CHEM 445 / BIOL 445
Biochemistry II

J. D. Cronk
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18. header

Lecture 18. Reciprocal regulation of glycogen metabolism

Friday 2 March 2007

Glycogen synthesis . Hormonal regulation of glycogen synthesis: Properties of insulin and and its effects on glycogen synthesis. Reciprocal regulation of glycogen synthesis and breakdown. Effects of the hormones epinephrine, glucagon, and insulin. Kinases and phosphatases that regulate glycogen metabolism: their targets, effects, and regulation. Glycogen storage diseases.

Reading: BTS6, Ch.21, pp.604-612.

  
18. Summary

Lecture 18 Summary

¶ Glycogen synthesis

Glucose 1-phosphate is further activated by conversion to UDP-glucose. Glycogen synthase transfers UDP-glucose to the nonreducing end of glycogen, forming a new a-1,4 linkage. Remodeling occurs via a branching enzyme. Glycogenin is a primer for glycogen synthesis.

¶ Reciprocal regulation of glycogen breakdown and synthesis

Coordinate control of glycogen metabolism: Epinephrine causes increased glycogen breakdown, while also slowing down glycogen synthesis. Protein phosphatase 1 (PP1) reverses activation by protein kinase A (PKA). PP1 itself is inhibited by PKA phosphorylation of its specific inhibitor and its glycogen binding subunit (Rg1). Insulin signaling is mediated by receptor tyrosine kinases (RTKs). An intracellular signal transduction pathway leads from these RTKs to phosphorylation and dephosphorylation events that downregulate glycogen breakdown and turn up the rate of glycogen synthesis. An insulin-sensitive protein kinase phosphorylates the Rg1 subunit of PP1 at a site different from that targeted by PKA, helping activate PP1. The phosphatase subsequently acts to slow down phosphorylase, phosphorylase kinase, and glycogen synthase. A model from the text for how blood glucose regulates the sequential deactivation of phosphorylase a followed by activation of glycogen synthase in the liver was presented. We are at this point well-prepared to understand the biochemical basis of some of the glycogen storage diseases that have been characterized.

Glycogen storage diseases

Defects in enzymes of glycogen metabolism result in a great variety of genetic diseases, as a search of the OMIM database with the term "glycogen storage" reveals.

 

Table: Glycogen storage diseases - examples

Name (OMIM link) Deficiency Notes
GSD I - Von Gierke disease Glucose 6-phosphatase [EC 3.1.3.9] Hepatomeglia, hypoglycemia, pleiotropic effects
GSD II - Pompe disease Alpha-glucosidase [EC 3.2.1.20];
lysosomal form 		Cardiomyopathy, severe
GSD III - Cori disease Amylo-a-1,6-glucosidase [EC 3.2.1.33]
or transferase [EC 2.4.1.25] 		Debranching deficiency
GSD IV - Andersen disease 1,4-a-glucan branching enzyme
[EC 2.4.1.18] 		Branching deficiency
GSD V - McArdle disease Glycogen phosphorylase
[EC 2.4.1.1]		 Glycogen phosphorylase deficiency
GSD-0 - Glycogen synthase
[EC 2.4.1.1] 		Hypoglycemia, rare

 

Study questions

  • Would you expect the liver to simultaneously show high rates of glycogen breakdown and glycolysis? Why or why not?

Page updated 01-14-07

References

1. Berg, Tymoczko, and Stryer. Biochemistry (BTS): 6th edition (2007, Freeman) Ch.7 (pp.183-204)
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