Bioc 460 Spring 1999
Lecture 33 - Chapter 23

- Regulation of phosphorylase activity
- Regulation of glycogen synthase activity
- Hormonal regulation of glycogen metabolism
- Glycogen storage diseases in man

See a snake ----> run (RLM 33.1)

See a cake ----> eat (RLM 33.2)

Glycogen degradation is dependent on active phosphorylase enzyme, which is itself regulated by both covalent modification (phosphorylation) and by allosteric control (energy charge). Importantly, regulation of muscle phosphorylase and liver phosphorylase is different.

Phosphorylase is found in cells in two conformations; an active conformation (R form) and an inactive conformation (T form). In muscle the phosphorylase can be activated by two mechanisms:

- inactive phosphorylase b can be converted to active phosphorylase a by serine phosphorylation.
- inactive phosphorylase b can be converted to active phosphorylase b by AMP binding (allostery).

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Figure 23.8

The active conformation (R state) required for phosphorylase function is the same regardless of whether this was achieved by serine phosphorylation (covalent modification) or allostery (AMP binding). Phosphorylase a is deactivated by dephosphorylation of the serine residue in a reaction catalyzed by protein phosphatase 1.

Figure 23.9

Figure 23.11

Liver phosphorylase differs from muscle phosphorylase in two ways:

1. Liver phosphorylase b is not activated by AMP (why does this make sense?).
2. Liver phosphorylase a is deactivated by glucose (why does this make sense?).

Remember that muscle does NOT contain glucose-6 phosphatase, whereas, liver does.

What enzyme phosphorylates phosphorylase?

Phosphorylase kinase phosphorylates phosphorylase b, however, phosphorylase kinase itself is only fully active once it is phosphorylated (Did you get all that???). Again, phosphorylase kinase is activated by phosphorylation (the kinase that does this is called protein kinase A ), which in turn leads to phosphorylation of phosphorylase b converting it to the active form (can now degrade glycogen by phosphorolysis to form glu-1-P). Phosphorylase kinase can also be partially activated by calcium in both muscle and liver cells.

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Glycogen synthase is also found in two forms; the phosphorylated b form is converted to the active a form by dephosphorylation, and the inactive phosphorylated b form can be activated by allosteric binding of glucose-6-P.

Protein kinase A is one of the enzymes that phosphorylates glycogen synthase to inactivate it. Remember that this same kinase also phosphorylates phosphorylase kinase which activates phosphorylase by phosphorylation. Active protein kinase A therefore leads to glycogen degradation.

Figure 23.13

Hormones have been identified that activate glycogen degradation (epinephrine, glucagon) and that activate glycogen synthesis (insulin). This makes sense because epinephrine signals that muscle activity is required (fight or flight), glucagon signals hunger, and insulin signals excess blood glucose (the fed state).

The key to hormonal regulation of glycogen metabolism is phosphorylation/dephosphorylation. For example, epinephrine signaling leads to protein kinase A activation which results in simultaneous activation of glycogen degradation and inactivation of glycogen synthesis (revised sentence).

Figure 23.14

Protein phosphatase 1 reverses the regulatory effects of kinases on glycogen metabolism. Protein kinase A inactivates protein phosphatase activity which enhances glycogen degradation. In contrast, insulin activates protein phosphatase which leads to the deactivation of glycogen degradation (dephosphorylation of phosphorylase kinase) and stimulation of glycogen synthesis (dephosphorylation of glycogen synthase).

Figure 23.15

Figure 23.16

Phosphorylase a in the liver is inactivated by glucose through a mechanism that involves protein phosphatase 1 dephosphorylation; a mechanism that is stimulated by glucose binding. Once protein phosphatase 1 is released from the now dephosphorylated phosphorylase (b form), it is free to catalyze the dephosphorylation of glycogen synthase, which as you remember (ha!) is the active form of the enzyme.

Figure 23.17

Defects in enzymes required for glycogen metabolism have been identified by clinical observations of patients with altered abilities to control glucose and energy production. Two examples of these glycogen storage diseases are:

1. Von Gierke's disease - defect in glucose-6-phosphatase or glucose-6 transporter.
2. McArdle's disease - defect in muscle phosphorylase.

Table 23.1

Figure 23.19

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Department of Biochemistry The University of Arizona Spring 1999  RLM@u.arizona.edu cusanovi@u.arizona.edu http://www.biochem.arizona.edu/classes/bioc460/spring/springindex.html All contents copyright © 1999. All rights reserved.