Gluco Neo Genesis

Gluconeogenesis- Steps,
regulation and significance
Dr. Adnan Riaz

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.
Dr. Adnan Riaz Gluconeogenesis
Substrates of Gluconeogenesis
• The major substrates are the glucogenic amino
acids, lactate and glycerol.
• 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.

•Glycolysis Step

5
Reactions of Gluconeogenesis
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 6-
phosphate from fructose 1,6-bisphosphate)
3. Third bypass (Formation of Glucose by
hydrolysis of glucose 6-phosphate)

6
First bypass (Formation of

Phosphoenolpyruvate from
pyruvate)
• 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.
7
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 CO2 to
pyruvate.

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.

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

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

12
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 6-
phosphate 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.
13
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 homeostasis-
tissues 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.

14
Formation of Glucose by
hydrolysis of glucose 6-
phosphate
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.

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.

16
Reactions of Gluconeogenesis
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 UDP-
glucose (the substrate for glycogen
synthase) by UDP-glucose pyro
phosphorylase, a reaction requiring
hydrolysis of UTP.

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Gluconeogenesis- Steps,

regulation and significance

Dr. Adnan Riaz

Dr. Adnan Riaz Gluconeogenesis

Dr. Adnan Riaz Gluconeogenesis

Dr. Adnan Riaz Gluconeogenesis

First bypass (Formation of

Reaction catalyzed by pyruvate

Dr. Adnan Riaz Gluconeogenesis

Dr. Adnan Riaz Gluconeogenesis

Dr. Adnan Riaz Gluconeogenesis

Dr. Adnan Riaz Gluconeogenesis

Third bypass (Formation of

• The fructose 6-phosphate generated by fructose

Third bypass (Formation of Glucose by

Dr. Adnan Riaz Gluconeogenesis

Dr. Adnan Riaz Gluconeogenesis

The glucose transporter in the endoplasmic

Dr. Adnan Riaz Gluconeogenesis

Dr. Adnan Riaz Gluconeogenesis

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