Glycogen Metabolism: Synthesis and Breakdown

Glycogen Metabolism: Synthesis and Breakdown

Glycogen, the storage form of glucose, is a branched polymer crucial for energy regulation in the body. Both glycogen and starch store glucose for future metabolic needs. In animals, glycogen provides a rapidly accessible source of glucose, especially for tissues like the brain and red blood cells, which heavily rely on glucose as their primary energy source. While other tissues can utilize fatty acids or amino acids for energy, a constant supply of glucose is essential for these critical tissues. Glycogen serves as a readily available reservoir, ensuring continuous energy supply during increased demand, such as exercise or fasting.

Glycogen Breakdown (Glycogenolysis)

• Liver Glycogen’s Role: Glycogen stores in the liver play a crucial role in maintaining a steady supply of glucose (~5 mM in blood) to all tissues. After a meal, when glucose levels are high, glycogen synthesis accelerates, allowing the liver to store excess glucose for future use. However, the liver’s glycogen capacity can only supply the brain with glucose for about half a day.
• Fasting and Gluconeogenesis: During fasting, when dietary glucose is limited, the body relies on gluconeogenesis – the synthesis of new glucose from non-carbohydrate precursors like amino acids. This process ensures essential tissues, such as the brain, receive a constant glucose supply.
• Glucose Metabolism Regulation: The regulation of glucose metabolism, including synthesis, storage, mobilization, and catabolism via pathways like glycolysis or the pentose phosphate pathway, is highly complex. It is sensitive to both immediate and long-term energy needs, ensuring glucose homeostasis and adaptation to varying metabolic conditions.

Glycogen Structure and Granules

Glycogen forms intracellular granules, 100- to 400-Å-diameter spheroidal molecules with up to 120,000 glucose units. These granules are prominent in glycogen-utilizing cells like muscle (1–2% glycogen by weight) and liver cells (up to 10% glycogen by weight). They also house enzymes for glycogen synthesis and degradation, along with regulatory proteins.

• Glycogen is a branched polysaccharide consisting of linear chains of glucose molecules linked by alpha-1,4-glycosidic bonds, with branches formed by alpha-1,6-glycosidic bonds.
• The advantage of its branched structure is increased solubility, rapid mobilization of glucose during glycogenolysis, and maximized storage capacity within cells.

Enzymes in Glycogen Breakdown

Glycogen breakdown involves three key enzymes:

• Glycogen Phosphorylase: Catalyzes glycogen phosphorolysis to produce glucose-1-phosphate (G1P).
• Glycogen Debranching Enzyme: Removes glycogen branches to expose more glucose residues.
• Phosphoglucomutase: Converts G1P to glucose-6-phosphate (G6P), which has various metabolic pathways.

Glycogen Phosphorylase Degrades Glycogen to Glucose-1-Phosphate

Glycogen phosphorylase is a dimeric enzyme composed of identical 842-residue subunits that catalyze glycogen breakdown. It is regulated by allosteric interactions and covalent modification (phosphorylation). Allosteric inhibitors (ATP, G6P, glucose) and activators (AMP) regulate it sensitively. The enzyme binds pyridoxal 5′-phosphate (PLP) as a cofactor via a Schiff base with Lys 680. PLP’s phosphate group acts as a general acid-base catalyst. Glycogenolysis proceeds via a random mechanism involving an enzyme-Pi-glycogen complex. The reaction forms an oxonium ion intermediate, similar to lysozyme’s transition state. The ΔG°ʹ for glycogen phosphorylase is +3.1 kJ·mol−1, but under physiological conditions, glycogen breakdown is exergonic (ΔG°ʹ = −5 to −8 kJ·mol−1).

Glycogen Debranching Enzyme: Glucosyltransferase Activity

Glycogen debranching enzyme acts as a glucosyltransferase, moving three glucose residues from a “limit branch” to another. This creates a new α(1→4) linkage. The remaining α(1→6) bond is hydrolyzed, yielding glucose and debranched glycogen. Approximately 10% of glycogen residues are converted to glucose. The enzyme has separate active sites for transferase and α(1→6)-glucosidase reactions, enhancing efficiency. Glycogen phosphorylase has a much higher reaction rate than debranching, leading to rapid degradation of outermost branches during high metabolic demand. Beyond this, glycogen degradation requires debranching, which occurs more slowly, limiting sustained exertion.

Phosphoglucomutase Interconverts Glucose-1-Phosphate and Glucose-6-Phosphate

Phosphoglucomutase converts G1P to G6P, similar to phosphoglycerate mutase. A phosphoryl group is transferred from the active phosphoenzyme to G1P, forming G1,6P, which rephosphorylates the enzyme to yield G6P. This reversible reaction is essential for glucose metabolism. Unlike phosphoglycerate mutase, phosphoglucomutase’s phosphoryl group is bound to a Ser hydroxyl group rather than a His imidazole nitrogen.

Glycogen Synthesis (Glycogenesis)

Key Concepts of Glycogen Synthesis

• Liver glycogen synthesis involves a series of conversions from glucose to glucose-6-phosphate, to UDP–glucose, and finally to glycogen.
• UDP–glucose is an activated molecule.
• Glycogen is extended from a primer built on and by the protein glycogenin.

Thermodynamics of Glycogen Synthesis

Glycogen synthesis from G1P is thermodynamically unfavorable without energy input. Thus, separate pathways for glycogen synthesis and breakdown are necessary, especially under similar physiological conditions. This separation is highlighted by McArdle’s disease, where individuals lack muscle glycogen phosphorylase but still have normal glycogen levels.

Enzymes in Glycogen Synthesis

Glycogen synthesis involves three key enzymes:

• UDP-Glucose Pyrophosphorylase: Catalyzes the formation of UDP-glucose from glucose-1-phosphate and UTP.
• Glycogen Synthase: Catalyzes the formation of α(1→4) glycosidic bonds between glucose residues to extend glycogen chains.
• Glycogen Branching Enzyme: Catalyzes the formation of α(1→6) glycosidic bonds, creating branches in the glycogen molecule.

UDP-Glucose Pyrophosphorylase Activates Glucosyl Units

Glycogen biosynthesis requires an exergonic step due to the thermodynamically unfavorable direct conversion of G1P to glycogen and Pi. Luis Leloir discovered in 1957 that combining G1P with uridine triphosphate (UTP), catalyzed by UDP-glucose pyrophosphorylase, forms uridine diphosphate glucose (UDPG). UDPG is an activated compound that donates a glucosyl unit to glycogen. Although UDPG formation has ΔG°′ ≈ 0, subsequent exergonic hydrolysis of pyrophosphate (PPi) by inorganic pyrophosphatase makes the overall reaction exergonic. This strategy involves cleaving a nucleoside triphosphate to form PPi, and using the free energy of PPi hydrolysis to drive an otherwise unfavorable reaction. The highly exergonic pyrophosphatase reaction prevents the reverse of the PPi-producing reaction.

Glycogen Synthase Extends Glycogen Chains

The transfer of a glucosyl unit from UDPG to glycogen forms a glycosyl oxonium ion by eliminating UDP. In the glycogen synthase reaction, the glucosyl unit of UDPG forms an α(1→4) glycosidic bond with glycogen. The ΔG°′ for this reaction is -13.4 kJ·mol−1, making it spontaneous. However, glycogen synthesis requires energy as one UTP molecule is cleaved to UDP for each glucose residue added to glycogen. UTP is replenished via nucleoside diphosphate kinase-mediated phosphoryl-transfer reaction. 1,5-gluconolactone inhibits glycogen synthase, glycogen phosphorylase, and lysozyme.

Human muscle glycogen synthase is a homotetramer of 737-residue subunits. The enzyme has two forms: a phosphorylated ‘b’ form (less active) and an original dephosphorylated ‘a’ form (more active). Glycogen synthase is allosterically inhibited by ATP, ADP, and Pi, with the phosphorylated form being nearly inactive in vivo. The dephosphorylated enzyme can be activated by G6P, varying the cell’s glycogen synthase activity. The mechanism of interconversion between phosphorylated and dephosphorylated forms is complex due to multiple phosphorylation sites.

Glycogenin Primes Glycogen Synthesis

Glycogenin primes glycogen synthesis by attaching glucose residues from UDPG to its Tyr 194, forming a primer. Glycogenin then extends the chain with additional UDPG-donated glucose residues. Glycogen synthase initiates glycogen synthesis by extending this primer. Each glycogen molecule is associated with one molecule each of glycogenin and glycogen synthase.

Glycogen Branching Enzyme: Segment Transfer

Glycogen synthase generates α(1→4) linkages to form α-amylose. Branching, which creates glycogen, is facilitated by amylo-(1,4→1,6)-transglycosylase, distinct from glycogen debranching enzyme. A 7-residue segment is transferred to form a branch, requiring a chain of at least 11 residues and a new branch point at least 4 residues away. Glycogen’s branching pattern is evolutionarily optimized for efficient glucose storage and mobilization.

Glycogen stores glucose as a polymer to avoid osmotic stress, maintaining a much lower glycogen concentration compared to free glucose residues. For optimal function, glycogen must maximize glucose storage, nonreducing ends, and release by glycogen phosphorylase through branching and chain length optimization. In a glycogen molecule, chains have two branches each, organized in tiers, with about 12 tiers in mature glycogen. Increasing branching increases outer tier residues but limits glycogen size and glucose density. Mathematical analysis suggests an optimal chain length of 13, matching glycogen chains in cells. Shorter chains pack more glucose and provide more phosphorylase attack points, but less glucose can be released before debranching. Longer chains allow continuous phosphorylolysis but fewer attack points. Thirteen residues balance glucose mobilization and speed. Amylopectin, like glycogen, has longer chains but lacks branches, designed differently for fuel mobilization.

Frequently Asked Questions (FAQs)

Q: Why must opposing biosynthetic and degradative pathways differ in at least one enzyme?
A: Opposing biosynthetic and degradative pathways must differ in at least one enzyme to prevent futile cycles where substrates are continuously synthesized and degraded.

Q: List the three enzymes involved in glycogen synthesis and describe the types of reactions they catalyze.
A: The three enzymes involved in glycogen synthesis are:

• UDP-glucose pyrophosphorylase: Catalyzes the formation of UDP-glucose from glucose-1-phosphate and UTP.
• Glycogen synthase: Catalyzes the formation of α(1→4) glycosidic bonds between glucose residues to extend glycogen chains.
• Glycogen branching enzyme: Catalyzes the formation of α(1→6) glycosidic bonds, creating branches in the glycogen molecule.

Q: What is the free energy source for glycogen synthesis?
A: The free energy source for glycogen synthesis is the hydrolysis of UTP during the formation of UDP-glucose.

Q: Describe the role of glycogenin.
A: Glycogenin initiates glycogen synthesis by catalyzing the attachment of glucose residues from UDP-glucose to itself, forming a primer for glycogen synthesis.