Glycogen Metabolism

Question 1

3 strategies in maintenance of blood glucose

Answer 1

• diet
• glycogen
• gluconeogenesis

Question 2

Glycogen

Answer 2

• Liver glycogen is rapidly mobilised in response to falling blood glucose levels
• Muscle glycogen is degraded in exercising muscle to provide the tissue with energy

Question 3

Gluconeogenesis

Answer 3

• newly synthesised glucose from non-carbohydrate sources ensures blood glucose levels are maintained in the absence of glycogen

Question 4

Glycogen structure

Answer 4

• Polymers of α-D-glucose
• Main chains α(1-4) glycosylic bonds, branches α(1-6) linkages
• Branched occur every 8-12 residues

Question 5

First step in glycogenesis

Answer 5

• Glucose phosphorylation
• conversion of glucose to G-6-P
• catalysed by hexokinases (glucokinase among them)

Question 6

Second step in glycogenesis

Answer 6

• Glucose-1-phosphate formation
• phosphoglucomutase catalyses transfer of phosphate group from carbon 6 to carbon 1 on the glucose molecule
• G-6-P converted to glucose-l-phosphate
• Phosphoglucomutase requires Mg+ and glucose-1,6-bisphosphate as cofactors
• reaction is reversible

Question 7

Bisphosphates and diphosphates

Answer 7

• bisphosphate: 2 phosphates bound at different sites on same molecule
• diphosphate: phosphates bound together by anhydride bond i.e. ADP

Question 8

Third step in glycogenesis

Answer 8

• Glucose activation
• G-1-P reacts with high energy nucleotide uridine triphosphate (UTP) to give uridine diphosphate glucose (UDPG) and pyrophosphate (PPi)
• catalysed by uridine diphosphate-glucose pyrophosphorylase, or glucose-1-P uridyltransferase
• Inorganic pyrophosphate rapidly hydrolyzed by pyrophosphatase, this reaction virtually irreversible

Question 9

Fourth step in glycogenesis

Answer 9

• Glucose addition to the polymer backbone
• UDPG-activated glucose is transferred to pre-existing glycogen
• One glycosidic linkage to carbon 4 of a terminal glucose of a glycogen chain is formed
• catalysed by glycogen synthase, requires presence of the pre-existing glycogen polymeric structure, which keeps adding glucose molecules via α1-4 bonds
• reaction is practically irreversible

Question 10

Fifth step in glycogenesis

Answer 10

• branch formation
• when glycogen synthase has built a glycogen chain of 10 or more glucose residues, another enzyme, amylo-α(1,4)-α(1,6)-glucantransferase (or branching enzyme), cuts a terminal segment of at least 6 glucose molecules and inserts it with an α1-6 glycosidic bond on a neighboring chain
• further elongation and branching forms glycogen

Question 11

Glycogenin

Answer 11

• acts as an acceptor of the first glucose molecule prior to the glycosidic linkage with a tyrosine protein
• process is autocatalytic, using UDPG as glucose donor
• catalyses the successive addition of units to form a linear chain from six to seven glucose molecules bound by α1-4 bonds
• Each glycogen molecule is covalently linked to an initiator protein

Question 12

Step 1 in glycogenolysis (glycogen degradation)

Answer 12

• glycogen phosphorylase cleaves α-1,4-glycosidic bonds of terminal glucose residues at non-reducing end of glycogen (i.e. the end of the glycogen molecule with a free 4-OH group)
  until only four glucosyl units remain on each chain before a branch point
• inorganic phosphate, cleaves glycosidic bond between C1 of terminal residue and C4 of adjacent glycogen molecule via phosphorolysis to yield glucose 1-phosphate

Question 13

Step 2 of glycogenolysis (glycogen degradation)

Answer 13

• debranching enzyme (with 4:4 transferase activity) shifts a block of 3 glycosyl residues from one outer branch to non reducing end
• remaining single glucose molecule has a α-1,6-glycosidic bond joined to the glycogen molecule

Question 14

Step 3 of glycogenolysis (glycogen degradation)

Answer 14

• the same debranching enzyme (also with amylo-a(1-6)-glucosidase activity) cleaves the linkage and results in the release of a free glucose molecule
• steps 1, 2 and 3 are repeated

Question 15

End products of glycogenolysis in the liver

Answer 15

• phosphoglucomutase is used to convert glucose 1-phosphate formed in the cleavage of glycogen into glucose 6-phosphate to enter the metabolic mainstream
• glucose 6-phosphatase converts the glucose 6-phosphate into glucose by cleaving the phosphoryl group

Question 16

End products of glycogenolysis in muscle cells

Answer 16

• hexokinase or glucokinase will metabolise glucose 6-phosphate to either pyruvate (aerobic conditions) or lactate (anaerobic conditions)

Question 17

Regulation of glycogen metabolism in liver

Answer 17

• well fed state: glycogenesis increases

- fasting state: glycogenolysis increases

Question 18

Regulation of glycogen metabolism in muscle

Answer 18

• Active exercise: glycogenolysis begins

- Resting muscle: glycogenesis begins

Question 19

PKA

Answer 19

• cAMP-dependent protein kinase A

Question 20

Hormone Regulation of Glycogen Metabolism via PKA

Answer 20

• fasting state: decrease in blood glucose, decrease in release of insulin, increase in release of glucagon, increase in PKA activity
• activation of the counter-regulatory response, epinephrine release from adrenal medulla, increase in PKA activity

Question 21

Glycogen phosphorylase exist in what 2 forms?

Answer 21

• Active [phosphorylated]

- Inactive [dephosphorylated]

Question 22

Effect of active PKA on Glycogen Phosphorylase

Answer 22

• Phosphorylated states of glycogen phosphorylase kinase and glycogen phosphorylase are maintained because protein phosphatase-1 is inactivated by inhibitor proteins that are also activated in response to cAMP.
• Insulin (well-fed state) increases phosphatase activity and leads to inactivation of glycogen phosphorylase

Question 23

Glycogen synthase exists in what 2 forms?

Answer 23

• Active [dephosphorylated]

- Inactive [phosphorylated]

Question 24

Allosteric Regulation of Glucogenesis & Glycogenolysis

Answer 24

• Glycogenesis is stimulated when glucose and energy is high
• Glycogenolysis is stimulated with glucose and energy is low
• During muscle contraction, ATP is supplied be the degradation of muscle glycogen to glucose 6P, which enters glycolysis.
• Glycogen phosphorylase kinase increases active form w/o the need to be phosphorylated by PKA (↑glycogenolysis)