TestQuestions-Glycogen

Molecular Biochemistry I

Glycogen Metabolism

Reading:

Textbook Reading: Voet & Voet, Biochemistry, 3rd Edition, Chapter 18.

Some recent articles (optional reading):
V. L. Rath, M. Ammirati, D. E. Danley, J. L. Ekstrom, E. M. Gibbs, T. R. Hynes, A. M. Mathiowetz, R. K. McPherson, T. V. Olson, J. L. Treadway, & D. J. Hoover (2000) "Human liver glycogen phosphorylase inhibitors bind at a new allosteric site," Chem. & Biol. 7: 677-682.
J. L. Buchbinder, V. L. Rath, & R. J. Fletterick (2001) "Structural relationships among regulated and unregulated phosphorylases," Annu. Rev. Biophys. Biomol. Struct. 30: 191-209.
A. Nakayama, K. Yamamoto & S. Tabata (2001) "Identification of the catalytic residues of bifunctional glycogen debranching enzyme," J. Biol. Chem. 276: 28824-28828.
B. J. Gibbons, P. J. Roach & T. D. Hurley (2002) "Crystal structure of the autocatalytic initiator of glycogen biosynthesis, glycogenin," J. Mol. Biol. 319: 463-477.
J. C. Ferrer, C. Favre, R. R. Gomis, J. M. Fernández-Novell, M. García-Rocha, N. de la Iglesia, E. Cid & J. J. Guinovart (2003) "Control of glycogen deposition," FEBS Lett. 546: 127-132.
J. I. Wolfsdorf & D. A. Weinstein (2003) "Glycogen storage diseases," Rev. in Endocrine & Metabolic Disorders 4: 95-102.
G. Jiang & B. B. Zhang (2003) "Glucagon and regulation of glucose metabolism," Am. J. Physiol. Endocrinol. Metab. 284: E671-E678.
J. Lomako, W. M. Lomako, & W. J. Whelan (2004) "Glycogenin: the primer for mammalian and yeast glycogen synthesis," Biochim. Biophys. Acta 1673: 45-55.
D. A. Weinstein, C. E. Correia, A. C. Saunders & J. I. Wolfsdorf (2006) "Hepatic glycogen synthase deficiency: An infrequently recognized cause of ketotic hypoglycemia," Molec. Genetics & Metab. 87: 284-288.
C. C. Greenberg, M. J. Jurczak, A. M. Danos & M. J. Brady (2006) "Glycogen branches out: new perspectives on the role of glycogen metabolism in the integration of metabolic pathways," Am J. Physiol. Endocrinol. Metab. 291: E1-E8.

Potential Test Questions:

1.Describe the regulation of the muscle Glycogen Phosphorylase enzyme by local allosteric regulators. What is the effect of phosphorylation of the enzyme via Phosphorylase Kinase? A diagram may be helpful. What is the significance of the allosteric regulation with regard to cellular metabolism?

2.a. Diagram and describe the reaction cascade by which cyclic AMP alters activity of the Glycogen Phosphorylase enzyme. (The process by which cyclic AMP production is activated by glucagon or epinephrine may be omitted here.) Include the effects of covalent modification on sensitivity of Glycogen Phosphorylase to allosteric regulators. What is the significance of such a regulatory cascade in liver in relation to the well being of the whole organism?
b. How does the rise in cytosolic [Ca⁺⁺] that occurs during activation of muscle contraction affect glycogen breakdown? How is this significant with regard to metabolism during muscle contraction?

3. Describe the separate roles of Glycogenin and Glycogen Synthase in glycogen synthesis. Summarize the reactions catalyzed by each enzyme. It is not necessary to include chemical structures or reaction mechanisms in this answer.

4. Explain how genetic deficiency of each of the following enzymes leads to intracellular glycogen accumulation (glycogen storage disease) along with the specific symptoms listed:

Deficiency of Glucose-6-phosphatase in liver, causing glycogen accumulation plus hypoglycemia (low blood glucose) when fasting.
Deficiency of Glycogen Phosphorylase in muscle, causing glycogen accumulation plus muscle cramps with exercise.
Deficiency of Phosphofructokinase in muscle, causing glycogen accumulation plus inability to exercise.

Studio Activity: OMIM

Online Mendelian Inheritance in Man (OMIM) is a database of information about genetic diseases, maintained by the Center for Medical Genetics, Johns Hopkins University, and the National Center for Biotechnology Information, National Library of Medicine, accessible via the World Wide Web at http://www.ncbi.nlm.nih.gov/Omim/

View the OMIM website for each of the glycogen storage diseases listed below. At each site, browse through the TEXT and the Clinical Synopsis. Other sections may also be of interest.

Type I: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=232200
Type IV: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=232500
Type V: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=232600
Type VII: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=232800

Question for in-class discussion. Students will be called on to explain, for each of the glycogen storage diseases listed below:

how the enzyme deficiency leads to cellular accumulation of glycogen
how the enzyme deficiency leads to other symptoms listed below
the rationale for treatment options, if any.

Also see Voet & Voet, Biochemistry, 3rd Edition, p. 651-654. At right is a summary of relevant pathways.

Glycogen Storage Disease Type	Symptoms to be explained, in addition to glycogen accumulation
Type I, liver deficiency of Glucose-6-phosphatase (von Gierke's disease)	hypoglycemia (low blood glucose) when fasting, liver enlargement.
Type IV, deficiency of branching enzyme in various organs, including liver (Andersen's disease)	liver dysfunction and early death.
Type V, muscle deficiency of Glycogen Phosphorylase (McArdle's disease)	muscle cramps with exercise.
Type VII, muscle deficiency of Phosphofructokinase.	inability to exercise.

Lecture notes on
Glycogen Metabolism

Interactive Quiz on
Glycogen Metabolism