Glycogen metabolism in muscle and liver Flashcards
Glycogen
Polysaccharide: storage form of glucose in the body
Stored in granules predominantly in liver and muscle as an energy reserve
Formed from dietary glucose by glycogenesis
Liver glycogen is utilised to maintain plasma glucose levels between meals, whereas muscle glycogen is required to sustain muscle contraction
Glycogen is degraded between meals in the liver by the glycogenolysis pathway to produce glucose-1-phosphate which can be converted to free glucose and exported into the bloodstream to maintain plasma glucose levels. It can also be broken down in muscle to provide the energy to support muscle contraction.
More glycogens is stored in muscle than in liver
Structure of glycogen
Found in the form of granules within cells. Highly branched polysaccharide of glucose consisting of (α-1,4)linked glucose molecules with an (α-1,6)branch every 8-14 glucose residues
Important to provide large number of ends at which phosphorylase and glycogen synthase can act to ensure rapid breakdown (mobilisation) and resynthesis
Breakdown in muscle and liver
In muscle: Muscle mobilises glycogen to fuel its own energy requirements via glycolysis to support contraction
In liver: Liver glycogen is converted to glucose for export to other tissues; it can do this because it expresses the enzyme glucose-6-phosphatase which muscle does not
Mechanism of glycogen breakdown
The α1-4 linkages are broken by phosphorlysis, catalysed by the enzyme glycogen phosphorylase
It removes single units from non-reducing ends of glycogen to form G-1-P
Phosphorlysis is analogous to hydrolysis (with phosphate acting like water in hydrolysis reactions)
ATP is not involved in this reaction
Glycogen Degradation
Phosphorylase can only break α-1,4 links up to within 4 glucose units from a branch point
Transferase activity of the debranching enzyme removes 3 residues from the branch and transfers them to the end of another chain in α-1,4-linkage
The single glucose unit left at the branch is removed by the action of the α-1,6-glucosidase activity of the debranching enzyme
The chain can then be broken down by phosphorylase until it meets the next branch point.
Cleavage of α-1,6-linkages at branch points
The α1-6 linkages are broken by the α-1,6-glucosidase enzyme activity of the debranching enzyme
It cleaves the bond to form free glucose by hydrolysis, does not involve phosphate
About 10% of glucose mobilized from glycogen is ‘free’ glucose, rather than glusoe-1-phosphate
Glycogen Synthesis - start
Glycogen synthase can add glucose units only to a pre-existing chain of more than four glucosyl residues
The priming function is carried out by a protein, glycogenin
UDP-glucose donates the first glucosyl residue and attaches it to the amino acid tyrosine in the glycogenin
Glycogenin extends the glucose chain by up to 7 additional residues from UDP-glucose via α-1,4-linkages
Glycogen synthase extends the chain in α1,4-linkages but cannot make branches
Branching enzyme transfers a block of 7 residues from a growing chain to create a new branch with an α-1,6-linkage
The new branch does not form within 4 residues of a pre-existing branch
Glycogen as an energy store
Glycogen is a GOOD energy store because it can be mobilised very rapidly:
o The enzymes phosphorylase and glycogen synthase are very sensitive to regulation by hormones, stress and muscle contraction
o The branched structure provides a large number of ends at which the polymer can be added to or broken down.
BUT it is a BAD store because glucose is hydrophilic and associates with water increasing the overall weight and bulk
Regulation of glycogen metabolism
Glycogen mobilisation accelerated: in liver between meals/when fasting; in muscle to fuel glycolysis during vigorous exercise
Glycogen synthesis is activated: to replenish liver glycogen stores after feeding, or muscle stores when exercise ceases; the pathway for glycogenesis is not a reversal of breakdown (requires energy)
Allosteric regulation of phosphorylase
Glycogen phosphorylase in muscle is subject to allosteric regulation by AMP, ATP and glucose-6-phosphate.
AMP (present when ATP is depleted during muscle contraction) activates phosphorylase.
ATP and glucose-6-phosphate, which both compete with AMP binding, inhibit phosphorylase. They are signs of high energy levels.
Thus, glycogen breakdown is inhibited when ATP and glucose-6-phosphate are plentiful
Allosteric regulation of glycogen synthase
Glycogen synthase is allosterically activated by glucose-6-phosphate (the opposite to the effect on phosphorylase)
Thus, glycogen synthesis is activated when glucose-6-phosphate is plentiful.
In liver - supply of glucose (and G-6-P) controls regulation; in muscle ATP and AMP and G-6-P availability controls
Regulation of glycogen metabolism by covalent modification
Mediated by the addition (and removal) of a phosphate group
Addition of a phosphate group is known as phosphorylation and is catalysed by protein kinases
This is a reversible modification; removal of phosphate groups (dephosphorylation) is catalysed by protein phosphatases
Phosphorlyase is activated by cAMP-dependent phosphorylation
The cAMP cascade results in phosphorylation of a hydroxyl group in a serine residue of glycogen phosphorylase, which promotes transition to the active state.
The phosphorylated enzyme is less sensitive to allosteric inhibitors, thus even if cellular ATP levels and glucose-6-phosphate are high, phosphorylase will be activated
Induction of cAMP cascade has opposite effect on glycogen synthase (converts the enzyme to the less active conformation - so glycogen synthesis is inhibited when protein kinases are activated)
Reciprocal regulation of phosphorylase and glycogen synthase
With metabolic enzymes if it is involved in a catabolic reaction (breaking down), the phosphorylated form is the active form
If it is involved in an anabolic reaction (building up), the phosphorylated form is the inactive form
