Lesson 19. GLYCOGEN DEGRADATION AND SYNTHESIS
Module 3. Metabolism
GLYCOGEN DEGRADATION AND SYNTHESIS
GLYCOGEN DEGRADATION AND SYNTHESIS
- Glycogen is a large polymer of glucose residues linked by α 1-4 glucosidic bonds with branches every 10 residues or so via α 1-6 glucosidic bonds. Glycogen provides an important energy reserve for the body.
- The two main storage sites are the liver and skeletal muscle where the glycogen is stored as granules in the cytosol. The granules contain not only glycogen but also the enzymes and regulatory proteins that are required for glycogen degradation and synthesis.
- Glycogen metabolism is important because it enables the blood glucose level to be maintained between meals (via glycogen stores in the liver) and also provides an energy reserve for muscular activity. The maintenance of blood glucose is essential in order to supply tissues with an easily metabolizable energy source, particularly the brain which uses only glucose except after a long starvation period.
- Glycogen degradation requires two enzymes; glycogen phosphorylase and glycogen-debranching enzyme.
- Glycogen phosphorylase (often called simply phosphorylase) degrades glycogen by breaking α 1-4 glycosidic bonds to release glucose units one at a time from the nonreducing end of the glycogen molecule (the end with a free 4’ OH group) as glucose 1-phosphate.
- The other substrate required is inorganic phosphate (Pi). The reaction is an example of phosphorolysis, that is breakage of a covalent bond by the addition of a phosphate group. The (reversible) reaction is as follows:
- Glycogen phosphorylase can remove only those glucose resides that are more than five residues from a branchpoint. Glycogen-debranching enzyme removes the α1-6 branches and so allows phosphorylase to continue degrading the glycogen molecule. The glucose 1-phosphate produced is converted to glucose 6-phosphate by the enzyme phosphoglucomutase:
- The fate of the glucose 6-phosphate depends on the tissue.
- Liver contains the enzyme glucose 6-phosphatase which converts the glucose 6-phosphate to glucose, which then diffuses out into the bloodstream and so maintains the blood glucose concentration:
- During glycogen degradation in muscle is required to produce energy quickly and so the glucose 6-phosphate is metabolized immediately via glycolysis. This tissue does not contain glucose 6-phosphatase.
Fig. 19.1 Glycogen degradation
19.3 Glycogen Synthesis
- Three enzymes are needed to synthesize glycogen:
- UDP–glucose pyrophosphorylase catalyzes the synthesis of UDP-glucose from UTP and glucose 1-phosphate:
The pyrophosphate (PPi) is immediately hydrolyzed by inorganic pyrophosphatase, releasing energy. Thus the overall reaction is highly exergonic and essentially irreversible.
- Glycogen synthase now transfers the glucosyl residue from UDP-glucose to the C4 OH group at the nonreducing end of a glycogen molecule, forming an α1-4 glycosidic bond.
- Glycogen synthase can only extend an existing chain. Thus it needs a primer; this is a protein called glycogenin. Glycogenin contains eight glucosyl units linked via α1-4 linkages, which are added to the protein by itself (i.e. autocatalysis). It is this molecule that glycogen synthase then extends. Each glycogen granule contains only a single glycogenin molecule at its core. The fact that glycogen synthase is fully active only when in contact with glycogenin .
- Branching enzyme [amylo-(1-4→1-6) transglycosylase is a different enzyme from glycogen-debranching enzyme. After a number of glucose units have been joined as a straight chain with α1-4 linkages, branching enzyme breaks one of the α1-4 bonds and transfers a block of residues (usually about seven) to a more interior site in the glycogen molecule, reattaching these by creating an α1-6 bond. The branches are important because the enzymes that degrade and synthesize glycogen (glycogen synthase and glycogen phosphorylase, respectively) work only at the ends of the glycogen molecule. Thus the existence of many termini allows a far more rapid rate of synthesis and degradation than would be possible with a nonbranched polymer.
Fig. 19.2 Glycogen synthesis
19.4 Control of Glycogen Metabolism
Glycogen degradation and glycogen synthesis are controlled both by allosteric regulation, covalent and by hormonal control.
19.4.1 Allosteric control and covalent modification
- Phosphorylase exists in a phosphorylated active a form and a dephosphorylated normally inactive b form. The two forms are interconverted by phosphorylase kinase and protein phosphatase I.
- In muscle, phosphorylase b is activated by the high concentrations of AMP generated by strenuous exercise and thus degrades glycogen, but the AMP stimulation is opposed by high concentrations of ATP and glucose 6-phosphate and so the enzyme is inactive in resting muscle.
- In liver, phosphorylase b is not responsive to AMP but phosphorylase a is deactivated by glucose so that glycogen degradation. Hence glucose production from glycogen occurs only when glucose levels are low.
- Conversely to phosphorylase glycogen synthase exists as a phosphorylated normally inactive b form and a dephosphorylated active a form.
- Epinephrine (adrenaline) stimulates glycogen degradation in skeletal muscle. Epinephrine and glucagon stimulate glycogen degradation in liver. The hormone binds to a plasma membrane receptor and activates adenylate cyclase via a G protein. Adenylate cyclase synthesizes cAMP from ATP which in turn activates protein kinase A. Protein kinase A phosphorylates phosphorylase kinase which activates it. The phosphorylase kinase then converts inactive phosphorylase b to active phosphorylase a by phosphorylation. The same active protein kinase A inactivates glycogen synthase by phosphorylation, converting active glycogen synthase a to glycogen synthase b. When hormone levels fall, stimulation of glycogen degradation is turned off by degradation of cAMP to 5’AMP by phosphodiesterase and by dephosphorylation of the phosphorylated forms of phosphorylase and synthase by protein phosphatase I.
- Insulin is released into the bloodstream when the blood glucose concentration is high and it stimulates glycogen synthesis. It binds to and activates a receptor protein kinase in the plasma membrane of target cells. This leads to activation of an insulin-responsive protein kinase then activates protein phosphatase I by phosphorylation. Activated protein phosphatase I ensures that phosphorylase and glycogen synthase are dephosphorylated, thus inhibiting glycogen degradation and activating glycogen synthesis.
Last modified: Saturday, 3 November 2012, 6:08 AM