Gluconeogenesis is the pathway by which organisms synthesize glucose from non-carbohydrate precursors like lactate, pyruvate, glycerol, and certain amino acids. This occurs mainly in the liver and to a lesser extent in the kidneys. While some steps are reversible versions of glycolysis, three irreversible steps of glycolysis are bypassed. Specifically, pyruvate is converted to oxaloacetate then phosphoenolpyruvate through carboxylation and decarboxylation reactions requiring ATP and GTP. This generates free glucose which is an important control point, as glucose-6-phosphate is typically further processed rather than released as free glucose except in a few tissues.

1. C H O M E TA B O L I S M
GLUCONEOGENESIS

2. In mammals, some tissues depend almost completely on glucose
for their metabolic energy
The brain alone requires about 120 g of glucose each day—more
than half of all the glucose stored as glycogen in muscle and liver.
However, the supply of glucose from these stores is not always
sufficient; between meals and during longer fasts, or after vigorous
exercise, glycogen is depleted.
For these times, organisms need a method for synthesizing
glucose from non-carbohydrate precursors. This is accomplished
by a pathway called…..
gluconeogenesis (“formation of new sugar”)

3. The important precursors of glucose in animals are three-carbon
compounds such as lactate, pyruvate, and glycerol, as well as
certain amino acids
In mammals, gluconeogenesis takes place mainly in the liver, and
to a lesser extent in renal cortex.

4. Gluconeogenesis and
glycolysis are not identical
pathways running in opposite
directions, although they do
share several steps
seven of the ten enzymatic reactions
of gluconeogenesis are the reverse
of glycolytic reactions.
In glycolysis, glucose is
converted into pyruvate; in
gluconeogenesis, pyruvate is
converted into glucose

5. However, three reactions of glycolysis are essentially irreversible
in vivo and cannot be used in gluconeogenesis:
• the conversion of glucose to glucose 6-phosphate by hexokinase,
•the phosphorylation of fructose 6-phosphate to fructose 1,6-
bisphosphate by phosphofructokinase-1,
•the conversion of phosphoenolpyruvate to pyruvate by pyruvate
kinase.
In gluconeogenesis, the three irreversible
steps are bypassed by a separate set of
enzymes

6. Conversion of Pyruvate to Phosphoenolpyruvate
This reaction cannot
occur by reversal of the
pyruvate kinase reaction
of glycolysis
• The carboxylation of pyruvate to form oxaloacetate at the expense
of a molecule of ATP.
• Then, oxaloacetate is decarboxylated and phosphorylated to yield
phosphoenolpyruvate, at the expense of the highphosphoryl-transfer
potential of GTP.

7. The first reaction is catalyzed by pyruvate carboxylase and the
second by phosphoenolpyruvate carboxykinase. The sum of these
reactions is:
Oxaloacetate Is Shuttled into the Cytosol and Converted into
Phosphoenolpyruvate
Pyruvate carboxylase is a mitochondrial enzyme, whereas the
other enzymes of gluconeogenesis are cytoplasmic.
Oxaloacetate, the product of the pyruvate carboxylase reaction, is
reduced to malate inside the mitochondrion for transport to the
cytosol.
cont….

8. 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.
Finally, oxaloacetate is simultaneously decarboxylated and
phosphorylated by phosphoenolpyruvate carboxykinase in the
cytosol.
The CO2 that was added to pyruvate by pyruvate carboxylase
comes off in this step.

9. The Conversion of Fructose 1,6-bisphosphate into Fructose 6-phosphate
The Generation of Free Glucose Is an Important Control Point
 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 (notably to form glycogen).
Generation of glucose does not take place in the cytosol, rather,
glucose 6-phosphate is transported into the lumen of the endoplasmic
reticulum, where it is hydrolyzed to glucose by glucose 6-
phosphatase.