugar nucleotide. A condensation reaction occurs between a nucleoside triphosphate (NTP) and a sugar phosphate. The negatively charged oxygen on the sugar phosphate serves as a nucleophile, attacking the phosphate of the nucleoside triphosphate and displacing pyrophosphate. The reaction is pulled in the forward direction by the hydrolysis of PPi by inorganic pyrophosphatase.
2. Although the chemical transformations of sugar nucleotides do not involve the atoms of the nucleotide itself, the nucleotide moiety has many groups that can undergo noncovalent interactions with enzymes; the additional free energy of binding can contribute significantly to catalytic activity.
3. Like phosphate, the nucleotidyl group (UMP or AMP, for example) is an excellent leaving group, facilitating nucleophilic attack by activating the sugar carbon to which it is attached.
4. By “tagging” some hexoses with nucleotidyl groups, cells can set them aside in a pool for one purpose (glycogen synthesis, for example), separate from hexose phosphates destined for another purpose (such as glycolysis).
Glycogen synthesis takes place in virtually all animal tissues but is especially prominent in the liver and skeletal muscles. The starting point for synthesis of glycogen is glucose 6-phosphate. As we saw in Chapter 14, this can be derived from free glucose in a reaction catalyzed by the isozymes hexokinase I and hexokinase II in muscle and hexokinase IV (glucokinase) in liver: D-Glucose ATP 88nD-glucose 6-phosphate ADP However, some ingested glucose takes a more roundabout path to glycogen. It is first taken up by erythrocytes and converted to lactate glycolytically; the lactate is then taken up by the liver and converted to glucose 6-phosphate by gluconeogenesis. To initiate glycogen synthesis, the glucose 6 phosphate is converted to glucose 1-phosphatein the phosphoglucomutase reaction:
Glucose 6-phosphate⇌glucose 1-phosphate
The product of this reaction is converted to UDP glucose by the action of UDP-glucose pyrophospho-ylase, in a key step of glycogen biosynthesis:
Glucose 1-phosphate+UTP→UDP-glucose PPi
Notice that this enzyme is named for the reverse reaction; in the cell, the reaction proceeds in the direction of UDP glucose formation, because pyrophosphate is rapidly hydrolyzed by inorganic pyrophosphatase (Fig. 15–7). UDP-glucose is the immediate donor of glucose residues in the reaction catalyzed by glycogen synthase, which promotes the transfer of the glucose residue from UDP-glucose to a nonreducing end of a branched glycogen molecule (Fig. 15–8). The overall equilibrium of the path from glucose 6-phosphate to lengthened glycogen greatly favors synthesis of glycogen. Glycogen synthase cannot make the (1→6) bonds found at the branch points of glycogen; these are formed by the glycogen-branching enzyme, also called amylo (1→4) to (1n6) transglycosylase or glycosyl (4n6)-transferase. The glycogen-branching enzyme catalyzes transfer of a terminal fragment of 6 or 7 glucose residues from the nonreducing end of a glycogen branch having at least 11 residues to the C-6 hydroxyl group of a glucose residue at a more interior position of the same or another glycogen chain, thus creating a new branch (Fig. 15–9). Further glucose residues may be added to the new branch by glycogen synthase. The biological effect of branching is to make the glycogen molecule more soluble and to increase the number of nonreducing ends. This increases the number of sites accessible to glycogen phosphorylase and glycogen synthase, both of which act only at nonreducing ends.
IGURE 15–8 Glycogen synthesis. A glycogen chain is elongated by glycogen synthase. The en zyme transfers the glucose residue of UDP-glucose to the nonreducing end of a glycogen branch to make a new (1→4) linkage.
FIGURE 15–9 Branch synthesis in glycogen. The glycogen-branching enzyme (also called amylo (1→4) to (1→6) transglycosylase or glycosyl-(4→6)-transferase) forms a new branch point during glycogen synthesis.
