1. Regulation of Glycogen Metabolism
MCBM II MMCM 31104
Year 1 MBBS Term 2
Element 5
Batch 17 (2011 intake)
Regulation of Glycogen Metabolism
Dr Girish Prabhu M.D
Associate Professor
AUFOM

2. Glycogen Metabolism and disorders Part II
Objectives:
The objective of this lecture is to discuss regulation of glycogen metabolism and glycogen storage diseases.
Learning Outcomes:
At the end of the lecture, students should be able to:
Explain regulation of glycogen metabolism by the covalent modification and allosteric mechanisms.
Compare the regulation of glycogen metabolism in muscle and liver.
Define glycogenosis or glycogen storage diseases.
List the glycogenosis and their enzyme deficiencies.
Explain biochemical basis of symptoms found in hepatic, myopathic and miscellaneous type of glycogenosis.

3. Regulation of Glycogen Metabolism in Liver
Degradative and biosynthetic pathways are regulated principally by changes in the insulin/glucagon ratio and by blood glucose levels, which reflect the availability of dietary glucose.
Degradation of liver glycogen is also activated by epinephrine, which is released in response to exercise, hypoglycemia, or other stress situations in which there is an immediate demand for blood glucose.

4. Regulation of Glycogen Metabolism in Skeletal muscle
Muscle glycogenolysis is regulated principally by AMP, which signals a lack of ATP, and by Ca2+ released during contraction.
Epinephrine, which is released in response to exercise and other stress situations, also activates skeletal muscle glycogenolysis. The glycogen stores of resting muscle decrease very little during fasting.

5. Activation of glycogen phosphorylase and inactivation of glycogen synthase by Covalent modification
Figure 1
Figure 2
Hormones Regulate Glycogen Metabolism
Both epinephrine and glucagon promote glycogen breakdown. Glucagon doesn't act on muscle.
Both act by increasing c AMP.
The second messenger cAMP can activate protein kinase A, which, in turn, phosphorylates and activates an enzyme known as phosphorylase kinase.
This kinase will phosphorylate glycogen phosphorylase b converting it into an active form of the enzyme known as glycogen phosphorylase a.
Protein kinase A also phosphorylates glycogen synthase and inactivates this enzyme activity.
Regulatory balance between anabolic and catabolic processes, which ensures that both are not activated at the same time.
Insulin may activate the phosphodiesterase that converts cAMP to AMP, thereby decreasing cAMP levels and inactivating protein kinase A.

6. Hormones (epinephrine and glucagon) regulate Glycogen catabolism : Role of c AMP   
Phosphorylase
kinase P C R
cAMP dependent
protein kinase
Phosphorylase
Adenylcyclase P

7. Regulation of Glycogen Metabolism
A phosphatase that inactivates the phosphorylated glycogen phosphorylase will activate glycogen synthase by dephosphorylation. Insulin promotes glycogen synthesis.

8. LIVER PHOSPHORYLASE IS A GLUCOSE SENSOR
Glucose binding to an allosteric site of the phosphorylase a isoenzyme of liver induces a conformational change that exposes its phosphorylated serine residue s to the action of phosphorylase a phosphatase 1(PP1).This phosphatase converts phosphorylase a to phosphorylase b sharply reducing the acyiovity of phosphorylase and slowing down glycogen breakdown in response to high blood glucose. Insulin acts indirectly to stimulate PP1 and slow glycogen breakdown.

9. Regulation of glycogen metabolism in muscle
AMP produced from the degradation of ATP during muscular contraction allosterically activates glycogen phosphorylase b.
The neural impulses that initiate contraction release Ca2+ from the sarcoplasmic reticulum.
The Ca2+ binds to calmodulin, which is a modifier protein that activates phosphorylase kinase.
3.Phosphorylase kinase is also activated through phosphorylation by protein kinase A.

10. Regulation of glycogen metabolism in muscle : allosteric effects
Muscle glycogen phosphorylase is a genetically distinct isoenzyme of liver glycogen phosphorylase and contains an amino acid sequence that has a purine nucleotide binding site.
When AMP binds to this site, it changes the conformation at the catalytic site to a structure very similar to that in the phosphorylated enzyme.

11. How muscle and liver glycogen metabolism differ
The regulation of skeletal muscle glycogen synthesis and degradation differs from that in liver in several important respects:
(a) glucagon has no effect on muscle,and thus glycogen levels in muscle do not vary with the fasting/feeding state.
(b) AMP is an allosteric activator of the muscle isozyme of glycogen phosphorylase,but not liver glycogen phosphorylase.
(c) the effects of Ca2+ in muscle result principally from the release of Ca2+ from the sarcoplasmic reticulum after neural stimulation, and not from epinephrine-stimulated uptake.
(d) glucose is not a physiologic inhibitor of glycogen phosphorylase a in muscle.
(e) glycogen is a stronger feedback inhibitor of muscle glycogen synthase than of liver glycogen synthase, resulting in a smaller amount of stored glycogen per gram weight of muscle tissue.

12. GLYCOGEN STORAGE DISEASES
The glycogen storage diseases or Glycogenosis result from a hereditary deficiency of one of the enzymes involved in the synthesis or sequential degradation of glycogen.

13. Glycogenosis Glycogenosis type I - Glucose-6-phosphatase deficiency
Glycogenosis type II - Acid maltase deficiency (AMD); Pompe disease
Glycogenosis type III - Debrancher enzyme deficiency; Cori-Forbes disease
Glycogenosis type IV - Brancher enzyme deficiency; Andersen disease
Glycogenosis type V - Muscle phosphorylase deficiency; McArdle disease
Glycogenosis type VI - Liver phosphorylase deficiency

14. CLINICAL FEATURES Symptoms in addition to excess glycogen storage:
When a genetic defect affects mainly an isoform of an enzyme expressed in liver, a common symptom is hypoglycemia, relating to impaired mobilization of glucose for release to the blood during fasting.
When the defect is in muscle tissue, weakness & difficulty with exercise result from inability to increase glucose entry into Glycolysis during exercise.
Additional symptoms depend on the particular enzyme that is deficient. 

15. Some important points
Deficiency of the enzyme glucose-6-phosphatase (von Gierke disease, or type I glycogenosis) is a prime example of the hepatic-hypoglycemic form of glycogen storage disease.
Deficiencies of muscle phosphorylase (McArdle disease, or type V glycogenosis) is a prime example of myopathic type of glycogenosis.

16. Some important points
Glycogenoses Type 2—Pompe disease or α-1,4-Glucosidase deficiency (lysosomal glucosidase) is a Lysosomal storage disease.
Cardiomegaly is the most prominent feature