Lesson 8.4 Glycogen regulationThe objectives of this lesson are to understand that:
- Biosynthetic and degradative pathways are almost always distinct
- Phosphorylation is a major regulatory mechanism
- Glycogen phosphorylase activity can be regulated by many mechanisms
- Control of glycogen phosphorylase and glycogen synthase involves reciprocal regulation
It is important to remember that at any given time, only one pathway, synthesis or degradation, will be active. The most important control mechanism for glycogen metabolism is phosphorylation/dephosphorylation of the enzymes involved. Phosphorylation of an enzyme can either activate its catalytic activity or inactivate its activity. The same is true for dephosphorylation. You will see examples where phosphorylation of one enzyme will increase its activity and phosphorylation of a second enzyme will decrease its activity.
Glycogen phosphorylase can exist in four different forms which vary in their activity as described below. The activity of glycogen phosphorylase can be regulated by reversible covalent modification (phosphorylation/dephosphorylation) and allosterically (AMP, ATP, glucose 6-phosphate, glucose). The allosteric changes reflect alterations in the physiological concentrations of metabolites while the phosphorylation reflects hormonal regulation (see lesson 8.6 for details). Note that the predominant forms are the relatively inactive, non-phosphorylated a form and the relatively active, phosphorylated a form. The R and T refer to relative conformations.
The different forms of glycogen phosphorylase |
|||
|---|---|---|---|
| Phosphorylase b | Active R form | Not phosphorylated | Converted to inactive T form by inhibitory effects of ATP and glucose 6-phosphate |
| Phosphorylase a | Inactive T form | Not phosphorylated | Converted to active R form by AMP; Converted to inactive T form by phosphorylation |
| Phosphorylase a | Inactive T form | Phosphorylated | Converted almost entirely to active R form once phosphorylated; Converted to inactive T form by dephosphorylation |
| Phosphorylase a | Active R form | Phosphorylated | Converted to inactive T form by high glucose levels (in muscle) |
Different forms of glycogen phosphorylase are present in the cell depending on the levels of AMP, ATP, glucose 6-phosphate, or glucose present. In addition, the presence of an active kinase or phosphatase alters the form present. A kinase is an enzyme which puts a phosphate on a protein and a phosphatase is an enzyme which removes a phosphate from a protein.
The allosteric regulation of glycogen phosphorylase differs in liver and muscle due to the differences in the fate of glucose produced. The purpose of glycogen breakdown in the liver is to provide glucose for the rest of the body. Therefore, high glucose levels convert the phosphorylated phosphorylase a to an inactive form of phosphorylase a. Also, AMP does not activate liver phosphorylase a. This mode of regulation is consistent with the function of the liver to provide glucose for export to other tissues.
Skeletal muscle uses glucose to provide energy for muscle contraction. Therefore, increased levels of AMP activate phosphorylase b to provide needed glucose for muscle contraction. In addition, muscle lacks the enzyme glucose 6-phosphatase which converts glucose 6-phosphate to glucose in the liver. This allows glucose phosphate generated in the muscle to be utilized there.
The physiological state of the muscle dictates which form of glycogen phosphorylase is present in muscle.
| Resting muscle | Phosphorylase a | Inactive T form |
| Working muscle | Phosphorylase a, phosphorylated form | Active R form |
Lesson 8.4 Glycogen regulation
