Glycogen Metabolism

Question 1

What are the bonds that link together units of glucose molecules?

Answer 1

Alpha 1,4 glycosidic bonds

Question 2

What is the bond found in the branch points of glucose monomers of separate chains?

Answer 2

Alpha 1,6 glycosidic bonds

Question 3

What is the end that contains a terminal glucose with a free hydroxyl group at C4?

Answer 3

The non-reducing end

Question 4

What does the reducing end have connected to it?

Answer 4

Glycogen in

Question 5

What does glycogenin make?

Answer 5

A primer which is crucial for the glycogen synthesis

Question 6

Where is glycogen stored?

Answer 6

Mostly found in the liver and the muscle and present as granules

Question 7

What is the function of glycogen in the liver?

Answer 7

Liver glycogen regulates blood glucose levels

- sensor and storage

Question 8

What is the function of glycogen in the muscle?

Answer 8

Provides a reservoir of fuel glucose for physical activity in the muscle

Question 9

What are the three ways that glycogen metabolism is regulated?

Answer 9

1. Allosteric control: molecules will bind to enzymes and turn them off
2. Covalent modifications through reversible phosphorylation of key enzymes
   - kinase and phosphatase
3. Hormonal control
   - insulin modulates
   - glucagon
   - epinephrine

Question 10

List the steps of glycogen degradation

Answer 10

1. Glycogen broken down to release glucose-1-phosphate
   - glycogen phosphorylase (rate-limiting)
2. Glycogen remnant remodeled to permit further degradation
3. Glucose-1-phosphate is converted to glucose-6-phosphate by phosphogluconutase
4. Glucose-6-phosphate can go to the muscle or brain and then go into glycolysis
   - in glycolysis makes pyruvate, lactate, CO2 and H2O
   - can be converted to glucose to go into the blood stream for other tissues to use
   - can go to the pentose phosphate pathway to make NADPH and ribose derivative

Question 11

What are the four key enzymes in glycogenolysis?

Answer 11

• One to degrade glycogen (chain shortening)
• 2 to remodel glycogen remnants
• one to convert glycogen breakdown product suitable for further metabolism

Question 12

What is the rate limiting step of glycogenolysis?

Answer 12

Glycogen phosphorylase (GP) catalyze so the cleavage of glycogen

Question 13

Where does chain shortening occur?

Answer 13

The non-reducing end of the polymer

Question 14

What is the mechanism of GP?

Answer 14

GP adds an orthophosphate and releases a glucose residue as glucose-1-phosphate

Question 15

When does phosphorolysis of glucose end?

Answer 15

Ends when GP gets within 4 residues of the alpha 1,6 linkage of a branch point

Question 16

What cofactor does GP use in chain shortening?

Answer 16

Pyridoxal phosphate (vitamin B6)

Question 17

What is the role of transferase in chain shortening?

Answer 17

Transferase transfers a block of 3 of the remaining 4 glucose to the non-reducing end of the main chain forming a alpha 1,4 bond

Question 18

What enzyme cleaves the alpha 1,6 bond of the glucose residue in order to release free glucose?

Answer 18

Debranching enzyme or alpha 1,6 glucosidase

Question 19

What enzymes are responsible for converting branched glycogen to a linear structure?

Answer 19

Transferase and alpha 1,6 glucosidase

Question 20

What does phosphoglucomutase do?

Answer 20

Converts Glucose-1-phosphate to glucose-6-phosphate by transferring a phosphoryl group from the enzyme to the substrate and transferring a different phosphoryl group back tot restore the enzyme to its initial state

Question 21

Where is glucose-6-phosphate ONLY found?

Answer 21

In the liver where it can get converted to glucose

Question 22

What regulates Glycogen phosphorylase (GP)?

Answer 22

1. Allosteric effectors

2. Reversible phosphorylation (responsive to hormones)

Question 23

What are the two forms of Glycogen phosphorylase (GP)?

Answer 23

• Active form “a” form (R relaxed state) found in the liver

- inactive form “b” form (T tense state) found in the muscle

Question 24

How does glucose inactivate the active form of GP?

Answer 24

By binding to the active site and stabilizing the conformation in the inactive T state, when glucose levels are high there is no need to breakdown glycogen to make glucose- we will just activate glycogen synthesis to make more glycogen to store

Question 25

Describe how muscle GP is regulated?

Answer 25

- in the muscle GP is found in the b form or inactive form - can be activated by AMP - AMP binds to the active site and converts b to the a state and the R state - when muscle contract ATP is converted to AMP and signals GP to breakdown glycogen - ATP and Glucose-6-phosphate are negative Allosteric regulators

Question 26

What is responsible for converting B form to A form of GP?

Answer 26

Phosphorylation of a single serine residue initiated by hormones and carried out by phosphorylase kinase (PK)

Question 27

Describe the activation of phosphorylase kinase

Answer 27

- Phosphorylase kinase is present in the active B form - 4 Ca bind during a muscle contraction, nerve impulse, or hormone signal - PK becomes partially active - PKA and hormones phosphorylate PK - PK is fully active - Fully active form can then convert Phosphorylase B to phosphorylase A by phosphorylation using ATP

Question 28

When is glucagon released and what does it act on?

Answer 28

Glucagon is released when blood sugar levels are low | Acts on the liver

Question 29

When is epinephrine released and what does it act on?

Answer 29

Released during muscle activity | Effects on the muscle

Question 30

What regulates glucagon and epinephrine release?

Answer 30

G protein coupled receptors (GPCR)

Question 31

What signals glycogen breakdown?

Answer 31

Epinephrine and glucagon

Question 32

Liver and muscle forms of GP are an example of

Answer 32

Isozyme

Question 33

Hers Disease is caused by

Answer 33

A mutation in liver GP

Question 34

McArdle syndrome is caused by

Answer 34

A mutation in muscle GP

Question 35

What are the three key events in glycogenesis?

Answer 35

1. Trapping and Activation of Glucose 2. Elongation of glycogen primer 3. Branching of glycogen chains

Question 36

What is the role of glucokinase/ hexokinase?

Answer 36

- Found in the cytosol of hepatocytes and muscle cells - Catalyze phosphorylation of glucose to glucose-6-phosphate - This traps the glucose in these cells

Question 37

What is the role of phosphoglucomutase in glycogenesis?

Answer 37

It reversible isomerizes glucose-6-phosphate to glucose-1-phosphate

Question 38

What is the role of Uridine diphosphate (UDP)-glucose pyrophosphorylase in glycogenesis?

Answer 38

- UDP transfers the Glucose-1-phosphate to uridine triphosphate (UTP) - This action generates UDP-glucose which is the active form of glucose - The breakdown of pyrophosphate to Pi generates energy and drives the reaction forward

Question 39

What is the rate limiting enzyme in glycogenesis?

Answer 39

Glycogen synthase - catalyze so the transfer of glucose from UDP-glucose to the non-reducing end of glycogen chain - forms the alpha 1,4 glycosidic bonds between glucose molecules

Question 40

What happens when glycogen chain reaches 11 residues?

Answer 40

Chain fragments (about 7 residues long) at the alpha 1,4 glycosidic link and reattached somewhere else through an alpha 1,6 link by enzyme glucosyl (4:6) transferase

Question 41

How can you increase solubility of glycogen?

Answer 41

Branching increases which also increases number of terminal non-reducing ends Branching increases rate at which glycogen can be synthesized and degraded

Question 42

What is the key enzyme of glycogen synthesis regulation?

Answer 42

Glycogen synthase

Question 43

What regulates Glycogen synthase kinase (GSK)?

Answer 43

Insulin and PKA

Question 44

What are the two key enzymes in the regulation of glycogen metabolism?

Answer 44

Glycogen phosphorylase and glycogen synthase - the rate limiting steps of degradation and synthesis

Question 45

What controls both glycogen breakdown and synthesis via PKA?

Answer 45

Glucagon and epinephrine controls both

Question 46

What happens in the fed state?

Answer 46

Glycogenesis is favored- glucose and insulin are both high and ATP is high - when glycogen synthesis favored, the dephosphorylates form of glycogen synthase (active) and glycogen phosphorylase (inactive) are predominant

Question 47

What occurs in the fasting state?

Answer 47

Blood glucose levels are low Glucagon levels are high Cellular calcium and AMP are elevated (in exercising muscle) Glycogenolysis is favored -when glycogen degradation is favored phosphorylated forms of glycogen synthase (inactive) and glycogen phosphorylase (active) are predominant

Question 48

Describe how insulin regulates glycogen metabolism

Answer 48

``` High blood glucose Release of insulin by beta cells of pancreas Binding of insulin to its receptor tyrosine kinase Activation of signaling cascade -4 key proteins: GLUT 4 (glucose transporter) Protein kinase B (PKB) Protein phosphatase 1 (PP1) Glycogen synthase kinase 3 (GSK3) ``` Formation of the insulin receptor complex Activation of PKB Translocation of GLUT to membrane PKB phosphorylated PP1 (activate) and GSK3 (inactivate) Active PP1 dephosphorylates glycogen synthase (active) and dephosphorylates glycogen phsophorylase (inactivate) NET RESULT: activation of glycogen synthase and inactivation of glycogen phosphorylase

Question 49

Describe Type 2 diabetes.

Answer 49

Reduced sensitivity to insulin Insulin resistant Mutations in insulin receptor and/or downstream signaling proteins Down-regulation in receptor levels triggered by elevated insulin (leading to endocytosis and degradation of the insulin receptor). Not replaced by translation

Question 50

What is the glucose sensor in liver cells?

Answer 50

Glycogen phosphorylase

Question 51

Describe the affects of McArdle syndrome?

Answer 51

Limited ability to perform strenuous exercise because of painful muscle cramps; otherwise patient is normal and well developed Defective phosphorylase in the muscle

Question 52

What is the clinical affect of Hers Disease?

Answer 52

Enlargement of the liver; hypoglycemia, ketosis, hyperuricemia, and hyperlipidemia Due to defective phosphorylase in the liver