Biochemistry

Lecture 5. Glycogen
metabolism and regulation.

Department of biochemistry and

medical chemistry
Ph.D. Chernousova Natalia

2020
 Stores of readily available glucose to supply the
tissues with an oxidizable energy source are found
principally in the liver, as glycogen. A second major
source of stored glucose is the glycogen of skeletal
muscle. However, muscle glycogen is not generally
available to other tissues, because muscle lacks the
enzyme glucose-6-phosphatase.
The major site of daily glucose consumption (75%) is
the brain via aerobic pathways. Most of the remainder
of is utilized by erythrocytes, skeletal muscle, and
heart muscle.
Section of glycogen showing α-1,4- and α-1,6-glycosidic linkages
Degradation of stored glycogen
(glycogenolysis) occurs through the action of
Glycogen phosphorylase.

The action of phosphorylase is to phosphorolytically

remove single glucose residues from a-(1,4)-linkages
within the glycogen molecules. The product of this
reaction is glucose-1-phosphate.

Pyridoxal phosphate (PLP), a derivative of vitamin B6,

serves as prosthetic group for Glycogen Phosphorylase.
Glycogenolysis
 Glycogen phosphorylase cannot remove glucose
residues from the branch points (a-1,6 linkages) in
glycogen. The activity of phosphorylase ceases 4
glucose residues from the branch point. The
removal of these branch point glucose residues
requires the action of debranching enzyme
(also called glucan transferase) which contains 2
activities: glucotransferase and glucosidase.
 Regulation of Glycogen Breakdown
In response to lowered blood glucose the a cells of the
pancreas secrete glucagon which binds to cell surface
receptors on liver and several other cells. Liver cells are the
primary target for the action of this peptide hormone. The
response of cells to the binding of glucagon to its cell surface
receptor is the activation of the enzyme adenylate cyclase
which is associated with the receptor. Activation of adenylate
cyclase leads to a large increase in the formation of cAMP.
cAMP binds to an enzyme called cAMP-dependent protein
kinase, PKA. Binding of cAMP to the regulatory subunits of
PKA leads to the release and subsequent activation of the
catalytic subunits. The catalytic subunits of PKA then
phosphorylate an enzyme phosphorylase kinase, which
enzyme then phosphorylates Glycogen Phosphorylase.
This identical cascade of events occurs in skeletal muscle cells as well.
However, in these cells the induction of the cascade is the result of
epinephrine binding to receptors on the surface of muscle cells.

Epinephrine is released from the adrenal glands in response to neural signals

indicating an immediate need for enhanced glucose utilization in muscle, the
so called fight or flight response. Muscle cells lack glucagon receptors. The
presence of glucagon receptors on muscle cells would be futile anyway since
the role of glucagon release is to increase blood glucose concentrations and
muscle glycogen stores cannot contribute to blood glucose levels.

In order to terminate the activity of the enzymes of the glycogen

phosphorylase activation cascade, once the needs of the body are met, the
modified enzymes need to be un-modified. In the case of Ca2+ induced
activation, the level of Ca2+ ion release from muscle stores will terminate
when the incoming nerve impulses cease. The removal of the phosphates on
phosphorylase kinase and phosphorylase-a is carried out by phosphoprotein
phosphatase-1.
 Glycogen Synthesis
Synthesis of glycogen from glucose is carried out the enzyme glycogen
synthase. This enzyme utilizes UDP-glucose as one substrate and the non-
reducing end of glycogen as another.
The activation of glucose to be used for glycogen synthesis is carried
out by the enzyme UDP-glucose pyrophosphorylase. This enzyme
exchanges the phosphate on C-1 of glucose-1-phosphate for UDP. The
energy of the phospho-glycosyl bond of UDP-glucose is utilized by glycogen
synthase to catalyze the incorporation of glucose into glycogen. UDP is
subsequently released from the enzyme.

Recently it has been discovered that a protein known as glycogenin is

located at the core of glycogen molecules. Glycogenin has the unusual
property of catalyzing its own glycosylation, attaching C-1 of a UDP-glucose
to a tyrosine residue on the enzyme. The attached glucose is believed to
serve as the primer required by glycogen synthase.
Glycogen Synthesis
The a-1,6 branches in glucose are produced by amylo-(1,4 - 1,6)-
transglycosylase, also termed the branching enzyme. This enzyme
transfers a terminal fragment of 6-7 glucose residues (from a polymer at
least 11 glucose residues long) to an internal glucose residue at the C-6
hydroxyl position.
Insulin, produced in response to high blood glucose, triggers a
separate signal cascade that leads to activation of Phosphoprotein
Phosphatase. This phosphatase catalyzes removal of regulatory
phosphate residues from Phosphorylase, Phosphorylase Kinase,
and Glycogen Synthase enzymes. Thus insulin antagonizes effects
of the cAMP cascade induced by glucagon and epinephrine.
 Glycogen storage diseases (GSD)

are genetic conditions in which the body has

an enzyme problem and is not able to store
or break down the complex sugar glycogen
properly. GSD affects the liver, muscles and
other areas of the body. Several types of
GSD can occur.
Thank you for attention