GLYCOGENESIS

AND
GLYCOGENOLYSIS
DR. HUDA
Fluctuation of glycogen stores
 Liver glycogen stores increase during the well-
fed state and are depleted during a fast
 Muscle glycogen is not affected by short
periods of fasting (a few days) and is only
moderately decreased in prolonged fasting
(weeks)
 Muscle glycogen is synthesized to replenish
muscle stores after they have been depleted,
for example, following strenuous exercise
GLYCOGENESIS
SYNTHESIS OF GLYCOGEN
(GLYCOGENESIS)
 Glycogenis synthesized from
molecules of α-D-glucose
 Theprocess occurs in the cytosol,
and requires energy supplied by
ATP (for the phosphorylation of
glucose) and uridine triphosphate
(UTP)
 Glycogen synthesis, like almost all the pathways of
glucose metabolism, begins with the phosphorylation of
glucose to glucose 6-phosphate by hexokinase or, in the
liver, glucokinase
 Glucose 6-phosphate is the precursor of glycolysis, the
pentose phosphate pathway, and of pathways for the
synthesis of other sugars
 In the pathway for glycogen synthesis,
glucose 6-phosphate is converted to
glucose 1-phosphate by
phosphoglucomutase, a reversible
reaction
 Glycogen is both formed from and
degraded to glucose 1-phosphate, but the
biosynthetic and degradative pathways
are separate and involve different
enzymes
 Glucose 6-phosphate is
isomerized to glucose 1-
phosphate by
phosphoglucomutase
 The enzyme itself is
phosphorylated, and the
phospho-group takes
part in a reversible
reaction in which
glucose 1,6-
bisphosphate is an
intermediate
 Next, glucose 1-phosphate reacts with
uridine triphosphate (UTP) to form the
active nucleotide uridine diphosphate
glucose (UDPGlc) and pyrophosphate ,
catalyzed by UDPGlc pyrophosphorylase
 The high-energy bond
in pyrophosphate (PPi),
the second product of
the reaction, is
hydrolyzed to two
inorganic
phosphates(Pi) by
pyrophosphatase,
which ensures that
synthesis of UDP-
glucose proceeds in the
direction of UDP-
glucose production
Synthesis of a primer to initiate
glycogen synthesis
 Glycogen synthase is responsible for
making the α(1→4) linkages in
glycogen
 Thisenzyme cannot initiate chain
synthesis using free glucose as an
acceptor of a molecule of glucose from
UDP-glucose
 Instead,
it can only elongate
already existing chains of glucose
 Therefore, a fragment of glycogen
can serve as a primer in cells
whose glycogen stores are not
totally depleted
 Inthe absence of a
glycogen fragment, a
protein, called
glycogenin, can serve
as an acceptor of
glucose residues
 The side chain hydroxyl
group of a specific
tyrosine serves as the
site at which the initial
glucosyl unit is attached
 Transfer of the first few molecules of
glucose from UDP-glucose to glycogenin is
catalyzed by glycogenin itself, which can
then transfer additional glucosyl units to
the growing α(1→4)-linked glucosyl chain
 This short chain serves as an acceptor of
future glucose residues as described below
 Glycogenin stays associated with and is
found in the center of the completed
glycogen molecule
ELONGATION OF GLYCOGEN CHAINS
BY GLYCOGEN SYNTHASE
 Elongation of a glycogen
chain involves the transfer
of glucose from UDP-
glucose to the
nonreducing end of the
growing chain, forming a
new glycosidic bond
between the anomeric
hydroxyl of carbon 1 of
the activated glucose and
carbon 4 of the accepting
glucosyl residue
 The "nonreducing end" of a
carbohydrate chain is one in which the
anomeric carbon of the terminal sugar
is linked by a glycosidic bond to
another compound, making the
terminal sugar "nonreducing"
 The enzyme responsible for making
the α(1→4) linkages in glycogen is
glycogen synthase
 TheUDP released when the
new α(1→4) glycosidic bond is
made can be converted back to
UTP by nucleoside
diphosphate kinase

 UDP + ATP UTP + ADP

Formation of branches in glycogen
 If no other synthetic enzyme acted
on the chain, the resulting structure
would be a linear (unbranched)
molecule of glucosyl residues
attached by α(1→4) linkages
 Such a compound is found in plant
tissues, and is called amylose
 In contrast, glycogen
has branches
located, on average,
eight glucosyl
residues apart,
resulting in a highly
branched, treelike
structure that is far
more soluble than
the unbranched
amylose
 Branches are made by the action of the "branching
enzyme," amylo-α(1→4)→α(1→6)-transglucosidase
 When the chain is at least 11 glucose residues long,
branching enzyme transfers a part of the α(1→4)
chain (at least six glucose residues) to a neighboring
chain to form α(1→6) linkage, establishing a branch
point
 The resulting new, nonreducing end as well
as the old nonreducing end from which the
five to eight residues were removed can now
be further elongated by glycogen synthase

Synthesis of additional branches:

 After elongation of these two ends has been
accomplished by glycogen synthase, their
terminal five to eight glucosyl residues can
be removed and used to make further
branches
GLYCOGENOLYSIS
DEGRADATION OF GLYCOGEN
(GLYCOGENOLYSIS)
 Thedegradative pathway that
mobilizes stored glycogen in liver
and skeletal muscle is not a
reversal of the synthetic reactions
 Instead,
a separate set of cytosolic
enzymes is required
 When glycogen is degraded, the
primary product is glucose 1-
phosphate obtained by breaking
α(1→4) glycosidic bonds
 Inaddition, free glucose is released
from each α(1→6) linked glucosyl
residue
SHORTENING OF CHAINS
 Glycogen
phosphorylase
sequentially cleaves the
α(1→4) glycosidic
bonds between the
glucosyl residues at the
nonreducing ends of the
glycogen chains by
simple phosphorolysis
until four glucosyl units
remain on each chain
before a branch point
 Thisenzyme contains a molecule
of covalently bound pyridoxal
phosphate that is required as a
coenzyme
 Theresulting structure is called a
limit dextrin, and phosphorylase
cannot degrade it any further
REMOVAL OF BRANCHES
 Branches are
removed by two
enzymic activities
 First, oligo- α(1→4)
→ α(1→4) glucan
transferase removes
the outer three of the
four glucosyl residues
attached at a branch
 It
next transfers them to the
non-reducing end of another
chain, lengthening it
accordingly
 Thus,
an α(1→4) bond is
broken and an α(1→4) bond is
made
 Next, the remaining
single glucose
residue attached in
an α(1→6) linkage
is removed
hydrolytically by
amylo-α(1→6)
glucosidase
activity, releasing
free glucose
 Boththe transferase and glucosidase
are domains of a single polypeptide
molecule, the "debranching enzyme

 The glucosyl chain is now available

again for degradation by glycogen
phosphorylase until four glucosyl
units from the next branch are reached
CONVERSION OF GLUCOSE 1-PHOSPHATE
TO GLUCOSE 6-PHOSPHATE
 Glucose 1 -phosphate,
produced by glycogen
phosphorylase, is
converted in the
cytosol to glucose 6-
phosphate by
phosphoglucomutase
- a reaction that
produces glucose 1,6-
bisphosphate as a
temporary but essential
intermediate
 In the liver, glucose 6-
phosphate is translocated
into the endoplasmic
reticulum(ER) by glucose
6-phosphate translocase
 There it is converted to
glucose by glucose 6-
phosphatase—the same
enzyme used in the last
step of gluconeogenesis
 The resulting glucose is
then transported out of
the ER to the cytosol
 Hepatocytes
release glycogen-
derived glucose
into the blood to
help maintain
blood glucose
levels until the
gluconeogenic
pathway is
actively producing
glucose
 In the muscle,
glucose 6-phosphate
cannot be
dephosphorylated
because of a lack of
glucose 6-
phosphatase
 Instead, it enters
glycolysis, providing
energy needed for
muscle contraction
GLYCOGEN STORAGE DISEASES
 These are a group of genetic diseases that
result from a defect in an enzyme required for
glycogen synthesis or degradation
 They result either in formation of glycogen
that has an abnormal structure, or in the
accumulation of excessive amounts of normal
glycogen in specific tissues as a result of
impaired degradation
 A particular enzyme may be defective in a
single tissue, such as the liver, or the defect
may be more generalized, affecting liver,
muscle, kidney, intestine, and myocardium
 The severity of the glycogen storage diseases
(GSDs) ranges from fatal in infancy to mild
disorders that are not life-threatening
 Some of the more prevalent GSDs are
illustrated
REGULATION OF GLYCOGEN SYNTHESIS AND
DEGRADATION
 The regulation of glycogen synthesis in different tissues matches
the function of glycogen in each tissue
 Liver glycogen serves principally for the support of blood
glucose during fasting or during extreme need (e.g., exercise),
and the degradative and biosynthetic pathways are regulated
principally by changes in the insulin/glucagon ratio and by
blood glucose levels, which reflect the availability of dietary
glucose
 Degradation of liver glycogen is also
activated by epinephrine, which is
released in response to exercise,
hypoglycemia, or other stress situations
in which there is an immediate demand
for blood glucose
 In contrast, in skeletal muscles, glycogen
is a reservoir of glucosyl units for the
generation of ATP from glycolysis and
glucose oxidation
 As a consequence, muscle glycogenolysis
is regulated principally by AMP, which
signals a lack of ATP, and by Ca2+ released
during contraction
 Epinephrine, which is released in response
to exercise and other stress situations, also
activates skeletal muscle glycogenolysis
 The glycogen stores of resting muscle
decrease very little during fasting