Gluconeogenesis & Glycogen 2011

Glucose and Glycogen Metabolism
Reference Text
Timberlake, K. (2009). Chemistry: An introduction to general, organic, and biological chemistry .
10th edn. Pearson Prentice Hall, New Jersey.
 Glycogenesis
 Glycogenolysis
 Gluconeogenesis
2
 A major fate of glucose
in animals is glycogen
synthesis.
 Up to this point we
have looked at burning
glucose for energy.
 This occurs in the “feast
phase” of metabolism.
 Lets look at this process.
 Two stages are present
 A storage (granules) form of glucose in liver and
muscles. Provides approx. 24hrs stable blood
glucose to retain nervous system function.
 A very small amount may be found in kidneys
and intestines. Glycogen stored in the muscles is
not available for other tissues.
Two discrete pathways:

1. Glycogenolysis-
 The catabolism of glycogen
2. Glycogenesis-
 The anabolism of glycogen
 In electron micrographs,
liver glycogen appears
as clusters of cytosolic
granules with a
diameter of 100 nm—
much larger than
ribosomes. The
enzymes required for
synthesis of glycogen
are found in muscle and
liver cells.
 The liver acts as a
central bank lending out
glucose via the
degradation of
glycogen.
 Glycogen forms the major source of energy for
muscular activity.
 But how is this energy released? By what
process?
 Another example of
glycogenolysis occurs
during a fasting state.
 During our sleep (and
between our meals)
our blood glucose
levels need to be
maintained.
The catabolism of glycogen to form glucose molecules.
 This occurs when blood glucose levels fall and is
performed by the liver.
 Glycogen is broken down to glucose-1-phosphate by the
enzyme “glycogen phosphorylase “ .
 Glucose-1-phosphate is broken down to glucose-6-
phosphate by “phosphoglucomutase” (a.k.a. mutase).
 Glucose-6-phosphate can:
1. Enter glycolysis
2. Or…..be converted to glucose (only in liver and
some intestinal cells) and sent to the blood to be
used by other cells. These enzymes are absent in
the muscle cells and the brain. They never want to
give up their glucose!!!
 Its the role of the liver to
provide stable blood sugar
levels between meals or
during strenous exercise.
 The liver acts like a central
bank during a financial crisis
providing sugar when
needed.
 The kidneys and intestine
play a minor role during this
function (less 10%).
 The liver can release sugar as
it is not the primary fuel for
this organ (fatty acids are).
 It does this through a
combination of glycogenolysis
and gluconeogenesis.
 The liver and muscles use glycogenolysis differently
 The liver synthesises glycogen back to glucose-6-phosphatase or
glucose.
 Glucose-6-phosphatase if it needs it for its own energy
 Glucose if it needs to send it to other cells
 This is because glucose-6-phosphatase cannot cross cell membranes, thus
has to be converted back to glucose (which costs energy).
 The liver (kidney cortex and intestinal cells) are the only
organs that have the enzyme glucose-6-phosphatase
which changes glucose-6-phosphate into glucose.
 This is to allow glucose, which can cross the cell membrane, to
be used by other cells (skeletal cells included).
 The liver is not only very efficient at storing glucose as

glycogen, but also at making glycogen back into the
glucose form.
 The muscles, however, cannot convert glucose-
6-phosphate to glucose because it does not have
the enzyme glucose-6-phosphatase.
 The muscles thus can only use their glycogen

stores to convert them to glucose-6-phosphate
which then enters glycolysis.
 They cannot “send” their glucose-6-phosphate to the
blood to be used by other cells. I.e. they do not share
their glycogen stores.
The hormones glucagon and adrenaline stimulate

glycogenolysis.
 What happens when the muscles and liver are
running low on glucose as there glycogen
stores are becoming exhausted???
 Gluco- = glucose
 -neo- = new
 -genesis = making
 i.e. making new glucose from non-glucose sources.
 This occurs from the conversion of non-glucose molecules such as amino

acids and glycerol (from fat).
Occurs predominantly in the cytosol of the cells in the liver. However, it can occur in
small amounts in the cortex of the kidneys.
 Takes place in the liver when the BGLs fall, glycogen is
depleted, and/or glucose is not available.
It is an essential pathway to provide glucose for the brain, the

nervous system and erythrocytes.
 Within a normal day, glycogen stores are sufficient to provide the
glucose needed by the body.
 Gluconeogenesis will start after that period if no carbohydrate foods

are ingested (24hours).
Glucose requirements also increase with strenous exercise. This is

especially true for prolonged efforts.
Once glycogen stores are depleted the liver provides the brain and muscles
with glucose from other sources.
 The gluconeogenic pathway converts pyruvate into glucose. Lactic
acid produced by anaerobic metabolism is converted first into
pyruvate. Therefore, pyruvate is the starting point for this process.
 Major precursors of glucose:

 Amino acids (glucogenic)
 Glycerol
 Others (oxaloacetate )
NOTE: All amino acids except leucine and lysine are glucogenic. During starvation the
body shifts away from amino acids towards glycerol (fat stores) to preserve muscular
tissue. Upon four fold decrease by day 40.
 You cannot re-make the
original precursors for
GNG once they have been
converted to glucose.
These are gone forever
and this can be
metabolically costly!
 This is mainly true for
amino acids used during
this process.
 Gluconeogenesis is NOT an exact
reversal of glycolytic pathway.
 3 steps are different and unique:

1. Pyruvate has to be converted to oxaloacetate
first.
2. Then it is converted to phosphoenolpyruvate
(the last step in glycolysis before pyruvate)
3. The conversion of glucose-6-phosphate to
glucose is not possible in muscle and brain.
 Biotin, magnesium, and manganese are all used in
this pathway. The energy costs to make glucose in
vitro are large.
 Six ATPs are needed for the conversion of

pyruvate to glucose. Only 2ATP are used to make
pyruvate from glucose.
 Glycolysis and GNG are reciprocally controlled.

 The two processes of glycolysis and gluconeogenesis
are not metabolically the same.
 This allows greater control of the processes and

increased biochemical flexibility.
 Produced during anaerobic metabolism by
muscles and erythrocytes.
Why do RBCs produce lactate?
The Cori-cycle
• The production of glucose from lactate
• Lactate is converted to pyruvate then to
glucose
 The synthesis of
glycogen from glucose
molecules (intracellular
polysaccharide).
 This process starts when
glucose enters the cell.
 Glucose molecules are
linked to each other by
the enzyme “glycogen
synthase”.
 After strenous
muscular activity the
body needs to
replenish glycogen
stores.
 It does this through
the glycogenesis
process.
 The first reaction converts excess glucose into glucose-6-phosphate
(hexokinase).
 1 molecule of ATP is needed for this reaction (extremely efficient process)
 Encouraged by the hormone insulin.
 Then glucose-6-phosphate is converted to glucose-1-phospate and then to

uridine-diphosphate glucose and this molecule is attached to the glycogen
molecule by glycogen synthase.
 For details of enzymes, see the diagram on the next page.
 Note that to “start” the glycogen molecule, a protein called “glycogenin”

is used as a “primer”.
 The glucose molecules are linked through α-1, 4
linkages.
 These linkages are catalysed by the enzyme glycogen synthase.
 Glycogen also has α-1, 6 linkages. These occur every 10

to 14 glucose units and are attached by a “branching
enzyme”.
 These α-1, 6 linkages increase the solubility of glycogen.
 ATP:
 One ATP is used for each molecule of glucose added
onto the glycogen.
 Control:
 Glycogenesis forms when the levels of glucose and
ATP are high.
 If both are high, the excess insulin will promote the
formation of glycogen.
 When your glycogen
stores are full- the
body diverts the
excess carbons
towards creating fat
molecules for storage
within adipose cells.
The two processes of glycogenolysis and glycogenesis
are not metabolically the same.
This allows greater control of the processes and

increased biochemical flexibility.

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Glucose and Glycogen Metabolism

Two discrete pathways:

 The liver is not only very efficient at storing glucose as

 The muscles thus can only use their glycogen

The hormones glucagon and adrenaline stimulate

 This occurs from the conversion of non-glucose molecules such as amino

It is an essential pathway to provide glucose for the brain, the

 Gluconeogenesis will start after that period if no carbohydrate foods

Glucose requirements also increase with strenous exercise. This is

 Major precursors of glucose:

 3 steps are different and unique:

 Six ATPs are needed for the conversion of

 Glycolysis and GNG are reciprocally controlled.

 This allows greater control of the processes and

Why do RBCs produce lactate?

 Then glucose-6-phosphate is converted to glucose-1-phospate and then to

 Note that to “start” the glycogen molecule, a protein called “glycogenin”

 Glycogen also has α-1, 6 linkages. These occur every 10

This allows greater control of the processes and

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