Glycogenolysis

Ana Raymundo MSc

INTRODUCTION
Glucose- preferred energy for the brain; required energy source for cells with few or no mitochondria Primary sources of blood glucose: - diet - not always a reliable source of glucose, sporadic - gluconeogenesis - this can provide sustained synthesis of glucose but is slow in responding to a falling blood glucose level

- degradation of glycogen - glycogen is rapidly released from the liver & kidney; when glycogen decreases, specific tissues synthesize glucose DE NOVO (AA as source of C for gluconeogenesis) - muscle glycogen - serves as fuel for ATP synthesis during muscle contraction - liver glycogen - maintains blood glucose conc. in early stages of a FAST

AMOUNTS OF LIVER AND MUSCLE GLYCOGEN

400 g of glycogen is 1- 2% of fresh weight of resting muscle 100 g of glycogen is 10% of fresh weight of well fed adult liver Glycogen has a molecular mass of 108 daltons Muscle glycogen is not affected by short periods of fasting & is moderately decreased in prolonged fasting

Recall: glucose and glycogen

Glycogen: made up of (14) and (16) glycosidic bonds

Glycogenolysis
Breakdown of glycogen Enzymes are different from glycogenesis Happens during the FASTING state AIM: break down glycogen to produce glucose or ATP Main enzyme: glycogen phosphorylase

Steps in Glycogenolysis
1. Shortening of chains 2. Removal of branches 3. Conversion of glucose 1-phosphate to glucose 6-phosphate

1. Shortening of chains
ENZYME: glycogen phosphorylase cleaves the (14) glycosidic bonds between the glucosyl residues at the non-reducing end Reaction: simple phosphorolysis producing glucose 1-phosphate Coenzyme: pyridoxal phosphate STOPS: when 4 glucosyl residues remain (dextrin)

Shortening of chains by glycogen phosphorylase producing G1P

Attacked by glycogen phosphorylase

Glycogen phosphorylase stops when there are only 4 remaining residues (limit dextran)

2. Removal of branches
Single bifunctional protein (debranching enzyme) has 2 components that will break down the dextrin (last 4 glucosyl residues)
Oligo (14) (14) glucan transferase
Removes the 3 remaining glucosyl residues Then attaches the residues to the nonreducing end thus elongating the chain Added residues can then be attacked by glycogen phosphorylase

Amylo (16) glucosidase

Removes (hydrolysis) the (16) which is the last remaining residue

Oligo (14) (14) glucan transferase

Amylo (16) glucosidase

3. Conversion of glucose 1-phosphate (G1P) to glucose 6-phosphate (G6P)

G1P converted to G6P by phosphoglucomutase in the cytosol In the liver: 1. G6P is translocated to the ER by G6P translocase 2. G6P is converted to glucose by glucose 6-phosphatase 3. Glucose is then translocated to the cytoplasm In muscles: There is no glucose 6-phosphatase so G6P enters glycolysis to produce ATP

Fate of G6P

Glycogenolysis Regulation
2 ways: 1. Allosteric regulation 2. Hormonal regulation

Well Fed State

Remember that there is: High glucose High G6P (since glucose is converted to G6P by glucokinase or hexokinase) High ATP (high energy) Therefore you do not want glycogenolysis (glycogen breakdown). You want glycogenesis (glycogen synthesis).

 Remember:
Glycogenolysis (glycogen breakdown) enzyme is glycogen phosphorylase Glycogenesis (glycogen synthesis) enzyme is glycogen synthase

Allosteric Regulation in the Liver (Well Fed State)

High ATP Inhibits glycogen phosphorylase no glycogenolysis High glucose Inhibits glycogen phosphorylase no glycogenolysis High G6P (because of high glucose) Inhibits glycogen phosphorylase no glycogenolysis activates glycogen synthase glycogenesis

Allosteric Regulation in Muscles (Well Fed State)

High ATP Inhibits glycogen phosphorylase no glycogenolysis High G6P (because of high glucose) Inhibits glycogen phosphorylase no glycogenolysis activates glycogen synthase glycogenesis

Allosteric Regulation in Muscles (Fasting State)

High AMP activates glycogen phosphorylase glycogenolysis High AMP because when you exercise, you use ATP. When you use ATP, you convert it to AMP so AMP increases. This signals the muscle to breakdown glycogen so you can replace the energy that was used during exercise.

Allosteric Regulation in Muscles (exercise or contraction)

1. When you exercise, muscle contracts releasing calcium from the endoplasmic reticulum. 2. Released calcium binds to calmodulin. 3. 4 calcium molecules are needed to form the CaCalmodulin complex.

4. The Ca-Calmodulin complex activates the enzyme phosphorylase kinase 5. Phosphorylase kinase in turn activates glycogen phosphorylase 6. glycogenolysis

Hormonal Regulation
Remember that during stress or fasting state: High glucagon High epinephrine During well-fed state: High insulin

Take note: G Protein Coupled Receptor (GPCR)

Receptor where epinephrine and glucagon bind After binding, the G protein attached to GPCR dissociates G Protein is composed of 3 subunits: , and The subunit is the one that attaches to adenylyl cyclase (AC)

Steps in Hormonal Regulation

1
2

1. Glucagon or epinephrine binds to GPCR 2. subunit of G protein dissociates and binds to adenylyl cyclase (AC) 3. Activated AC converts ATP to cAMP

4. cAMP activates protein kinase A (PKA)

PKA has 4 subunits: 2 regulatory and 2 catalytic Activated PKA: R and C subunits dissociate

4 5
6

5. The C subunit activates glycogen phosphorylase kinase b by phosphorylating it 6. Glycogen phosphorylase kinase b (inactive) becomes glycogen phosphorylase kinase a (active)
Remember: active form of glycogen phosphorylase kinase is phosphorylated

8 7

7. Glycogen phosphorylase kinase a activates glycogen phosphorylase b (inactive) by phosphorylating it 8. Glycogen phosphorylase a then proceeds to glycogenolysis
Remember: active form of glycogen phosphorylase (a) is phosphorylated

Insulin (high during well-fed so it will inhibit glycogenolysis)

Insulin will inhibit by activating the enzyme phosphatase which will in turn dephosphorylate glycogen phosphorylase kinase a and glycogen phosphorylase a rendering these enzymes inactive

Inhibition of glycogen synthase during glycogenolysis by epinephrine and glucagon

Recall that glycogen synthase is for glucogenesis but you do not want that when Epi and glucagon are present (fasting or times of stress) so you need to inhibit glycogen synthase

1. Glucagon or Epi binds to GPCR 2. subunit of G protein dissociates and binds to AC thus activating AC 3. AC converts ATP to cAMP 4. cAMP activates PKA 5. Catalytic (C) subunit dissociates from Regulatory (R) subunit

6. C subunit inactivates glycogen synthase by phosphorylating it 7. Glycogenesis inhibited Remember: glycogen synthase b (inactive form) is inactive because it is phosphorylated.

Enzyme Glycogen phosphorylase kinase Glycogen phosphorylase Glycogen synthase

Active form Phosphorylated

Inactive form Dephosphorylated

Phosphorylated Dephosphorylated

Dephosphorylated Phosphorylated

Enzyme that phosphorylates always kinase Enzyme that Dephosphorylates always phosphatase

Glycogen Storage Diseases