Glycogen metabolism part-2

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

Learning objectives
 To understand:
 The Purpose
 Role of Enzymes and coenzymes, and
 The steps involved in the pathway of Glycogenolysis

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.

Glycogen structure

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.

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.

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.

Enzymes of Glycogenolysis
Phosphorylase
Bifunctional-
Debranching
enzyme
Phospho-
glucomutase
Glucose-6-
Phosphatase

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.

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

Specific steps of Glycogenolysis
 Step-1- Depolymerization (Release of Glucose-1-P from
Glycogen)
 Enzyme- Phosphorylase
 Coenzyme– Pyridoxal phosphate
 Reaction involved :

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.

Phosphoroyltic cleavage
Why not hydrolytic cleavage ?

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.

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.

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.

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.

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

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.

Reaction catalyzed by Phosphoglucomutase

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.

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.

Reaction catalyzed by Glucose-6-
Phosphatase

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.

Regulation of glycogen metabolism
 To be continued in the next section…

Thank you

Glycogen metabolism part-2

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