Gluconeogenesis is the synthesis of glucose from non-carbohydrate sources, critical for maintaining glucose supply during starvation, particularly for the brain and red blood cells. Key precursors include lactate, amino acids, and glycerol, with primary gluconeogenic activity occurring in the liver and kidney via a series of enzymatic reactions that convert pyruvate into glucose. The process is regulated by various metabolites, and its rate is influenced by the concentrations of glucose and other precursors.

1. • Is the synthesis of glucose from non carbohydrate
precursors
• This particular process is important because the
brain and red blood cells depend on glucose
• the direct glucose reserves are sufficient to meet
glucose needs for about a day
• During a longer period of starvation, glucose
must be formed from noncarbohydrate sources
Gluconeogenesis

2. • The gluconeogenic pathway converts pyruvate
into glucose
• precursors of glucose are first converted into
pyruvate or enter the pathway and later
intermediates such as oxaloacetate and
dihydroxyacetone phosphate
• The major noncarbohydrate precursors are
lactate, amino acids, and glycerol.

3. • 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
• Amino acids are derived from proteins in the
diet and, during starvation, from the
breakdown of proteins in skeletal muscle

4. • Glyceral is derived from the hydrolysis of
triglycerides in fat cells
• Glycerol may enter either the gluconeogenic or
the glycolytic pathway at dihydroxyacetone
phosphate
• The major site of gluconeogenesis is the liver
• a small amount also takes place in the kidney
• Little gluconeogenesis takes place in the brain,
skeletal muscle, or heart muscle

5. • gluconeogenesis in the liver and kidney helps
to maintain the glucose level in the blood so
that brain and muscle can extract sufficient
glucose from it to meet their metabolic
demands
• Gluconeogenesis is not a reversal of glycolysis

6. Formation of Oxaloacetate and
phosphoenolpyruvate
• The first step in gluconeogenesis is 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 high
phosphoryl-transfer potential of GTP
• Both of these reactions take place inside the
mitochondria
• The first reaction is catalyzed by pyruvate carboxylase
and the second by phosphoenolpyruvate carboxykinase

7. • Biotin in covalently attached to pyruvate
carboxylase and serves as a carrier of
activated CO2
• Pyruvate carboxylase is activated by acetyl-
CoA

8. 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, the
reaction catalyzed by malate dehydrogenase which is
linked to NADH
• When malate has been transported across the
mitochondrial membrane, it is reoxidized to
oxaloacetate by an NAD+ linked malate dehydrogenase
in the cytosol

9. • Finally, oxaloacetate is simultaneously decarboxylated
and phosphorylated by phosphoenolpyruvate
carboxykinase in the cytosol
• Recall that, in glycolysis, the presence of a phosphoryl
group traps the unstable enol isomer of pyruvate as
phosphoenolpyruvate
• In gluconeogenesis, the formation of the unstable enol
is driven by decarboxylation—the oxidation of the
carboxylic acid to CO2—and trapped by the addition of
a phosphate to carbon 2 from GTP
• The enzyme is activated by glucagon and cortisol

10. Conversion of Fructose 1,6-bisphosphate into
Fructose 6-phosphate and Pi Is an Irreversible Step
• 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 1,6-
bisphosphate to fructose 6-phosphate and Pi
• The enzyme responsible for this step is fructose
1,6-bisphosphatase

11. The Generation of Free Glucose
• The fructose 6-phosphate generated by fructose
1,6-bisphosphatase is readily converted into
glucose 6-phosphate
• In most tissues, gluconeogenesis ends here
• Why?
• This final step in the generation of glucose does
not take place in the cytosol.
• glucose 6-phosphate is transported into the
lumen of the endoplasmic reticulum, where it is
hydrolyzed to glucose

12. Regulation and control
• The rate of glycolysis is also determined by the
concentration of glucose, and the rate of
gluconeogenesis is by the concentrations of
lactate and other precursors of glucose
• The interconversion of fructose 6-phosphate
and fructose 1,6-bisphosphate is stringently
controlled
• AMP stimulates phosphofructokinase,
whereas ATP and citrate inhibit it