Gluconeogenesis is a metabolic pathway
occurring in living beings for synthesis of
glucose from non-carbohydrate precursors. It
converts pyruvate and its related three- and
four-carbon compounds into glucose. It is an
irreversible process . It occurs in cytosol.
CONVERSION OF PYRUVATETO PHOSPHOENOL
Pyruvate is transported from cytosol to
mitochondria or generated from alanine by
transamination within mitochondria.Then, pyruvate
carboxylase, an enzyme that uses biotin as a co-
enzyme; converts pyruvate to oxaloacetate.
PYRUVATE + HCO₃⁻ + ATP OXALOACETATE + ADP +
Because mitochondrial membrane has no
transporter for oxaloacetate, so pyruvate is reduced to
malate by malate dehydrogenase at the expense of
OXALOACETATE + NADH + H⁺ ↔ L-MALATE + NAD⁺
Malate leaves the mitochondrion through a
specific transporter in the inner mitochondrial
membrane and in cytosol, it is re-oxidised to
oxaloacetate, with the production of cytosolic
MALATE + NAD⁺OXALOACETATE + NADH + H⁺
The oxaloacetate is then converted to PEP by
OXALOACETATE + GTP ↔PEP + CO₂ + GDP
CONVERSION OF PEPTO 2-PHOSPHOGLYCERATE-
This step is reverse of the step in glycolysis. This
reaction is performed by Enolase.
CONVERSION OF 2-PHOSPHOGLYCERATETO 3-
This step is also reverse of the step in glycolysis. This
step is catalyzed by the enzyme Phosphoglycerate
CONVERSION OF 3-PHOSPHOGLYCERATE TO 1,3-
This step is reverse of the step in glycolysis as well.
This step is catalyzed by Phosphoglycerate Kinase.
REDUCTION OF 1,3 BISPHOSPHOGLYCERATETO
This step is reverse of the step in glycolysis. In this
step, 1,3-Bisphosphoglycerate is reduced to
Glyceraldehyde-3-phosphate by the enzyme
Glyceraldehyde 3-phosphate dehydrogenase.
INTERCONVERSION OFTRIOSE PHOSPHATES-
This step is reverse of the step in glycolysis. The
Glyceraldehyde 3-phosphate is interconverted to
Dihydroxyacetone phosphate byTriose isomerase
CONVERSION OF DIHYDROXYACETONE
PHOSPHATE TO FRUCTOSE 1,6-BISPHOSPHATE-
This step is also reverse of the step in glycolysis.
This step is performed by the enzyme Fructose 1,6
CONVERSION OF FRUCTOSE 1,6
BISPHOSPHATETO FRUCTOSE 6- PHOSPHATE –
This is an irreversible step where Fructose 1,6
Bisphosphate is converted to Fructose 6- Phosphate
by the Mg⁺⁺-dependent enzyme, Fructose 1,6
Bisphosphatase which promotes the hydrolysis of
the C-1 phosphate.
Fructose 1,6 Bisphosphate + H₂O Fructose 6-
Phosphate + Pi
CONVERSION OF FRUCTOSE 6-PHOSPHATE TO
GLUCOSE 6-PHOSPHATE –
This step is reverse of the step in glycolysis.This
reversible conversion of a ketose to an aldose is
done by the enzyme Phosphohexose Isomerase.
CONVERSION OF GLUCOSE 6- PHOSPHATE TO
It is the final reaction of gluconeogenesis where
Glucose 6-Phosphate is dephosphorylated to yield
Glucose by another Mg⁺⁺-dependent enzyme
Glucose 6-Phosphate + H₂O Glucose + Pi
THE THREE BYPASS REACTIONS
Almost all the steps of Gluconeogenesis are
reverse of Glycolysis except three reactions-
1. CONVERSION OF PYRUVATETO PHOSPHOENOL
2. CONVERSION OF FRUCTOSE 1,6 BISPHOSPHATETO
FRUCTOSE 6- PHOSPHATE
3. CONVERSION OF GLUCOSE 6- PHOSPHATETO
Here a different set of enzymes are utilized than
Glycolysis and are characterized by a large –ve free
energy change, ∆G whereas in the other reactions, the
value of ∆G is near to 0.
There are 3 steps involved in regulation of
1. CONVERSION OF PYRUVATE TO
When the cell’s energy need is being met,
oxidative phosphorylation slows down,
NADH:NAD⁺ rises and inhibits citric acid cycle
due to which Acetyl-CoA accumulates. Since
Acetyl-CoA is an positive allosteric modulator
of Pyruvate Carboxylase, it stimulates
gluconeogenesis and increases the formation of
glucose from pyruvate.
2. CONVERSION OF FRUCTOSE 1,6-
BISPHOSPHATETO FRUCTOSE 6-
The enzyme FBPase-1 involved in this
reaction is strongly inhibited by AMP. So,
when a high proportion of the cell’s adenylate
is in the form of ATP, gluconeogenesis is
3. HORMONAL REGULATION OF
The hormonal regulation of gluconeogenesis is
mediated by Fructose 2,6-Bisphosphate, an
allosteric effector for the enzyme FBPase-1.The
hormones epinephrine and glucagon decreases
the concentration of Fructose 2,6-Bisphosphate
by raising cAMP and bringing about
phosphorylation, i.e., inactivation of PFK-2 and
activates FBPase-2 leading to breakdown of
Fructose 2,6-Bisphosphate. Insulin increases the
concentration of Fructose 2,6-Bisphosphate by
Glycogenolysis is a metabolic process by
which glycogen, the primary carbohydrate
stored in the liver and muscle cells of animals, is
broken down into glucose to provide immediate
energy and to maintain blood glucose levels
Glycogen is catabolized by removal of a
glucose monomer through cleavage with
inorganic phosphate to produce glucose-1-
phosphate.This derivative of glucose is then
converted to glucose-6-phosphate, an
intermediate in glycolysis.
It takes place in the muscle and liver
tissues, where glycogen is stored, as a hormonal
response to epinephrine and/or glucagon.
The overall reaction for the 1st step is:
Glycogen (n residues) + Pi ↔ Glycogen (n-1
Here, glycogen phosphorylase cleaves the
bond at the C1 position by substitution of a
phosphoryl group. It breaks down glucose
polymer at [α14] linkages until 4 linked
glucoses are left on the branch.
Pyridoxal phosphate is an important co-
factor in this reaction, as its phosphate group
acts as a general acid catalyst, promoting attack
by Pi on the glycosidic bond.
The second step involves the
enzyme oligo α[1→6] to α[1→4]
glucantransferase or debranching enzyme,
which transfers the three remaining glucose
units to another 1,4 terminal of glycogen,
which exposes the α[1→6] branching point.
The final action of this enzyme is
the hydrolysis of the remaining glucose
attached at the α[1→6] branch point, which
gives one free glucose molecule.
The third and last stage converts G1P
(glucose-1-phosphate) to G6P (glucose-6-
phosphate) through the enzyme
G1P ↔ G6P
Here the enzyme donates a phosphoryl
group to C-6 of the substrate and accepts a
phosphoryl group from C-1.
FATES OF GLUCOSE 6 PHOSPHATE
This G6P can enter glycolysis and serve as
an energy source to support muscle
In liver, it releases glucose into blood when
blood glucose level drops.
REGULATION OF GLYCOGEN PHOSPHORYLASE
Glycogen phosphorylase is activated in response
to Glucagon or Epinephrine which raise the
[cAMP] level and activate Protein KinaseA. PKA
phosphorylates and activates Phosphorylase
Kinase, which converts Glycogen Phosphorylase
B to its active A form.
Phosphoprotein Phosphatase 1 reverses the
phosphorylation of Glycogen Phosphorylase A,
Glucose binds to the liver isozyme of Glycogen
Phosphorylase,favoring its dephosphorylation
Lehninger’s principles of Biochemistry by
David L. Nelson and Michael M. Cox
Britannica Online Encyclopaedia