6. GLYCOGENESIS AND GLYCOGENOLYSIS

Glycogenesis and Glycogenolysis

Introduction to Glycogenesis:

Glycogenesis is the process of synthesizing glycogen from glucose molecules, primarily occurring in the cytosol of liver and muscle cells. This energy-consuming pathway requires ATP and UTP as co-factors along with glucose.

Synthesis of UDP-Glucose:

Glucose is first phosphorylated to glucose-6-phosphate by hexokinase (muscle) or glucokinase (liver). The enzyme phosphoglucomutase converts glucose-6-phosphate into glucose-1-phosphate. Subsequently, UDP-glucose pyrophosphorylase synthesizes UDP-glucose from glucose-1-phosphate and UTP, forming an activated glucose donor for glycogen elongation.

Primer Requirement and Glycogenin:

Glycogen synthesis requires a primer, typically a fragment of pre-existing glycogen. In its absence, the protein glycogenin initiates this by self-glycosylation attaching glucose residue from UDP-glucose to the hydroxyl of its tyrosine residue. Glycogenin extends the chain initiating glycogen assembly.

Glycogen Synthase and Branching Enzymes:

Glycogen synthase catalyzes the formation of α-1,4 glycosidic linkages elongating the glycogen chains. Branching enzyme (glucosyl α-4,6 transferase) creates α-1,6 branches by transferring segments of 5-8 glucose units to create new non-reducing ends. This branching enhances solubility and accessibility for rapid glycogen metabolism.

Glycogenolysis: Degradation of Glycogen

Glycogenolysis is the controlled breakdown of glycogen to supply glucose, mainly in liver and skeletal muscle. This catabolic pathway employs distinct enzymes from glycogenesis and involves cleavage of α-1,4 and α-1,6 glycosidic bonds.

Enzymatic Actions:

Glycogen Phosphorylase: Sequentially cleaves α-1,4 linkages releasing glucose-1-phosphate by phosphorolysis until four residues remain near a branch point, forming a limit dextrin.
Debranching Enzyme: Bifunctional enzyme with glucosyltransferase activity transfers three outer glucose residues of a branch to another chain; α-1,6 glucosidase hydrolyzes the α-1,6 bond releasing free glucose.
Phosphoglucomutase: Converts glucose-1-phosphate into glucose-6-phosphate, which enters glycolysis or is dephosphorylated in liver for blood glucose release.

Lysosomal Degradation:

Minor glycogen degradation occurs in lysosomes through acid maltase (α-1,4-glucosidase). Deficiency causes Pompe disease, a glycogen storage disorder characterized by glycogen accumulation.

Regulation of Glycogen Metabolism:

Tight regulation coordinates glycogen synthesis and breakdown to maintain glucose homeostasis, primarily controlled by allosteric effectors, hormones, and calcium ion levels.

Allosteric Regulation:

High levels of glucose-6-phosphate activate glycogen synthase and inhibit glycogen phosphorylase, promoting synthesis during energy abundance. ATP similarly inhibits glycogen phosphorylase, while free glucose in liver acts as additional inhibitor.

Hormonal Control via cAMP:

Glucagon, epinephrine, and norepinephrine trigger adenylate cyclase activation producing cAMP, which activates protein kinase A (PKA). PKA phosphorylates and alters the activity of glycogen synthase and phosphorylase through phosphorylation-dephosphorylation mechanisms, switching between active and inactive forms to regulate metabolism based on physiological demands.

Calcium Ion Influence:

Muscle contraction releases Ca2+, binding calmodulin and activating phosphorylase kinase independently of cAMP, facilitating rapid glycogen breakdown to meet immediate energy needs.