Gluconeogenesis Steps Regulation

Gluconeogenesis- Steps,
regulation and significance

Biochemistry For Medics
www.namrata.co

2
Biochemistry for medics

01/24/14

Introduction
• Gluconeogenesis is the process of converting
noncarbohydrate precursors to glucose or
glycogen.
• Gluconeogenesis meets the needs of the body
for glucose when sufficient carbohydrate is not
available from the diet or glycogen reserves.
• A supply of glucose is necessary especially for
the nervous system and erythrocytes.
• Failure of gluconeogenesis is usually fatal.

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Substrates of Gluconeogenesis
• The major substrates are the glucogenic amino
acids, lactate, glycerol, and propionate.
• These noncarbohydrate precursors of glucose
are first converted into pyruvate or enter the
pathway at later intermediates such as
oxaloacetate and dihydroxyacetone phosphate.
• Liver and kidney are the major gluconeogenic
tissues.

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Reactions of Gluconeogenesis
Thermodynamic barriers
• In glycolysis, glucose is converted into pyruvate; in
gluconeogenesis, pyruvate is converted into
glucose.
• However, gluconeogenesis is not a reversal of
glycolysis.
• Three nonequilibrium reactions in glycolysis
catalyzed by hexokinase, phosphofructokinase and
pyruvate kinase are considered thermodynamic
barriers which prevent simple reversal of glycolysis
for glucose synthesis.

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In gluconeogenesis, the following new steps
bypass these virtually irreversible reactions of
glycolysis:
1. First bypass (Formation of
Phosphoenolpyruvate from pyruvate)
2. Second bypass (Formation of Fructose 6phosphate from fructose 1,6-bisphosphate)
3. Third bypass (Formation of Glucose by
hydrolysis of glucose 6-phosphate)

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First bypass (Formation of
Phosphoenolpyruvate from
pyruvate)

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• Reversal of the reaction catalyzed by pyruvate
kinase in glycolysis involves two endothermic
reactions.
• Phosphoenolpyruvate is formed from pyruvate
by way of oxaloacetate through the action of
pyruvate carboxylase and
phosphoenolpyruvate carboxykinase.
• Pyruvate carboxylase is a mitochondrial
enzyme, whereas the other enzymes of
gluconeogenesis are cytoplasmic.

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Reaction catalyzed by pyruvate
carboxylase
• Mitochondrial pyruvate carboxylase catalyzes
the carboxylation of pyruvate to oxaloacetate, an
ATP-requiring reaction in which the vitamin
biotin is the coenzyme.
• Biotin binds CO2 from bicarbonate as
carboxybiotin prior to the addition of the CO 2 to
pyruvate.

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Transportation of Oxaloacetate
• Oxaloacetate, the product of the pyruvate carboxylase
reaction, is reduced to malate inside the mitochondrion for
transport to the cytosol.
• The reduction is accomplished by an NADH-linked malate
dehydrogenase.
• When malate has been transported across the mitochondrial
membrane, it is reoxidized to oxaloacetate by an NAD+-linked
malate dehydrogenase in the cytosol.

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Decarboxylation of oxaloacetate
A second enzyme, phosphoenolpyruvate carboxy
kinase, catalyzes the decarboxylation and
phosphorylation of oxaloacetate to
phosphoenolpyruvate using GTP as the
phosphate donor.

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Decarboxylation of oxaloacetate
Biological Significance
o In liver and kidney, the reaction of succinate
thiokinase in the citric acid cycle produces GTP
(rather than ATP as in other tissues), and this GTP
is used for the reaction of phosphoenolpyruvate
carboxykinase,
o thus providing a link between citric acid cycle
activity and gluconeogenesis, to prevent excessive
removal of oxaloacetate for gluconeogenesis, which
would impair citric acid cycle activity.

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Second bypass (Formation of Fructose
6-phosphate from fructose 1,6bisphosphate)
bisphosphate

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• On formation, phosphoenolpyruvate is
metabolized by the enzymes of glycolysis but
in the reverse direction.
• These reactions are near equilibrium under
intracellular conditions; so, when conditions
favor gluconeogenesis, the reverse reactions
will take place until the next irreversible step
is reached.
• This step is the hydrolysis of fructose 1,6bisphosphate to fructose 6-phosphate and Pi.

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Second bypass (Formation of
Fructose 6-phosphate from fructose
1,6-bisphosphate)

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• Fructose 1,6-bisphosphatase catalyzes this exergonic
hydrolysis.
• Its presence determines whether a tissue is capable of
synthesizing glucose (or glycogen) not only from
pyruvate, but also from triose phosphates.
• It is present in liver, kidney, and skeletal muscle, but is
probably absent from heart and smooth muscle.
• Like its glycolytic counterpart, it is an allosteric enzyme
that participates in the regulation of gluconeogenesis.

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Third bypass (Formation of
Glucose by hydrolysis of glucose
6-phosphate)
• The fructose 6-phosphate generated by fructose
1,6-bisphosphatase is readily converted into
glucose 6-phosphate.
• In most tissues, gluconeogenesis ends here. Free
glucose is not generated; rather, the glucose 6phosphate is processed in some other fashion,
notably to form glycogen.
• One advantage to ending gluconeogenesis at
glucose 6-phosphate is that, unlike free glucose,
the molecule cannot diffuse out of the cell.

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Third bypass (Formation of Glucose by
hydrolysis of glucose 6-phosphate)
• To keep glucose inside the cell, the generation of free
glucose is controlled in two ways. First, the enzyme
responsible for the conversion of glucose 6-phosphate into
glucose, glucose 6-phosphatase, is regulated.
• Second, the enzyme is present only in tissues whose
metabolic duty is to maintain blood-glucose homeostasistissues that release glucose into the blood.
• These tissues are the liver and to a lesser extent the
kidney the enzyme is absent in muscle and adipose
tissue, which therefore, cannot export glucose into the
blood stream.

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Formation of Glucose by
hydrolysis of glucose 6phosphate


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o This final step in the generation of glucose does not
take place in the cytosol.
o Rather, glucose 6-phosphate is transported into the
lumen of the endoplasmic reticulum, where it is
hydrolyzed to glucose by glucose 6-phosphatase,
which is bound to the membrane.
o An associated Ca2+binding stabilizing protein is
essential for phosphatase activity.
o Glucose and Pi are then shuttled back to the cytosol
by a pair of transporters.

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Formation of Glucose by hydrolysis of
glucose 6-phosphate

The glucose transporter in the endoplasmic
reticulum membrane is like those found in the
plasma membrane.

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oIn the kidney, muscle and
especially the liver, G6P be shunted
toward glycogen if blood glucose
levels are adequate.
oThe reactions necessary for
glycogen synthesis are an alternate
bypass series of reactions
o The G6P produced from
gluconeogenesis can be converted
to glucose-1-phosphate (G1P) by
phosphoglucose mutase (PGM).
o G1P is then converted to UDPglucose (the substrate for glycogen
synthase) by UDP-glucose pyro
phosphorylase, a reaction requiring
hydrolysis of UTP.

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Energetics of gluconeogenesis
• Six nucleotide triphosphate molecules are hydrolyzed to
synthesize glucose from pyruvate in gluconeogenesis,
whereas only two molecules of ATP are generated in
glycolysis in the conversion of glucose into pyruvate.
• Thus it is not a simple reversal of glycolysis but it is
energetically an expensive affair.
• The overall reaction of gluconeogenesis is-

The overall reaction of glycolysis is-

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Substrates of Gluconeogenesis
The major substrates are the glucogenic amino
acids, lactate, glycerol, and propionate.
A)Glucogenic amino acids- Amino acids are
derived from the dietary proteins, tissue proteins
or from the breakdown of skeletal muscle
proteins during starvation.
After transamination or deamination, glucogenic
amino acids yield either pyruvate or
intermediates of the citric acid cycle.

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Glucogenic amino acids
• Amino acids that are degraded to pyruvate, αketoglutarate, succinyl CoA, fumarate, or oxaloacetate
are termed glucogenic amino acids. The net synthesis of
glucose from these amino acids is feasible because
these citric acid cycle intermediates and pyruvate can be
converted into phosphoenolpyruvate.
• Amino acids that are degraded to acetyl CoA or
Acetoacetyl CoA are termed ketogenic amino acids
because they can give rise to ketone bodies or fatty
acids.

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Entry of glucogenic amino acids
1) Pyruvate is the point of entry for alanine,
serine, cysteine, glycine, Threonine, and
tryptophan
2) Oxalo acetate- Aspartate and Asparagine are
converted into oxaloacetate, a citric acid cycle
intermediate. Aspartate, a four-carbon amino
acid, is directly transaminated to oxaloacetate.
3) α-Ketoglutarate is the point of entry of several
five-carbon amino acids that are first converted
into glutamate.

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The entry of glucogenic amino acids
4) Succinyl CoA is a point of
entry for some of the
carbon atoms of
methionine, isoleucine, and
valine. Propionyl CoA and
then Methylmalonyl CoA
are intermediates in the
breakdown of these three
nonpolar amino acids.
5) Fumarate is the point of
entry for Aspartate, Phenyl
alanine and Tyrosine.

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Entry of lactate in to the pathway of
gluconeogenesis

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B) Lactate- Lactate is formed by active skeletal
muscle when the rate of glycolysis exceeds the
rate of oxidative metabolism. Lactate is readily
converted into pyruvate by the action of lactate
dehydrogenase.

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gluconeogenesis
Biological Significance
During anaerobic glycolysis in skeletal muscle,
pyruvate is reduced to lactate by lactate
dehydrogenase (LDH). This reaction serves two
critical functions during anaerobic glycolysis.

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gluconeogenesis
Biological Significance (contd.)
o First, in the direction of lactate formation the
LDH reaction requires NADH and yields NAD+
which is then available for use by the
glyceraldehyde-3-phosphate dehydrogenase
reaction of glycolysis.
o These two reactions are, therefore, intimately
coupled during anaerobic glycolysis.

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gluconeogenesis
Biological Significance (contd.)
Secondly, the lactate produced by the LDH
reaction is released to the blood stream and
transported to the liver where it is converted to
glucose. The glucose is then returned to the
blood for use by muscle as an energy source
and to replenish glycogen stores. This cycle is
termed the Cori cycle.

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Cori’s cycle


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• The liver furnishes glucose to contracting skeletal
muscle, which derives ATP from the glycolytic
conversion of glucose into lactate.
• Contracting skeletal muscle supplies lactate to the liver,
which uses it to synthesize glucose.
• These reactions constitute the Cori cycle

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Entry of propionate in to the
pathway of gluconeogenesis

C) Propionate- Propionate is a major precursor of glucose in
ruminants; it enters gluconeogenesis via the citric acid
cycle.
o After esterification with CoA, Propionyl-CoA is carboxylated
to D-Methylmalonyl-CoA, catalyzed by Propionyl-CoA
carboxylase, a biotin-dependent enzyme
o Methylmalonyl-CoA Racemase catalyzes the conversion of
D-Methylmalonyl-CoA to L-Methylmalonyl-CoA, which then
undergoes isomerization to succinyl-CoA catalyzed by
Methylmalonyl-CoA mutase.
o Methylmalonyl CoA Isomerase/ mutase is a vitamin B12
dependent enzyme, and in deficiency methylmalonic acid
is excreted in the urine (methylmalonic aciduria).

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Fate of Propionyl co A


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In non-ruminants, including humans, propionate arises from the
Beta -oxidation of odd-chain fatty acids that occur in ruminant lipids,
as well as the oxidation of isoleucine and the side-chain of
cholesterol, and is a (relatively minor) substrate for
gluconeogenesis.

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Entry of glycerol in to the pathway of
gluconeogenesis
• The hydrolysis of triacylglycerols in fat cells yields
glycerol and fatty acids. Glycerol may enter either the
gluconeogenic or the glycolytic pathway at
Dihydroxyacetone phosphate
• In the fasting state glycerol released from lipolysis of
adipose tissue triacylglycerol is used solely as a
substrate for gluconeogenesis in the liver and kidneys.
• This requires phosphorylation to glycerol-3-phosphate by
glycerol kinase and dehydrogenation to
Dihydroxyacetone phosphate (DHAP) by
glyceraldehyde-3-phosphate dehydrogenase (G3PDH).

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Entry of glycerol in to the pathway of
gluconeogenesis

•

Glycerol kinase is absent in adipose tissue, so glycerol released by hydrolysis of triglycerides can not be utilized for re -esterification, it is a waste
product.

•
•

It is carried through circulation to the liver and is used for gluconeogenesis or glycolysis as the need may be.
In fact adipocytes require a basal level of glycolysis in order to provide them with DHAP as an intermediate in the synthesis of triacylglycerols.

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“It is incorrect to say that fats can
not be converted to glucose”
• Triglycerides (fats) on hydrolysis yield fatty acids and glycerol.
• Even chain fatty acids are not the glucogenic precursors,
• Oxidation of these fatty acids yields enormous amounts of
energy on a molar basis, however, the carbons of the fatty
acids cannot be utilized for net synthesis of glucose.
• The two carbon unit of acetyl-CoA derived from β-oxidation of
fatty acids can be incorporated into the TCA cycle, however,
during the TCA cycle two carbons are lost as CO2.
• Moreover the formation of acetyl CoA from pyruvate is an
irreversible step, thus acetyl CoA can not be converted back
into glucose.

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“It is incorrect to say that fats can
not be converted to glucose”
• Odd chain fatty acids on oxidation produce Propionyl co
A which is a substrate for gluconeogenesis through
formation of succinyl co A.
• Glycerol component of fats can also be utilized for the
formation of glucose through formation of Dihydroxy
acetone phosphate.
• Hence therefore except for even chain fatty acids, the
other fat components are glucogenic, so the above given
statement that “It is incorrect to say that fats can not be
converted to glucose”, is a justified statement.

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Regulation of Gluconeogenesis
• Gluconeogenesis and glycolysis are coordinated
so that within a cell one pathway is relatively
inactive while the other is highly active.
• The amounts and activities of the distinctive
enzymes of each pathway are controlled so that
both pathways are not highly active at the same
time.

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Regulation of Gluconeogenesis

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• Changes in the availability of substrates are
responsible for most changes in metabolism
either directly or indirectly acting via changes in
hormone secretion.
• Three mechanisms are responsible for
regulating the activity of enzymes –
(1)changes in the rate of enzyme synthesis,
(Induction/Repression)
(2)covalent modification by reversible
phosphorylation, and
(3) allosteric effects.

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Induction & Repression of Key
Enzymes
• The amounts and the activities of essential
enzymes are regulated by hormones.
• The enzymes involved catalyze nonequilibrium
(physiologically irreversible) reactions.
• Hormones affect gene expression primarily by
changing the rate of transcription, as well as by
regulating the degradation of mRNA.

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Induction & Repression of Key
Enzymes
• Insulin, which rises subsequent to eating, stimulates the
expression of phosphofructokinase, pyruvate kinase,
and the bifunctional enzyme that makes and degrades
F-2,6-BP.
• Glucagon, which rises during starvation, inhibits the
expression of these enzymes and stimulates instead the
production of two key gluconeogenic enzymes,
phosphoenolpyruvate carboxykinase and fructose 1,6bisphosphatase.
• Transcriptional control in eukaryotes is much slower than
allosteric control; it takes hours or days in contrast with
seconds to minutes.

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2) Covalent Modification by
Reversible Phosphorylation
• It is a rapid process.
• Glucagon and epinephrine, hormones that are
responsive to a decrease in blood glucose, inhibit
glycolysis and stimulate gluconeogenesis in the liver
by increasing the concentration of cAMP.
• This in turn activates cAMP-dependent protein
kinase, leading to the phosphorylation and
inactivation of pyruvate kinase.
• They also affect the concentration of fructose 2,6bisphosphate and therefore glycolysis and
gluconeogenesis are appropriately regulated .

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3) Allosteric Modification
It is an instantaneous process.
a) Role of Acetyl co A
• As an allosteric activator of pyruvate carboxylase
• This means that as acetyl-CoA is formed from pyruvate,
it automatically ensures the provision of oxaloacetate
and, therefore, its further oxidation in the citric acid
cycle, by activating pyruvate carboxylase
• The activation of pyruvate carboxylase and the
reciprocal inhibition of pyruvate dehydrogenase by
acetyl-CoA derived from the oxidation of fatty acids
explain the action of fatty acid oxidation in sparing the
oxidation of pyruvate and in stimulating
gluconeogenesis.

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3) Allosteric Modification(contd.)
B) Role of ATP and AMP
o The interconversion of fructose 6-phosphate and fructose 1,6bisphosphate is stringently controlled
o Phosphofructokinase (phosphofructokinase-1) occupies a key
position in regulating glycolysis and is also subject to feedback
control.
o
AMP stimulates phosphofructokinase, whereas ATP and citrate
inhibit it.
o Fructose 1,6- bisphosphatase, on the other hand, is inhibited by
AMP and activated by citrate.
o
A high level of AMP indicates that the energy charge is low and
signals the need for ATP generation.
o
Conversely, high levels of ATP and citrate indicate that the energy
charge is high and that biosynthetic intermediates are abundant.
Under these conditions, glycolysis is nearly switched off and
gluconeogenesis is promoted.

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Role of ATP and AMP
o The interconversion of phosphoenolpyruvate and
pyruvate also is precisely regulated.
o Pyruvate kinase is controlled by allosteric effectors and
by phosphorylation.
o High levels of ATP and alanine, which signal that the
energy charge is high and that building blocks are
abundant, inhibit the enzyme in liver.
o Likewise, ADP inhibits phosphoenolpyruvate carboxy
kinase.
o Hence, gluconeogenesis is favored when the cell is rich
in biosynthetic precursors and ATP.

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c) Role of Fructose 2,6-Bisphosphate
o The most potent positive allosteric activator of
phosphofructokinase-1 and inhibitor of fructose 1,6bisphosphatase in liver is fructose 2,6-bisphosphate.
o It relieves inhibition of phosphofructokinase-1 by ATP
and increases the affinity for fructose 6-phosphate.
o It inhibits fructose 1,6-bisphosphatase by increasing the
Km for fructose 1,6-bisphosphate
o Its concentration is under both substrate (allosteric) and
hormonal control (covalent modification)

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c) Role of Fructose 2,6-Bisphosphate (contd.)
o Fructose 2,6-bisphosphate is formed by phosphorylation
of fructose 6-phosphate by phosphofructokinase-2.
o The same enzyme protein is also responsible for its
breakdown, since it has fructose 2,6-bisphosphatase
activity.
o This bifunctional enzyme is under the allosteric control
of fructose 6-phosphate, which stimulates the kinase and
inhibits the phosphatase.

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c) Role of Fructose 2,6-Bisphosphate (contd.)
• When there is an abundant supply of glucose, the
concentration of fructose 2,6-bisphosphate increases,
stimulating glycolysis by activating phosphofructokinase-1
and inhibiting fructose 1,6-bisphosphatase.
• In the fasting state, glucagon stimulates the production of
cAMP, activating cAMP-dependent protein kinase, which
in turn inactivates phosphofructokinase-2 and activates
fructose 2,6-bisphosphatase by phosphorylation.
• Hence, gluconeogenesis is stimulated by a decrease in
the concentration of fructose 2,6-bisphosphate, which
inactivates phosphofructokinase-1 and relieves the
inhibition of fructose 1,6-bisphosphatase.

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Reciprocal Regulation of
Gluconeogenesis and Glycolysis in
the Liver

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oGlycolysis and
Gluconeogenesis are
reciprocally regulated .
oWhen glycolysis is on
Gluconeogenesis is turned off
especially in the fed state,
whereas under conditions of
starvation, gluconeogenesis is
fully on and glycolysis is turned
off.
o Both the cycles are never
active at the same pace at the
same time.

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Clinical significance
Alcohol-related hypoglycemia
o It is due to hepatic glycogen
depletion combined with alcoholmediated inhibition of
gluconeogenesis.
o It is most common in
malnourished alcohol abusers
o The implications of alcohol abuse
are due to altered NAD+/NADH
ratio
o Excessive NADH
• inhibits fatty acid oxidation that
provides ATP
• Pyruvate to lactate reaction is
favored depleting supply of
pyruvate for gluconeogenesis.

47

Hypoglycemia in premature and Low
birth weight infants

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o Premature and low-birth-weight babies are more susceptible to
hypoglycemia, since they have little adipose tissue to provide
alternative fuels such as free fatty acids or ketone bodies during the
transition from fetal dependency to the free-living state
o The enzymes of gluconeogenesis may not be completely functional
at this time,
o Little glycerol, which would normally be released from adipose
tissue, is available for gluconeogenesis, but that is not sufficient to
fulfill the energy needs.
o Small for date babies have inadequate glycogen stores as well, so
at the time of need there is diminished outpouring of glucose.
o The situation worsens further due to prematurity since the glycogen
stores are laid in the last months of pregnancy.
o Hence a premature baby has diminished stores and frequently
undergoes hypoglycemia.

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Hypoglycemia in babies of diabetic
mothers
• The growing fetus of a diabetic mother is
exposed to maternal hyperglycemia which leads
to hyperplasia of pancreatic islet cells.
• After delivery the baby fails to suppress the
excessive insulin secretions and develops
hypoglycemia.

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Maternal or fetal hypoglycemia
• Maternal and fetal hypoglycemia may also be
observed during pregnancy,
• fetal glucose consumption increases and there
is a risk of maternal and possibly fetal
hypoglycemia,
• particularly if there are long intervals between
meals or at night.
• Basic reason is imbalance between demand and
supply of glucose

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Role played by kidney in
gluconeogenesis
• During periods of severe hypoglycemia that
occur under conditions of hepatic failure, the
kidney can provide glucose to the blood via
renal gluconeogenesis.
• In the renal cortex, glutamine is the preferred
substance for gluconeogenesis.
• Glutamine is produced in high amounts by
skeletal muscle during periods of fasting as a
means to export the waste nitrogen resulting
from amino acid catabolism.

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gluconeogenesis(contd.)
• Through the actions of transaminases, a mole of waste
ammonia is transferred to α-ketoglutarate via the
glutamate dehydrogenase catalyzed reaction yielding
glutamate.
• Glutamate is then a substrate for glutamine synthetase
which incorporates another mole of waste ammonia
generating glutamine.
• The glutamine is then transported to the kidneys where
the reverse reactions occur liberating the ammonia and
producing α-ketoglutarate which can enter the TCA cycle
and the carbon atoms diverted to gluconeogenesis via
oxaloacetate.

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gluconeogenesis(contd.)
• This process serves two important functions.
• The ammonia (NH3) that is liberated
spontaneously ionizes to ammonium ion (NH 4+)
and is excreted in the urine effectively buffering
the acids in the urine.
• In addition, the glucose that is produced via
gluconeogenesis can provide the brain with
critically needed energy.

53

Summary Chart- Regulation of
Gluconeogenesis

01/24/14

Induction/
Repression

Clinical
Significance

Enzyme

Effect of
substrate
concentration

Allosteric
modification/
Feed back
Inhibition

Pyruvate
carboxylase

Inhibited by high
carbohydrate diet

Activator-Acetyl Induced by
CoA
Glucocorticoids,
glucagon,
Inhibitor
epinephrine
ADP
Repressed by
Insulin

Activity
increases in
Diabetes
Mellitus

Activator-Citrate Induced by
Glucocorticoids,
Inhibitor
glucagon,
AMP, Fr 2,6
epinephrine
bisphosphate
Repressed by
Insulin

Activity
increases in
Diabetes
Mellitus

Stimulated during
fasting
Fructose 1,6 Inhibited by high
bisphosphata carbohydrate diet
se
Stimulated during
fasting

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For further reading

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Gluconeogenesis Steps Regulation

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