An overview of glycogen degradation

1. Glycogen metabolism- Part-2
(Glycogen degradation)
Namrata Chhabra, M.D., Biochemistry
1/6/2017Namrata Chhabra, M.D., Biochemistry 1

2. Learning objectives
 To understand:
 The Purpose
 Role of Enzymes and coenzymes, and
 The steps involved in the pathway of Glycogenolysis
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3. Introduction
 Glycogen is a storage form of glucose.
 It is a very large, branched polymer of glucose residues that
can be broken down to yield glucose molecules when energy
is needed.
 Most of the glucose residues in glycogen are linked by α-1,4-
glycosidic bonds.
 Branches at about every tenth residue are created by α-1,6-
glycosidic bonds.
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4. Glycogen structure
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5. Purpose of Glycogenolysis
 The controlled breakdown of glycogen and release of
glucose increase the amount of glucose that is
available between meals. Hence, glycogen serves as a
buffer to maintain blood-glucose levels.
 Glycogen's role in maintaining blood glucose levels is
especially important because glucose is virtually
the only fuel used by the brain, except during
prolonged starvation.
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6. Purpose of Glycogenolysis
 The glucose from glycogen is readily mobilized and
is therefore a good source of energy for sudden,
strenuous activity.
 Unlike fatty acids, the released glucose can provide
energy in the absence of oxygen and can thus
supply energy for anaerobic activity.
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7. Enzymes involved in Glycogenolysis
 The efficient breakdown of glycogen requires four
enzyme activities:
 one to degrade glycogen,
 two to remodel glycogen so that it remains a
substrate for degradation, and
 one to convert the product of glycogen breakdown
into a form suitable for further metabolism.
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8. Enzymes of Glycogenolysis
Phosphorylase
Bifunctional-
Debranching
enzyme
Phospho-
glucomutase
Glucose-6-
Phosphatase
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9. Major coenzyme of Glycogenolysis
 Pyridoxal phosphate (PLP), a derivative of vitamin
B6, is the major coenzyme involved in the glycogen
degradation.
 serves as prosthetic group for Glycogen
Phosphorylase.
 It is held at the active site of Phosphorylase enzyme
by a Schiff base linkage, formed by reaction of the
aldehyde group of PLP with the ε-amino group of a
lysine residue.
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10. Glycogen degradation is not just the
reverse of glycogenesis
Glycogenesis
 Glucose-> Glucose-6-P
 Glucose-6-P –> Glucose-1-P
 Polymerization
 Branching
 Polymerization
 Glycogenolysis
 Depolymerization- Removal of
glucose as glucose-1-P
 Debranching
 Depolymerization
 Conversion of Glucose-1-P to
Glucose-6-P
 Conversion of Glucose-6-P to
free Glucose
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11. Specific steps of Glycogenolysis
 Step-1- Depolymerization (Release of Glucose-1-P from
Glycogen)
 Enzyme- Phosphorylase
 Coenzyme– Pyridoxal phosphate
 Reaction involved :
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12. Step-1- Reaction catalyzed by
Phosphorylase
 Phosphorylase catalyzes the sequential removal of
glucosyl residues from the nonreducing ends of the
glycogen molecule (the ends with a free 4-OH group.
 Orthophosphate splits the glycosidic linkage between
C-1 of the terminal residue and C-4 of the adjacent
one.
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13. Phosphoroyltic cleavage
Why not hydrolytic cleavage ?
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14. Advantages of Phosphoroyltic cleavage
 The phosphoroylytic cleavage of glycogen is energetically
advantageous because the released sugar is already
phosphorylated.
 In contrast, a hydrolytic cleavage would yield glucose, which
would then have to be phosphorylated at the expense of the
hydrolysis of a molecule of ATP to enter the glycolytic pathway.
 An additional advantage of phosphoroylytic cleavage for muscle
cells is that glucose 1-phosphate, negatively charged under
physiological conditions, cannot diffuse out of the cell.
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15. Problem with Phosphorylase
 The α-1,6-glycosidic bonds at the branch points are
not susceptible to cleavage by phosphorylase.
 Glycogen phosphorylase stops cleaving α -1,4
linkages when it reaches a terminal residue four
residues away from a branch point.
 Because about 1 in 10 residues is branched, glycogen
degradation by the phosphorylase alone would come
to a halt after the release of six glucose molecules per
branch.
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16. Step-2- Remodeling and Debranching
 Special Bifunctional
enzyme with two enzyme
activities
 Transferase and
Debranching (α-1,6-
glucosidase)
 Both these enzymes
remodel the glycogen for
continued degradation by
the phosphorylase.
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17. Role of Transferase
 Transferase shifts a block of three glucosyl
residues from one outer branch to the other.
 This transfer exposes a single glucose residue
joined by an α-1,6-glycosidic linkage.
 Debranching enzyme, hydrolyzes the α -1, 6-
glycosidic bond, resulting in the release of a
free glucose molecule.
 The transferase and α-1,6-glucosidase convert
the branched structure into a linear one,
which paves the way for further cleavage by
phosphorylase.
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18. Phosphorylase versus debranching
enzyme- Outcomes
 Glucose-1-P is released as
an outcome of reaction
catalyzed by
Phosphorylase
 Free glucose is released
by the action of
debranching enzyme
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19. Step-3- Conversion of Glucose-1-P to
Glucose-6-P
 Phosphoglucomutase converts glucose 1-phosphate into glucose 6-
phosphate in a reversible reaction.
 The catalytic site of an active mutase molecule contains a
phosphorylated serine residue.
 The phosphoryl group is transferred from the serine residue to the
C-6 hydroxyl group of glucose 1-phosphate to form glucose 1,6-
bisphosphate.
 The C-1 phosphoryl group of this intermediate is then shuttled to
the same serine residue, resulting in the formation of glucose 6-
phosphate and the regeneration of the phosphoenzyme.
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20. Reaction catalyzed by Phosphoglucomutase
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21. Step-4- Fate of Glucose-6-P
 Glucose 6-phosphate derived from
glycogen can
 (1) be used as a fuel for anaerobic or
aerobic metabolism as in, for instance,
muscle;
 (2) be converted into free glucose in the
liver and subsequently released into the
blood;
 (3) be processed by the pentose
phosphate pathway to generate NADPH or
ribose in a variety of tissues.
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22. The fate is different in liver and muscle
 The liver contains a hydrolytic enzyme, glucose 6-phosphatase,
which cleaves the phosphoryl group to form free glucose and
orthophosphate.
 Glucose 6-phosphatase is absent from most other tissues.
Consequently, glucose 6-phosphate is retained for the
generation of ATP.
 In contrast, glucose is not a major fuel for the liver. The liver
releases glucose into the blood during muscular activity and
between meals to be taken up primarily by the brain and
skeletal muscle.
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23. Reaction catalyzed by Glucose-6-
Phosphatase
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24. Glycogenesis versus Glycogenolysis
• Glycogenolysis and
Glycogenesis are not
the just the reverse
of each other.
• The reaction
pathways, enzymes
and coenzymes are
all different and,
• both the ways are
reciprocally
regulated.
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25. Regulation of glycogen metabolism
 To be continued in the next section…
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26. Thank you
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