Week 6: Glycogen and Coordination of Fuel Metabolism

Question 1

What are the three main glycogen storage diseases? What are the pathologies of each?

Answer 1

Type Ia, von Gierke’s disease - glucose-6-phosphate deficiency

Andersen’s disease - defect in the glycogen branching enzyme

McArdle’s disease - muscle glycogen phosphorylase deficiency

Question 2

What is the pathology of von Gierke’s disease?

Answer 2

Glucose-6-Pase deficiency causes hypoglycemia, lack of glycogenolysis normally induced by epinephrine and glucagon

Question 3

What is the pathology of Andersen’s disease?

Answer 3

Defect in the glycogen branching enzyme causes cirrhosis and abnormal glycogen (glycogen does not branch, so is spiky and basically pokes holes in membranes instead of being rounded), diminished hyperglycemic response to epinephrine

Question 4

What is the pathology of McArdle’s disease?

Answer 4

Muscle glycogen phosphorylase deficiency - high muscle glycogen, reduction in blood lactate and pyruvate after exercise, no post-exercise pH drop, normer hyperglycemic response to epinephrine

Question 5

Describe the branching of glycogen, including how often glycogen branches

Answer 5

Glycogen is a chain of glucose molecules linked through α(1-4) glycosidic bonds, and branches every 8-12 residues via α(1-6) linkages

Question 6

What are the body’s main sources of metabolic fuel?

Answer 6

Glucose/carbohydrates

Fatty acids and Triacylglycerols (TAGs)

Ketone bodies

Amino acids/protein

Question 7

Where is glycogen usually found?

Answer 7

In the liver and muscle

Question 8

How does glycogen mitigate issues that glucose usually causes in cells? How much is present in the main areas of interest?

Answer 8

Glucose exerts high osmotic pressure on cells, as it draws water in with it as it moves into the cell–this can lyse cells. Individually, glucose molecules are soluble in water. On average, muscle cells are 0.5% glycogen by weight, and liver cells are 4% by weight.

Question 9

Why do fats usually yield much more metabolic energy than carbohydrates? How much more energy, on average?

Answer 9

Fats are less oxidized (more hydrogen/reducing potential) than carbohydrates or proteins, and have 6 times the metabolic energy of hydrated glycogen.

Question 10

What are the advantages and disadvantages of glycogen storage?

Answer 10

Advantages:

Rapid mobilization, metabolized both aerobically and anaerobically, released units can directly maintain essential blood levels of glucose

Disadvantages:

Hygroscopic (binds a TON of water), short term storage (liver depletes itself of glycogen after 12h of fasting)

Question 11

How are glucose units removed from glycogen branches?

Answer 11

Glycogen phosphorylase uses a phosphate group to attack the reducing end of glucose molecules (at the 1C or anomeric position), releasing the molecule as Glucose-1-P

Question 12

What happens to an individual glucose molecule after it is removed from a glycogen branch?

Answer 12

Phosphoglucomutase converts G-1-P to G-6-P, which can be hydrolyzed to glucose by G6P phosphatase

Question 13

What amino acid is involved in the conversion of G1P to G6P, and how does the conversion occur?

Answer 13

Phosphglucomutase has a serine residue bound to a phosphate group, which transfers the phosphate moiety to the C6 position on the glucose molecule. Then, the -OH group of serine abstracts the phosphate from the C1 position, leaving G6P

Question 14

Explain how the glycogen debranching enzyme plays a role in glucose release? Walk through each step

Answer 14

Glycogen phosphorylase removes glucose molecules from a branch until it is 4 glucose residues away from a branch point. Then, the debranching enzyme catalyzes a reaction to move a 3-glucose trisaccharide from the “limit” (short) branch, and adds it to the non-reducing end of another branch. Then, intrinsic α(1-6) glucosidase on the debranching enzyme hydrolyzes the remaining glucose unit on the limit branch

Question 15

What is the rate-limiting element of glycogenolysis during exercise?

Answer 15

The debranching of glycogen is the rate-limiting step of glucose metabolism from glycogen

Question 16

Explain how glucose-6-phosphate allows release of glucose into the bloodstream

Answer 16

(1) The G6P transporter moves G6P into the lumen of the ER
(2) G6Pase removes the phosphate group, leaving glucose and a Pi molecule
(3) Glucose enters back into the cytosol via the T2 transporter, and Pi moves back in via the T3 transporter
(4) The GLUT2 glucose transporter allows glucose to exit the cell and enter into the bloodstream

Question 17

What does the formation of glycogen require, and what molecule/group initiates this? What enzyme initiates the process?

Answer 17

Glycosidic bond formation requires energy, which is conferred to individual glucose molecules by activating G1P to form UDP-glucose. This is accomplished by UDP-glucose pyrophosphorylase.

Question 18

Explain how UDP-glucose forms

Answer 18

G1P attacks the α phosphate group on a UTP molecule, forming UDP-glucose and a pyrophosphate molecule. Part of the energy for bond formation is created by breaking the pyrophosphate molecule down into individual Pi molecules.

Question 19

What happens in the second step of glycogen synthesis? What enzyme mediates this process?

Answer 19

Glycogen synthase adds the UDP-glucose molecule to the nonreducing end of a glycogen chain with n > 4 residues.

Question 20

What is the function of glycogenin? What amino acid on the protein helps catalyze formation of the molecule formed? How does the ultimate molecular formation help initiate very fast glycolytic processes when energy is needed?

Answer 20

Glycogenin acts as a “seed molecule” for glycogen, and the tyrosine moiety allows up to 8 glucose residues to bind autocatalytically. Glycogen can then branch from this initial 8-glucose chain (the “primer) into second, third, fourth, and outer tier (unbranched) chains.

Each branching element doubles the number of reducing ends available, so there are more nonreducing ends available for faster metabolism when energy is needed.

Question 21

What is the function of the branching enzyme in glycogen?

Answer 21

The branching enzyme transfers a 7-residue segment from the non-reducing end of glycogen to the C6-OH group on the same or on another chain.

Question 22

Explain the interconversion between the enzyme phosphorylase a and phosphorylase b, and it’s function in glycolysis. What enzymes catalyze this process?

Answer 22

Unphosphorylated phosphorylase b will not readily phosphorylate glycogen (to produce glucose). When activated by phosphorylase b kinase (activated by glucagon in the liver, and Ca2+ and AMP in the muscle) is phosphorylated on a two serine residues, it undergoes a conformational change to become phosphorylase a, the active form that will participate in glycolysis. It is inactivated by phosphorylase a phosphatase (PP1)

Question 23

What is interesting about phosphorylase b kinase?

Answer 23

It the enzyme itself (phosphorylase b kinase), which phosphorylates phosphorylase b (first regulatory protein) into phosphorylase a to initiate glycogenolysis, is regulated by phosphorylation.

Phosphorylase kinase b is the inactive form of the second regulatory protein, and is itself phosphorylated into it’s active form, phosphorylase kinase a, by PKA (cAMP-dependent) OR by Ca2+. Inactivation of phosphorylase kinase a is initiated by phosphoprotein phosphatase-1.

Question 24

Explain the intraconversion between glycogen synthase a and glycogen synthase b

Answer 24

The UNPHOSPHORYLATED glycogen synthase A is activated by phosphoprotein phosphatase 1 (dephosphorylates, inhibited by glucagon, activated by glucose, G6P and insulin to indicate high glucose levels and the need for storage)

The PHOSPHORYLATED glycogen synthase B is inactivated via phosphorylation by 3 enzymes:

glycogen synthase kinase 3 (GSK-3) (inhibited by insulin to indicate the need for storage, wouldn’t want to store and break down simultaneously)

protein kinase A

glycogen phosphorylase kinase

Question 25

What is the preferred fuel of red blood cells?

Answer 25

Glucose in it’s free form

Question 26

What is the preferred fuel for the brain? What uses a large portion of the brain’s energy and is a normal metabolic process in all cells

Answer 26

Usually glucose, but under starvation conditions, ketone bodies can supply a major portion of the brain’s energy demands (can’t completely satisfy without glucose). 20% of the brain’s energy is expended on the Na+/K+ ATPase.

Question 27

What is the preferred fuel for skeletal muscle?

Answer 27

Glucose, FAs, and ketone bodies all work. Glucose, during bursts of physical activity, FAs in the resting state, and ketone bodies during starvation. Muscles can mobilize glucose from stored glycogen in the muscle.

Question 28

What is the preferred fuel for the heart?

Answer 28

Fatty acids and ketone bodies, due to the largely aerobic nature of heart muscle mitochondria. Under a heavy workload, glucose consumption can be increased.

Question 29

What is the preferred fuel for adipose tissue?

Answer 29

Storage reservoir for TAGs, but glucose is their major fuel. FAs are mobilized by hydrolysis of TAGs to FAs and glycerol. To store TAGs, fatty acyl-CoA is esterified to glycerol-3-phosphate. The process of hydrolysis and re-esterification of TAGs is happening continuously.

Question 30

What is the preferred fuel for the liver?

Answer 30

The body’s metabolic clearinghouse. Synthesizes FAs for storage in adipose, and provides metabolic fuel to the brain, muscle and organs. It releases glucose in the bloodstream to maintain a constant concentration of about 5 mM. When fuel stores are high, the liver synthesizes glycogen. It does not use glucose for fuel, but rather carries out the beta-oxid. of FAs during high metabolic demand to create glucose for itself and other tissues.

Question 31

Explain how fuel is exchanged between the brain, liver, muscle, adipose tissue, and kidneys during both the fasting (black) and well-fed (red) state

Answer 31

See photo