Glycogenoses Case (Exam II) Flashcards
Describe the cascade of events that leads to the coordinate activation of glycogen phosphorylase and the inactivation of glycogen synthase in liver when the glucagon to insulin ratio is increased.
When glucagon is increased the cascade of events that leads to the coordinate activation of glycogen phosphorylase and the inactivation of glycogen synthase in liver is:
- Binding of the hormone to a cell-surface G-protein coupled receptor (GPCR) activates the α subunit of the G protein resulting in activation of adenylate cyclase, the enzyme that catalyzes the conversion of ATP to the second messenger, cAMP.
- cAMP activates protein kinase A (PKA).
- Protein kinase A phosphorylates
- 1) glycogen synthase, converting it from its active (deP) I or a form to its inactive (P) D or b form.
- 2) glycogen phosphorylase kinase which phosphorylates glycogen phosphorylase, converting it from its inactive (deP) b form to its active (P) a form.
- glycogen phosphorylase kinase also phosphorylates and inactivates glycogen synthase.
- PKA also results in the inhibition of phosphoprotein phosphatase by phosphorylating and activating protein phosphatase inhibitor, thus maintaining the phosphorylated (active) form of phosphorylase kinase and phosphorylase, and the phosphorylated (inactive) form of synthase.
Is any free glucose produced by glycogenolysis in muscle? Explain. What is its fate?
Yes, from release of the branch-point glucose as free glucose by the α 1 → 6 glucosidase activity of the debranching enzyme. However, much of this glucose is rapidly phosphorylated in muscle and so does not enter the blood.
a. What is the cause of AZ’s severe fasting hypoglycemia? b. Why isn’t gluconeogenesis providing the necessary glucose? c. Why is the hypoglycemia not responsive to glucagon?
The cause of the severe fasting hypoglycemia is the inability of AZ to maintain blood glucose by liver glycogenolysis or gluconeogenesis. This inability is due to lack of glucose-6-phosphatase, the enzyme that catalyzes the final step (glucose-6-phosphate → glucose + Pi) in each pathway. Neither endogenous nor exogenous glucagon is effective due to the lack of this enzyme.
In a patient with type Ia glycogen storage disease, the elevation in blood urate is thought to be due, at least in part, to a decrease in Pi. a. Why might Pi be decreased? b. Why might this lead to an increase in urate?
Pi may be decreased because P is trapped in the form of phosphorylated glycolytic intermediates. The shortage of Pi restricts the conversion of ADP to ATP, causing an increase in ADP relative to ATP. Two ADP can be acted upon by adenylate kinase, generating AMP + ATP. The AMP is degraded, resulting in increased production of urate. The ATP gets hydrolyzed to ADP and the cycle continues. The shortage of Pi also relieves the physiological block on AMP deaminase (deaminates adenosine in AMP to inosine, forming IMP), increasing the degradation of adenine nucleotides to urate. [Note: The shortage of Pi also reduces glycogen degradation, contributing to its accumulation.]
Why is blood lactate elevated in a patient with type Ia glycogen storage disease
Blood lactate is increased because the increase in glucose-6-phosphate, in addition to driving glycogen synthesis, increases glycolysis. Also, in the absence of Pi we can’t drive ATP synthesis from ADP and so there is a decrease in cellular respiration (respiratory control) leading to increased NADH. The increase in NADH drives pyruvate to lactate by lactate dehydrogenase (LDH). NOTE: the lactic acid may be used by the brain as an alternate fuel. This may explain why loss of consciousness did not occur with the very low blood glucose levels. The lactic acid may account for the decreased bone mineralization seen in children with GSD Ia.
Explain the significance of the finding that freezing and thawing the microsomal (ER) fraction did NOT increase the activity of glucose-6-phosphatase?
Glucose-6-phosphatase is an enzyme of the ER membrane, and its active site faces the lumen. Freezing and thawing disrupts the ER membrane, making material normally sequestered in the ER readily available to the cytosol. If such treatment results in an increase in glucose-6- phosphatase activity, it would suggest that the process of getting the substrate (glucose-6- phosphate) to the enzyme, rather than the enzyme itself, is defective. In the case of AZ no increase in activity was seen and so the transporter is not the problem. Note that glc 6-Pase also is found in the kidney.
a. In the first few hours after birth there is a remarkable induction of glucose-6-phosphatase in the normal neonate. Why?
b. Why were there no apparent signs of enzyme deficiency in AZ in the first few months of life?
a. The metabolic status of the neonate shifts from anabolic to catabolic as the hormone balance shifts from high insulin-low glucagon to high glucagon-low insulin in the period between birth and the first feeding. The fuel that sustains the infant over the first twelve hours is liver glycogen, after which blood glucose is replenished from gluconeogenesis. The liberation of free glucose from both processes is dependent on the activity of glucose-6-phosphatase.
b. In the first few months, babies are fed on a schedule. At 2-3 months, they start to go for longer periods between feedings.
Type II (Pompe disease) is caused by a deficiency in the lysosomal enzyme (acid α-glucosidase) that catabolizes any glycogen brought into the lysosome. Though muscle, and especially cardiac muscle, is most seriously affected, the disorder is described as a “generalized glycogenosis”. Explain. Note: enzyme replacement therapy (ERT) with human recombinant acid α-glucosidase (Myozyme) was approved in 2006.
It is termed a generalized glycogenosis because it affects all tissues that have lysosomes.
Describe the structure of the glycogen that accumulates in debranching enzyme deficiency (Type III, Cori disease).
A deficiency in debranching enzyme leads to glycogen that has shorter than normal outer chains. Since glycogen phosphorylase is not affected glycogen can be degraded to the “limit dextrin” stage, leaving short chains attached to a branch point.
a. Describe the structure of the glycogen that accumulates in branching enzyme deficiency (Type IV, Andersen disease). What aspect of glycogen metabolism is affected in Type IV?
b. Fasting hypoglycemia is not a characteristic of Type IV. What does this say about the ability of the degradative enzymes to use glycogen with an abnormal structure as a substrate? Does this mean Type IV is generally benign?
a. A deficiency in branching enzyme leads to glycogen that has fewer branch points and longer than normal outer chains. Since the synthase is unaffected, glucosyl units are linked by α 1-4 bonds; however, the deficiency in branching enzyme limits the transfer of glucosyl units and their attachment by α 1-6 links to create branches. Glycogen synthesis, in contrast to the other types where it is degradation that is affected. [Note that in Type O synthesis also is affected.]
b. They are able to use it, although at a decreased rate. No, liver damage leads to death at an early age in the infantile-onset form
a. What is the structure of the glycogen that accumulates in muscle phosphorylase deficiency (Type V, McArdle disease)?
b. Why does blood lactate fail to rise after anaerobic exercise in Type V?
a. It is normal.
b. The deficiency in muscle phosphorylase (myophosphorylase) translates into a deficiency in the ability to begin the process of converting muscle glycogen into glucose and ultimately lactate
a. Why does a deficiency in liver phosphorylase (Type VI, Hers disease) lead to accumulation of liver glycogen?
b. Why is the fasting hypoglycemia in Type VI less severe than in Type I?
a. A deficiency in liver phosphorylase, the rate-limiting enzyme of glycogenolysis, decreases the ability to use liver glycogen as a source of blood glucose and so leads to an accumulation of glycogen (with a normal structure).
b. Fasting hypoglycemia is much less severe in Type VI because there is no impediment to gluconeogenesis: the release of free glucose from glucose-6-phosphate is unaffected.
a. What reaction in what pathway is catalyzed by phosphofructokinase-1 or PFK-1?
b. If PFK-1 is deficient, what effect is seen on glycogen metabolism? On muscle function?
c. PFK-1 is a tetrameric protein made up of 4 subunits that are variably expressed in different tissues. Muscle PFK-1 is a homotetramer of M subunits (M4), while in RBC’s 2 different subunits (M & L) are made.
Note: Liver primarily contains L subunits. In classical PFK-1 deficiency, only the M subunit is defective. 1) Assuming random tetramer formation, how many isozymes can be made in RBC’s? 2) Use your answer to the above to explain why RBC’s show some degree of normal PFK-1 activity in Type VII.
a. Phosphofructokinase 1 or PFK-1 catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate in glycolysis.
b. If PFK-1 is deficient glucose-6-phosphate accumulates (the glucose-6-phosphate to fructose-6-phosphate reaction is reversible) and, since it is an allosteric activator of glycogen synthase, increases glycogen synthesis. Muscle fatigue as seen. PFK-1 deficiency is quite rare, however.
c. 1) five (M4, M3L, M2L2, ML3, L4)
2) unaffected (normal) L4 isozyme
Why would defects in phosphorylase kinase lead to glycogen accumulation?
Phosphorylase kinase phosphorylates glycogen phosphorylase thereby activating it. A defect in phosphorylase kinase results in a decreased ability to degrade glycogen, and so results in increased storage of glycogen.
Glycogen Storage Disease Ia: von Gierke disease
Deficiency: Glucose-6-phosphatase (liver) (also kidney)
Findings: Hepato/renomegaly Fasting hypoglycemia Lactic acidemia Hyperuricemia Hyperlipidemia
Special: Severe fasting hypoglycemia is hallmark symptom
