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Bioc 460 Spring 1999
Lecture 32 - Chapter 23
- Overview
of glycogen metabolism
- Glycogen degradation
- Glycogen synthesis
Overview
of glycogen metabolism
Glycogen is the storage form of glucose in animals. It is a large branched polymer containing multiple a-1,4-glycosidic bonds to form a chain with occasional branch points through a-1,6-glycosidic bonds. This branched structure increases the number of free ends to facilitate rapid removal and addition of glucose residues. Importantly, liver and muscle are the primary tissue depots of glycogen. There are tissue-specific differences in key glycogen metabolizing enzymes.
Figure 23.1
Figure 23.5
Glycogen degradation and glycogen synthesis are tightly controlled to prevent futile cycling. Enzymes required for degradation are shut off when synthesis is favored, and visa versa. Covalent modification by phosphorylation is the mechanism by which these enzymes are controlled. Glucose-1-P is the shared intermediate in these two pathways as it is the first product released from degradation, and the precursor substrate for glycogen synthesis.
Degradation: Glycogen(n residues) + Pi ---> Glycogen(n-1 residues) + Glucose-1-P
Synthesis: Glycogen(n residues) + Glucose-1-P ---> [UDP-glucose] ---> Glycogen(n+1 residues)
The role of [de]branching enzymes in breaking and forming a-1,6-glycosidic bonds is important to understanding the structure and function of glycogen as a form of stored energy.
Glycogen degradation
Glycogen degradation in the liver is critical to providing glucose to the brain in between meals (primarily during sleep), whereas, glycogen in the muscle is used as source of glucose for energy production during exercise. The first step in glycogen breakdown is phosphorolytic cleavage of glucose by the enzyme glycogen phosphorylase.
Glycogen(n residues) + Pi ---> Glycogen(n-1 residues) + Glucose-1-P
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Phosphorolysis is the cleavage of a
bond by orthophosphate (in contrast to hydrolysis). Phosphorylase
catalyzes the release of glucose units from free ends of glycogen
polymers. The Glu-1-P product is retained inside the cell because
of its ionized state (negative charge from the phosphate). Glu-1-P
is readily converted to Glu-6-P by phosphoglucomutase. Glu-6-P is a substrate for glycolysis
in the muscle (and sometimes
liver).
However, most of the time in
the liver, Glu-6-P is dephosphorylated by Glucose-6 phosphatase, a liver enzyme that promotes the release of
glucose into the blood.
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Phosphorylase removes glucose through cleavage of a-1,4-glycosidic bonds, however, removal of glucose units at branch points (a-1,6-glycosidic bonds) is more complex. First a transferase enzyme shifts 3 glucose units to a free end, and then the Debranching enzyme, a-1,6-glycosidase, cleaves the glycosidic bond releasing free glucose (not Glucose-1-P).
Figure 23.3
Figure 23.4
Glycogen synthesis
Pathways for glycogen degradation and glycogen synthesis are separate. The phosphorylase reaction is not readily reversible because the concentration of Pi in cells is 100-fold higher than that of Glu-1-P. Glycogen is synthesized through a distinct pathway utilizing uridine diphosphate glucose (UDP-glucose) as an activated form of glucose.
The first reaction in glycogen synthesis is catalyzed by UDP-glucose pyrophosphorylase which produces UDP-glucose and pyrophosphate from Glu-1-P and UTP. Since pyrophosphate (PPi) is rapidly hydrolyzed to orthophosphate (2 Pi) by the enzyme pyrophosphatase, the reaction is considered irreversible and pulled far to the right.
Glucose-1-P + UTP + H2O <----> UDP-glucose + 2 Pi
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The enzyme glycogen synthase catalyzes the transfer of UDP-glucose to a growing glycogen chain by forming a a-1,4-glycosidic bond. Glycogen synthase can only add glucose residues if the polysaccharide chain already contains more than four residues. Priming of glycogen chains is done by glycogenin, a protein that has glucose units attached to a specific tyrosine residue. Glycogen synthase interacts with glycogenin to initiate the process. Alternatively, glucose units are simply added to termini remaining after glycogen degradation.
Branching enzyme creates a-1,6-glycosidic bonds by moving about 7 glucose residues from a growing chain to create a branch. Branching increases the solubility of glycogen, but more importantly, creates a large number of termini to accelerate glycogen degradation by phosphorylase and glycogen synthesis by glycogen synthase.
Glycogen is a very efficient storage form of glucose. It only costs one high energy phosphate bond for every glucose-6-P that is incorporated into glycogen (this comes from the regeneration of UTP). Moreover, the energy breakdown from the degradation of glycogen into glucose-1-P and glucose is minimal since only ~10% of the glucose units are at branch points (glucose needs to be phosphorylated by hexokinase before it can enter glycolysis). Since the storage of glucose as glycogen requires only 1 ATP per unit stored, and complete oxidation of Glu-6-P yields about 31 ATPs, glycogen is nearly 97% efficient at storing energy (1/31 = 3% investment).
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Regulation of glycogen degradation and synthesis is the "fun" part of this process!
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