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Glycogenesis

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Deepak Kumar Audesh Bhat

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In: Carbohydrate Metabolism ISBN: 978-1-53612-907-6
Editor: Shashank Kumar © 2017 Nova Science Publishers, Inc.

Chapter 8

GLYCOGENESIS

Audesh Bhat1, PhD and Deepak Kumar2,, PhD

1
Centre for Molecular Biology, Central University of Jammu,
Jammu, India
2
Department of Botany, Central University of Jammu,
Jammu, India

ABSTRACT
The glycogen metabolism plays a key role in the maintenance of
glucose level in the body. It includes two major processes; one is the
synthesis of glycogen from glucose through two independent processes
known as glycogenesis and glyconeogenesis depending upon the source
of the glucose and second is the breakdown of glycogen known as
glycogenolysis. Both glycogen synthesis and its breakdown are
reciprocally controlled, which involves three hormones; insulin, glucagon
and epinephrine and several allostearic factors. This reciprocal regulation
ensures a steady supply of glucose, a primary molecule used for the
production of energy molecule ATP. Under the condition of high blood
glucose levels, the excessive glucose is converted into glycogen mainly in
the muscle and liver cells, which acts as the two major sources of stored
glycogen in animals. Insulin, which is produced by the β-cells of the
pancreas, plays a key role in this process as it facilitates the uptake of
glucose, promotes glycogenesis and inhibits glyconeogenesis. Therefore,


Corresponding Author Email: [email protected] [email protected].

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132 Audesh Bhat and Deepak Kumar

any alteration either in its production or sensitivity leads to metabolic

disorders such as diabetes. In this chapter we will discuss the various
aspects of glycogen such as its synthesis, structure, function, regulation,
and disorders due to abnormal glycogen metabolism.

INTRODUCTION
All living organisms need energy to carry out the diverse biological
activities in order to survive. This energy is provided by the energy rich
molecule known as adenosine triphosphate (ATP), which is produced from
carbohydrates, proteins, and lipids. Under the conditions of sufficient
supply of ATPs, the processes of glycolysis, glycogeneolysis, and the citric
acid cycle are inhibited, thereby stopping the production of ATPs and
promoting the storage of these macronutrients for future energy needs.
Glycogenesis is one such process that plays an important metabolic role by
converting excessive glucose into glycogen, primarily in the muscle and
liver cells [1]. The process of glycogenesis involves a step-wise addition of
glucose molecules to glycogen chain to build a multi-branched
homopolymer. The multi-branched structure of glycogen provides the
advantage of mobilizing multiple glucose units at a time during the process
of glycogen breakdown known as glycogenolysis. Glycogen is
predominantly stored in the muscle (1-2% fresh weight) and liver cells (up
to 8% fresh weight) and in lower amounts in nearly all the other tissue
cells. In the muscle cells, the process of glycogenesis is stimulated by
insulin by facilitating the uptake of glucose. In the liver cells, insulin is not
required for the transport of glucose; however, it has profound effects on
glucose metabolism in these cells by stimulating glycogenesis and
inhibiting glycogenolysis. The muscle glycogen serves only as a fuel
reserve for the synthesis of ATP during muscle contraction whereas the
liver glycogen is mobilized to maintain the blood glucose concentration,
thus used throughout the body including the central nervous system.

STRUCTURE AND FUNCTIONS OF GLYCOGEN

Glycogen, which serves as a storage form of glucose in animals and
some other organisms was discovered in 1857 by French physiologist
Claude Bernard. Glycogen is a multi-branched homopolysaccharide

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 Glycogenesis 133

formed through a step-wise process of joining glucose molecules through

α(1→4)glycosidic bonds to build the linear chains and through α(1→6)
glycosidic bonds to join the side chains. Each glycogen granule has
glycogenin protein at its core because of the way it is synthesised [2].
Structurally glycogen is similar to amylopectin, a component of starch but
is extensively branched, large and more compact than starch, reaching a
molecular weight of up to 108 Da. Unlike amylopectin (branches after
every 25-30 glucose units), branching in glycogen is more frequent
approximately after every 10 glucose units and are formed by a smaller
numbers of glucose units. Due to structural and chemical similarities with
starch, an analogue of glycogen that serves as energy storage in plants,
glycogen is also known as animal starch. Glycogen is located in the cytosol
of the cell in the form of hydrated granules (three or four parts of water per
part of glycogen) of diameter between 1 to 4 µm and forms complexes
with regulatory proteins and enzymes responsible for its synthesis and
degradation [3].
Glycogen functions as a secondary long-term energy reservoir in
animals that can be mobilized quickly to provide glucose to meet the
energy demand in between meals and during starvation. In animals,
glycogen represents less than 1% of the body’s caloric stores whereas the
triacylglycerols stored in adipose tissue are the most abundant form and
represent the primary energy stores. There are two major stores of
glycogen in animals. One is the liver glycogen, which represents 10% of
the liver weight and second is the muscle glycogen, which represents 1%
of the muscle weight. Although in a higher concentration in the liver, the
glycogen in the muscle is much higher due to greater muscle mass. When
glucose levels fall in the blood, glycogen in the hepatocytes is broken
down into glucose units through glycogenolysis and released into the
blood. This helps to maintain a normal sugar levels in the blood, thus
preventing any hypoglycaemic condition. In the muscle cells, the glucose
produced from glycogen remains within the cell and is used as an energy
source for its own function. This is due to the fact that the muscle cells lack
glucose-6-phosphatase, an enzyme required for the release of glucose into
the blood stream. In the brain, small amount of glycogen is stored
primarily in the astrocytes, which accumulates during sleep and is
mobilized upon waking, suggesting its functional role in the conscious
brain. Glycogen also plays a specialized role in fetal lung type II

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134 Audesh Bhat and Deepak Kumar

pulmonary cells. At about 26 weeks of gestation, type II pulmonary cells

start to accumulate glycogen, which is then used as a major substrate to
synthesize the pulmonary surfactant lipids of which dipalmitoyl-
phosphatidylcholine is the major component.

SYNTHESIS OF GLYCOGEN
The various steps involved in the synthesis of glycogen take place in
the cytosol and require ATP and UTP, besides glucose. The process of
glycogen synthesis begins with the phosphorylation of glucose at C-6
position, thus facilitating the entrance of glucose into a series of metabolic
reactions that culminate in the synthesis of glycogen. As illustrated in
figure 1, glucose first gets converted into glucose-6-phosphate by ATP in
an irreversible enzymatic reaction catalyzed by glucokinase in the liver and
by hexokinase in the muscle and other tissue cells. In the second step,
glucose-6-phosphate is reversibly converted to glucose-1-phosphate by
phosphoglucomutase through glucose- 1,6-bisphosphate intermediate. The
phosphoryl group of the phosphoglucomutase is transferred to C-1 of the
glucose-6-phosphate, resulting in the formation of glucose- 1,6-
bisphosphate. The phosphoryl group at C-6 then gets transferred to the
serine residue of phosphoglucomutase, thus forming glucose-1-phosphate.
The third step involves the conversion of glucose-1-phosphate to active
nucleotide uridine diphosphate glucose (UDP-glucose), the immediate
precursor of glycogen synthesis by uridine triphosphate (UTP) in an
enzymatic reaction catalyzed by glucose-1-phosphate uridylyltransferase
(or UDP-glucose pyrophosphorylase). One molecule of UTP is used in this
step and one molecule of pyrophosphate (PPi) is formed. This PPi gets
quickly hydrolyzed by pyrophosphatase into two molecules of inorganic
phosphate (Pi), thereby rendering the freely reversible reaction into
practically irreversible one. Since UDP-glucose has two phosphoryl bonds,
it is more reactive than glucose and is held more securely in the active site
of the glycosyl transferases. The biogenesis of glycogen from UDP-
glucose involves two enzymes; glycogen synthase and amylo-α(1,4→1,6)-
glucosyl transferase. Glycogen synthase catalyzes the transfer of glycosyl
group of UDP-glucose to the non-reducing ends of a pre-existing
tetrasaccaride composed of four α(1,4)-linked glucosyl residues. The first

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residue of this tetrasaccaride is linked to a specific amino acid tyrosine at

position 194 in a “primer” protein called glycogenin, which has a Mg2+-
dependent autocatalytic activity. The hydroxyl group of this tyrosine is the
site at which the initial glucose unit is attached. The further elongation of
the linear chain is catalyzed by glycogen synthase by transferring glucose
from UDP-glucose to the growing glycogen chain via α(1,4)-glycosidic
linkage. The amylo-α(1,4→1,6)-glucosyl transferase, also known as
branching enzyme (systematic name: 1,4-alpha-D-glucan:1,4-alpha-D-
glucan 6-alpha-D-(1,4-alpha-D-glucano)-transferase) catalyzes the
formation of side chain by breaking the α(1,4) chains and attaching these
broken chains to the carbon atom 6 of a glucose unit, thus attaching a
string of seven glucose units via α(1,6) linkage to the linear glycogen
chain[4]

Figure 1. Steps of glycogenesis pathway.

The mechanism for α(1,4) joining of glucose units is that glycogen

synthase binds to UDP-glucose causing it to break down into an oxonium
ion which can readily add to the 4-hydroxyl group of a glucosyl residue on
the 4 end of the glycogen chain. After every 10 to 14 glucose units, a side
branch with an additional chain of glucose units occurs.

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136 Audesh Bhat and Deepak Kumar

REGULATION OF GLYCOGEN METABOLISM

Glycogen metabolism is under the tight control of different hormones
and allosteric regulators. This regulation ensures that the blood glucose
levels stay normal and that there is no energy wastage. The relationship
between glycogen synthesis and glycogen breakdown is reciprocal, with
factors that enhance synthesis inhibit the breakdown (Figure 2). Both
processes are controlled through a complex mechanism involving allosteric
regulators and three hormones; insulin, glucagon, and epinephrine. The
effects of glucagon, insulin, and epinephine on glycogen metabolism are
summarized in figure 2. Insulin promotes glycogen synthesis by activating
glycogen synthase phosphatase, which in turn converts the inactive form of
glycogen synthase into active form following dephosphorylation. The
active form is converted back to inactive form by the action of glycogen
synthase kinase (GSK). By regulating glycolysis, glycogenesis, and
glyconeogenesis pathways in the liver, insulin lowers blood glucose
concentration [5]. Glucagon and epinephrine on the other hand promote
glycogen breakdown. One of the major control pathways of glycogen
metabolism is the protein kinase A (PKA) mediated varied
phosphorylation of glycogen synthase and glycogen phosphorylase [1, 6].
This is regulated by enzymes that are under the control of hormonal
activity, which in turn is regulated by many factors. Depending upon the
phosphorylation status catalyzed by PKA, a protein kinase activated by
cAMP, both glycogen synthase and glycogen phosphorylase exist in active
and inactive forms that are interconvertible. In contrast to glycogen
phosphorylase, which is active in its phosphorylated form, glycogen
synthase is inactive when phosphorylated. Upon phosphorylation catalyzed
by a large number of kinases, among which GSK3 and casein kinase 1
(CS1) are physiologically the most important ones, the active form of
glycogen synthase known as the I (independent) form is converted to the
inactive or D (dependent) form. In contrast to glycogen synthase, the active
form of glycogen phosphorylase (phosphorylase a) is formed by the
phosphorylation of inactive form (phosphorylase b) at specific serine
residue catalyzed by phosphorylase kinase enzyme. Under high blood
glucose levels, the two main enzymes; glycogen synthase and glycogen
phosphorylase are dephosphorylated, thus initiating the process of
glycogen synthesis. Under stress conditions or low glucose levels,

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 Glycogenesis 137

adrenaline or glucagon is released which bind to their G-protein coupled

receptors resulting in the activation of PKA, thereby promoting the process
of energy generation through glycogen breakdown and inhibiting the
process of glycogen synthesis. This amplifies the effect of activating
glycogen phosphorylase. Known as co-ordinate reciprocal control, this
inhibition is achieved by a similar mechanism as PKA acts to
phosphorylate the enzyme, which lowers the activity. Insulin has an
antagonistic effect to epinephrine signaling via the beta-adrenergic
receptor. Insulin binding to its receptor results in the activation of Akt,
which in turn activates phosphodiesterase (PDE). PDE then inhibits cAMP
action and causes inactivation of PKA, which will cause hormone sensitive
lipase (HSL) to be dephosphorylated and inactivated so that lipolysis and
lipogenesis is not occurring simultaneously.

Figure 2. Regulation of glycogen metabolism. The release of insulin from pancreatic β-

cells and its subsequent binding to the receptor stimulates the pathway of glycogenesis
and inhibits glycogenolysis in part by decreasing the synthesis of cAMP and activation
of phosphoprotein phosphatase. On the other hand, the release of glucagon from
pancreatic α-cells and/or release of epinephrine from the adrenal gland in response to
stress and the subsequent binding of these hormones to their respective receptors
initiate a reaction cascade that results in the conversion of glycogen to glucose 1-
phosphate and the inhibition of glycogenesis.

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138 Audesh Bhat and Deepak Kumar

Besides the hormonal control, glycogen metabolism is also regulated

by several allosteric regulators. Calcium ions and cAMP in the muscle
cells bind to sites on glycogen phosphorylase b (inactive) and promote its
conversion to phosphorylase a (active). Glycogen phosphorylase is
converted back to phosphorylase b under the presence of high levels of
ATP and glucose-6-phosphate, which act as allosteric inhibitors of
glycogen phosphorylase. Similarly, calcium ions inhibit glycogen synthase
indirectly through their activation of PKA. In hepatocytes, glucose is an
allosteric regulator that promotes the inhibition of glycogen phosphorylase.

DISORDERS OF GLYCOGEN METABOLISM

As discussed above, the excessive blood glucose gets converted and
stored as glycogen and when required, these stores are mobilized to meet
the energy demand. Defects in either of these processes cause either
hyperglycemia, a condition of high blood glucose levels or hypoglycemia,
a condition of low blood glucose levels. Disorders affecting glycogen
synthesis are less common than disorders that affect glycogen breakdown.
The most common and highly prevalent disorder associated with abnormal
glycogen metabolism is diabetes, a hyperglycemia condition that is either
caused by insufficient insulin production or failure of cells to respond to
insulin signaling. There are two major sets of disorders associated with
abnormal glycogen metabolism. One set is due to defective glycogen
storage and another due to defective glycogen mobilization. Abnormal
glycogen storage may happen when enzyme of glycolysis or glycogenesis
are affected leading to abnormal cell function, abnormal metabolism and
abnormal glycogen structure. In some inheritable diseases, deficiency of
enzymes of glycolysis, glycogenesis and glycogenolysis lead to abnormal
level of glycogen in the cell. Based on the variation in the levels of
glycogen stored in the muscles and liver, eight types of glycogen storage
disorders have been identified. Type I disorder, also known as Von
Gierke’s disease is caused due to the deficiency of enzyme glucose-6-
phosphatase. This leads to accumulation of glycogen and decrease in its
breakdown in the liver and kidney cells. Type II disorder, also known as
Pompe’s disease is caused by the deficiency of lysosmal α1-4 -glucosidase
(also called as acid maltase), an enzyme that hydrolyzes glycogen in the

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 Glycogenesis 139

lysosomes. This results in the accumulation of glycogen within the cells

containing lysosomes. Type III disorder, also known as limited dextrinosis
or Cori’s syndrome or Forbes diseases is caused due to the deficiency of
glycogen debranching enzyme amylase α1-6 glucosidase. This leads to
excessive branching in glycogen (α1-6 linkage is high but α1-4 linkage is
short) and formation of abnormal glycogen in the liver and muscle cells.
Type IV disorder, also known as amylopectinosis or Andersen’s diseases is
caused by the deficiency of branching enzyme amylo-α(1,4→1,6) glucosyl
transferase. This leads to the synthesis and accumulation of abnormal
glycogen similar to amylopectin with long chain and short branches in the
liver, muscle, and/or other tissues. Type V disorder, also known as
McArdle’s disease is caused due to the deficiency in muscle phosphorylase
(myophosphorylase), leading to increased level of glycogen deposition in
the muscles causing pain during movements. Type VI disorder, also known
as Hers’ disease is caused by the deficiency of phosphoglucomutase,
resulting in decreased concentration of glucose and increased levels of
glycogen in the cells. Type VII disorder, also known as Tarui’s disease is
caused due to the deficiency of phosphofructokinase, an enzyme that
convert fructose-6-phosphate into fructose-1,6-diphosphate. This leads to
increased production of glycogen from glucose-6-phosphate produced
from fructose-6-phosphate. Unlike most other glycogen storage disorders,
Tarui’s disease directly affects glycolysis. Likewise, several other
glycogen metabolism disorders have been identified that are caused due to
liver glycogen stores mobilization failure because of enzyme deficiencies.
This condition is known as hepatomegaly. There are four forms (I, III, VI,
IX) that present with hepatomegaly and short stature. The clinical
phenotype is highly variable in some form such as in form IX due to
hepatic phosphorylase kinase deficiency. In this scenario, hepatomegaly is
absent as the enzyme block occurs prior to glycogen deposition.

ACKNOWLEDGMENT
AB acknowledges Central University of Jammu for providing
necessary infrastructure facilities and the financial support in the form of
Minor Research Grant (No: CUJ/Acad/Proj-CMB/2017/159). DK
acknowledges Central University of Jammu for providing necessary

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 140 Audesh Bhat and Deepak Kumar

infrastructure facilities along with financial support in the form of Minor

Research Grant (No: CUJ/Acad/Proj-PLS/2017/158) and also to SERB,
DST for providing financial support.

REFERENCES
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metabolism. In The Endocrine Pancreas and Regulation of
Metabolism, Cherrington AD and Jefferson LS (eds), Vol. 2, pp.
609–647. New York, NY: Oxford University Press.
[2] Berg, et al., (2012). Biochemistry(7th, International ed.). Freeman, W.
H. p. 650.
[3] Kreitzman, S. N., Coxon, A. Y., Szaz, K. F.(1992). Glycogen
storage: illusions of easy weight loss, excessive weight regain, and
distortions in estimates of body composition. The American Journal
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[4] Newgard, C. B., Hwang, P. K., Fletterick, R. J. (1989). “The family
of glycogen phosphorylases: structure and function.” Critical
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[5] Pessin, J. E., Saltiel, A. R. (2000) Signaling pathways in insulin
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[6] Bollen, M., Keppens, S., Stalmans, W. (1998) Specific features of
glycogen metabolism in the liver. Biochem. J. 336:Pt 119–31.

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