glycogen metabolism in the muscle and liver

Question 1

what is glycogen? 4

Answer 1

• Polysaccharide: storage form of glucose in the body
• Stored in granules predominantly in liver and muscle as an energy reserve
• Glycogen is formed from dietary glucose by the process of glycogenesis
• Liver glycogen is utilised to maintain plasma glucose levels between meals, whereas muscle glycogen is required to sustain muscle contraction

Question 2

how is glycogen degraded?

Answer 2

• Glycogen is degraded between meals in the liver by the glycogenolysis pathway to produce lucose-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

Question 3

where is the most glycogen stored? 6

Answer 3

• In the fed state:
• 10% of weight of the liver
• 2% of the weight of muscle
• BUT
• 40% of human body weight is muscle
• 2.5% of human body weight is liver
• SO overall, more glycogen stored in the muscle
• The liver contains less glycogen than is required to sustain glucose metabolism for 24 hours therefore require de novo synthesis by gluconeogenesis

Question 4

what is the structure of glycogen? 2

Answer 4

• Found in the form of granules within cells. Highly branches polysaccharide of glucose consisting of (alpha-1,4) linked glucose molecules with an (alpha-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 and resynthesis

Question 5

which linkages are used to form glycogen? 2

Answer 5

• alpha-1,4

- alpha1,6

Question 6

describe glycogenolysis? 3

Answer 6

• In time of metabolic need, cells switch on the breakdown of stored glycogen very rapidly using a combination of signals
• This process is often known as mobilisation
• The breakdown products meet different needs in liver and muscle

Question 7

describe glycogen breakdown in muscle?

Answer 7

• Muscle mobilises glycogen to fuel its own energy requirements via glycolysis to support contraction

Question 8

describe glycogen breakdown in liver? 2

Answer 8

• Liver glycogen is converted to glucose between meals for export to other tissues
• Liver can do this because it expresses the enzyme glucose-6-phosphatse which muscle does not

Question 9

describe the relationship between blood glucose and liver glycogen stores throughout the day? 2

Answer 9

• Glycogen stores rise after a meal in response to an increase in blood glucose; between meals glycogen stores fall as glucose is released from liver glycogen to stabilize the concentration of glucose in the blood
• Overnight glycogen stores are mobilized to help maintain blood glucose concentration

Question 10

describe the mechanism of glycogen breakdown? 4

Answer 10

• The alpha 1-4 linkages are broken by phosphorolysis, catalysed by the enzyme glycogen phosphorylase
• It removes single units from noon-reducing ends of glycogen to form glucose-1-phosphate
• Phosphorolysis is analogous to hydrolysis (with phosphate acting like water in hydrolysis reactions)
• ATP is not involved in this reaction

Question 11

describe glycogen degradation? 4

Answer 11

• Phosphorylase can only break alpha-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 alpha-1,4-linkage
• The single glucose unit left at the branch is removed by the action of the alpha-1,6-glucosidase activity of the debranching enzyme
• The chain can then be broken down by phosphorylase until it meets the next branch point

Question 12

describe the cleavage of alpha 1,6 linkages at branch points? 2

Answer 12

• The alpha-1,6 linkages are broken by the alpha-1,6-GLUCOSIDASE enzyme activity of the debranching enzyme
• It cleaves the bond to form free GLUCOSE by hydrolysis, does not involve phosphate

Question 13

give a summary of glycogenolysis? 4

Answer 13

ccurs in response to low glucose in the plasma or muscle contraction

• Major enzyme responsible for controlling the rate of breakdown is glucose phosphorylase which breaks the bond between the (alpha1-4) linked glucose residues by the addition of phosphate to produce glucose-1-phosphate
• Phosphorylase cannot break (alpha1-6) bonds and therefore breakdown also requires a debranching enzyme to complete the removal of (alpha-1,6) glucose links. This is a hydrolysis reaction and produces glucose
• In muscle the glucose-1-phosphate enters glycolysis, after conversion to glucose-6-phosphate to produce energy to sustain contraction. Cannot be exported to the blood as muscle lacks glucose-6-phosphatase. In liver, it is converted to glucose and exported into the bloodstream to maintain plasma glucose levels

Question 14

describe glycogenesis? 4

Answer 14

• Glycogen is formed form UDP-glucose
• UDP-glucose is a high energy form of glucose
• Consumption of UTP is energetically equivalent to ATP consumption (the process requires energy input)
• Glycogen synthase adds glucose units in alpha-1,4-linkage onto the glycogen chain using UDP-glucose

Question 15

how does glycogen synthesis start? 4

Answer 15

• 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 alpha-1,4- linkages

Question 16

describe the introduction of branches during glycogen synthesis? 3

Answer 16

• Glycogen synthase extends the chain in alpha-1,4-linkages but cannot make branches
• Branching enzyme transfers a block of 7 residues from a growing chain to create anew branch with an alpha-1,6-linkage
• The new branch does not form within 4 residues of a pre-existing branch

Question 17

describe glycogen as an energy store? 4

Answer 17

• Glycogen is a GOOD energy store because it can be mobilised very rapidly:
• The enzymes phosphorylase and glycogen synthase are very sensitive to regulation by hormones, stress and muscle contraction
• 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

Question 18

when is glycogenolysis accelerated? 2

Answer 18

• In liver in between meals or during extended fasting, when glucose is required for glycolysis by the brain and red blood cells
• In muscle to fuel glycolysis during vigorous exercise

Question 19

when is glycogenesis activated? 2

Answer 19

• To replenish liver glycogen stores after feeding or muscle stores when exercise ceases
• The pathway for glycogen synthesis is not a simple reversal of breakdown and requires energy input

Question 20

describe the allosteric regulation of phosphorylase? 4

Answer 20

• Glycogen phosphorylase in muscle is subject to allosteric regulation by AMP, ATP and glucose-6-phosphate
• Amo (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

Question 21

describe the allosteric regulation of glycogen synthase? 2

Answer 21

• Glycogen synthase is allosterically activated by glucose-6-phosphate (the opposite to effect on phosphorylase)
• Thus, glycogen synthesis is activated when glucose-6-phosphate is plentiful

Question 22

describe the regulation of glycogen metabolism by covalent modification? 3

Answer 22

• 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 reversible modification; removal of phosphate groups (dephosphorylation) is catalysed by protein phosphatases

Question 23

describe how phosphorylase is activated? 3

Answer 23

• 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

Question 24

what effect does the induction of cAMP have on glycogen synthase? 3

Answer 24

• the opposite effect
• Phosphorylation of glycogen synthase converts the enzyme to the b (less active) conformation
• Therefore, glycogen synthesis is inhibited when protein kinases are activated

Question 25

what is ‘a’ in enzyme terms?

Answer 25

‘a’ is the form of enzyme that tends to be active and independent of allosteric regulators (phosphorylation form of glycogen phosphorylase)

Question 26

what is ‘b’ in enzyme terms?

Answer 26

‘b’ is the form of the enzyme that is dependent on the local allosteric controls (the dephosphorylated form of glycogen phosphorylase)

Question 27

describe active and inactive form of metabolic enzymes? 2

Answer 27

• 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