2nd Unit / Ch 11 Glycogen Metabolism (Glycogenolysis)

Question 1

Glycogen Structure and Function 11.1

In what two tissues and in what subcellular locale is glycogen stored?

Answer 1

Glycogen, a branched homopolymer of glucose, is stored in the cytosol of liver and muscle cells primarily..

Question 2

Glycogen Structure and Function 11.1

What is the function of stored glycogen?

Answer 2

Glycogen serves as a rapidly mobilized glucose reserve. Glycogen stored in the liver is used to maintain blood glucose, whereas that stored in muscles is used to power contraction. [ Note: Liver
glycogen can maintain blood glucose for 10–18 hours.]

Question 3

Glycogen Structure and Function 11.1

In addition to glycogen, what are the other two sources of blood glucose?

Answer 3

In addition to glycogen stored in the liver, diet and gluconeogenesis (in the liver and kidneys) are sources of blood glucose.

Question 4

Glycogen Structure and Function 11.1

What would be the expected signs and symptoms in someone with a deficiency in the ability to store or
utilize glycogen?

Answer 4

Deficiencies in the ability to store or use glycogen in the liver would result in fasting hypoglycemia. Deficiencies in the storage or use of glycogen in muscles would result in muscle
weakness (exercise intolerance).

Question 5

Glycogenesis 11.2

As shown, glycogen is a branched homopolymer of glucose. What form of glucose is used as the
substrate in glycogenesis?

Answer 5

The substrate for glycogenesis is
UDP-glucose, which is made from
glucose 1-P and UTP by UDPglucose
pyrophosphorylase .+

Question 6

Glycogenesis 11.2

What enzymes are required for glycogenesis?

Answer 6

GS and branching enzyme are
required for glycogenesis from
UDP-glucose.

Question 7

Glycogenesis 11.2

What is glycogenin ?

Answer 7

Glycogenin is the enzyme that makes the primer for GS. It autoglucosylates (using UDP-glucose) at a specific Tyr
and makes a short chain of glucose residues linked by (1➔4) glycosidic bonds. GS extends the chain. A primer
is needed because GS cannot initiate
synthesis from two molecules of UDP-glucose.

Question 8

Glycogenesis 11.2

How would branching enzyme deficiency affect glycogen structure? What are the clinical consequences?

Answer 8

Branching enzyme ( 4:6 transferase) moves up to 8 glucose residues
from an end to an internal position, breaking an (1➔4) bond and forming (1➔6) bond, thereby creating a branch.
Deficiency of 4:6 transferase activity (Andersen disease , type IV GSD )
results in glycogen with few branches and long outer chains causing decreased solubility, which can result in cirrhosis.

Question 9

Glycogenolysis 11.3

What enzyme denoted by the red question mark catalyzes the reaction shown? Where in the cell is the enzyme found? What coenzyme does it require?

Answer 9

The enzyme is cytosolic glycogen phosphorylase, which uses Pi to sequentially cleave (1➔4) bonds in glycogen to generate glucose 1-P. PLP (from vitamin B6 ) is the coenzyme. The process stops when four glucose residues remain at the branch point, a structure known
as a limit dextrin. [Note: Limited degradation of glycogen occurs in the lysosomes by a-glucosidase.]

Question 10

Glycogenolysis 11.3

How would debranching enzyme deficiency affect glycogen structure? What are the clinical consequences?

Answer 10

Debranching enzyme is bifunctional. It moves the outer three glucose residues from a limit dextrin to an end ( 4:4 transferase activity). It then removes the terminal glucose residue as free (nonphosphorylated) glucose ( 1:6 glucosidase activity). Debranching enzyme deficiency

(Cori disease, type III GSD) results in glycogen with short branches. Hypoglycemia and muscle weakness can result from decreased ability to mobilize stored glycogen.

Question 11

Glycogenolysis 11.4

What happens to the glucose 1-P produced by the glycogen phosphorylase reaction shown?

Answer 11

The glucose 1-P produced by glycogen phosphorylase is converted to glucose 6-P by phosphoglucomutase. Glucose 1,6-bisP is an intermediate in the reaction.

Question 12

Glycogenolysis 11.4

What is the role of glucose 6-phosphatase in glycogenolysis?

Answer 12

Glucose 6-phosphatase hydrolyzes glucose 6-P in the liver (and the kidneys), generating free glucose that can enter the blood. [Note: Because glucose 6-phosphatase is not found in muscle, muscle glycogen degradation does not contribute to blood glucose maintenance.]

Question 13

Glycogenolysis 11.4

Would the hypoglycemia caused by glucose 6-phosphatase deficiency be less or more severe than that caused by a defect in hepatic glycogen phosphorylase?

Answer 13

Glucose 6-P is produced by the penultimate reaction in both glycogenolysis and gluconeogenesis. Therefore, glucose 6-phosphatase deficiency ( von Gierke disease , type Ia GSD ) would prevent blood glucose maintenance by both processes and result in a severe, fasting hypoglycemia. In contrast, hepatic glycogen phosphorylase deficiency ( Hers disease , type VI GSD ) would affect
only liver glycogenolysis.

Question 14

Glycogen Metabolism Regulation 11.5

Which enzyme(s) shown is inactivated by phosphorylation?

Answer 14

Phosphorylation inactivates GS, the regulated enzyme of glycogenesis. The phosphorylated form of GS is the inactive, or “ b ,” form.

Question 15

Glycogen Metabolism Regulation 11.5

How do glucagon (in the liver) and epinephrine (in the liver and muscles) cause coordinated regulation of glycogen metabolism?

Answer 15

Glucagon and epinephrine, through cAMP-mediated activation of PKA, result in phosphorylation (inactivation) of GS of glycogenesis and phosphorylation of phosphorylase kinase and phosphorylase of glycogenolysis. The phosphorylated form of phosphorylase kinase and phosphorylase is the active, or “ a ,” form.

Question 16

Glycogen Metabolism Regulation 11.5

Why might endurance athletes greatly increase their carbohydrate consumption several days before an athletic event?

Answer 16

Increased carbohydrate consumption is a strategy used by some athletes to replenish/increase their glycogen stores by increasing glucose, the glycogenesis substrate. The stored glycogen can be used to power muscle contraction, thereby improving performance (ideally).

Question 17

Glycogen Metabolism Regulation 11.6

What effect(s) do **glucose 6-P** and **ATP** have on the enzymes of glycogen metabolism (shown) in the liver?
In muscle?

Answer 17

Glucose 6-P and ATP each allosterically inactivate the phosphorylated (a) form of glycogen phosphorylase in both liver and muscle, thereby inhibiting glycogenolysis. Glucose 6-P allosterically
activates the phosphorylated (b) form of GS, thereby activating glycogenesis in both liver and muscle.
[Note: Glucose allosterically inactivates the phosphorylase in liver. AMP activates it in muscle.]

Question 18

Glycogen Metabolism Regulation 11.6

HORMONES meet the needs of the body, and ALLOSTERIC EFFECTORS meet the needs of a particular tissue.

How does a rise in cytosolic Ca2 + result in glycogen phosphorylase kinase activation?

Answer 18

Ca2+ binds to the calmodulin subunit of phosphorylase kinase b , causing a conformational change that activates the kinase even without enzyme phosphorylation.

Question 19

Glycogen Metabolism Regulation 11.6

What causes a rise in Ca2+ in muscle? In liver?

Answer 19

Exercise causes a rise in cytosolic Ca2+ in muscle. Neural stimulation of muscle causes membrane depolarization and release of Ca2+ from the sarcoplasmic reticulum. [Note: The rise in AMP in exercising muscle also activates glycogenolysis by directly activating glycogen phosphorylase .] In the liver, epinephrine binding to a-adrenergic GPCRs results in formation of IP3 (causes release of Ca2+
from the ER in liver) and DAG (activates PKC, which phosphorylates [inactivates] GS).

Question 20

CASE CARD

A 12-year-old boy is being evaluated for the cause of the muscle cramps and exertional fatigue that recently have caused him to sit on the sidelines during baseball drills. He reports that his urine was normal in color after the earlier episodes. A forearm lactate test is administered in which blood lactate, as well as CK, is measured before and after 30 hand contractions. Urinary myoglobin also is measured before and after the exercise. The results show that
blood lactate failed to rise with the exercise, but urinary myoglobin levels did rise ( myoglobinuria ). CK was elevated before and after exercise. Based on the results, a diagnosis of muscle glycogen phosphorylase ( myophosphorylase ) deficiency ( McArdle disease , GSD type V ) is made. No specific treatments are available for this AR disorder.

Answer 20

GSDs are rare genetic disorders that affect the various proteins of glycogen metabolism. They typically affect glycogen degradation (as with myophosphorylase deficiency, shown) or, more rarely, glycogen synthesis (as with branching enzyme deficiency ). They result either in the formation of glycogen with an abnormal structure or excessive accumulation of normal glycogen. Severity ranges from mild to fatal in early childhood. Because liver and muscle are
the primary sites of glycogen synthesis and use, the presenting symptoms are either hepatomegaly with hypoglycemia or muscle weakness. In the patient, blood lactate failed to rise with exercise because of decreased glucose availability for glycolysis as a result of a deficiency in muscle glycogenolysis.

Question 21

Why are most GSDs not lysosomal disorders?

Because glycogen metabolism occurs primarily in the cytosol, most GSDs (in contrast to other storage diseases) are not lysosomal disorders. An exception is

A Pompe disease = LYSOSOMAL `(1→4)-GLUCOSIDASE DEFICIENCY

Answer 21

Lysosomal storage disease
􀁳 Generalized (but primarily heart, liver, muscle)
􀁳 Excessive glycogen concentrations
found in abnormal vacuoles in the lysosomes
􀁳 Normal blood sugar levels
􀁳 Massive cardiomegaly
􀁳 Enzyme replacement therapy available
􀁳 Infantile form: early death typically from
heart failure
􀁳 Normal glycogen structure