2. Introduction
• The formation of new glucose from non carbohydrate
sources
• Occurs in the liver 90% and 10% in the kidney
• Involves both cytosolic and mitochondria enzymes
• Liver and kidney contains all enzymes of
gluconeogenesis.
• It does not occur in skeletal muscles due to deficiency
of glucose -6-p
• It does not occur in heart muscle, smooth muscles, and
adipose tissues due to deficiency of fructose 1-6 dip
3. Cont.. .
• Important in maintaining blood glucose during a
night fast when glucose levels are low
• The source of glucose for the brain and
erythrocytes
• Erythrocytes cannot use any metabolite but
glucose-no mitochondria; carries out anaerobic
respiration
• Brain can use ketone bodies in absence of glucose
• Gluconeogenesis ensures adequate supply of
glucose to brain and erythrocytes
4. Importance
• Glucose is the only source of energy:
– Nervous system
– Skeletal system
• Glucose is required :
– Adipose tissues: as a source of glycerol
– Mammary gland: as a source of lactose
6. Gluconeogenesis …
• Occurs in all animals, plants, fungi and
microbes
• Occurs largely in the liver; some in
renal cortex
• Of 10 enzymatic steps, 7 are reversals
of glycolytic reactions
7. Glucogenic precursors
• Lactate from fermentation of red blood cells
and muscles
• Glycerol from degradation of fats in adipose
tissues
• Glycogenic amino acids (Alanine & Aspartate)
NB. Acetyl CoA is not a glucogenic precursor in
animals but in plants and other microorganisms
as animals do not have a glyoxalate pathway
• Only two A.As are solely ketogenic i.e. cannot
give you glucose- lysine & leucine
14. First bypass step is
generation of PEP
from pyruvate via
oxaloacetate
*Note: Oxaloacetate can
not cross the mito
membrane barrier.
In order to cross the
mitochondria membrane,
oxaloacetate must:
1.Be reduced to malate
2.Go through the malate
shuttle
3.Be re-oxidized back to
oxaloacetate
15. Addition of CO2 to pyruvate to form
oxaloacetate
Hydrolysis of ATP
19. Glucose 6-phosphatase removes the
phosphate to liberate free glucose
• This is primarily a function of the liver to buffer
blood glucose levels
• G6Pase is NOT present in brain and muscle!
(Gluconeogenesis does not occur in these tissues)
glucose-6-P + H2O glucose + Pi
G6Pase
20. Liver is the major source of blood
glucose from GN
Is the primary
gluconeogenic organ
Produces glucose for
export to brain, muscle,
RBC’s
Uses many small
metabolites and fatty
acids to feed GN
Liver function is highly
sensitive to insulin &
glucagon
21. The Cori Cycle
2 ATP
6 ATP
2
Lactate and glucose shuttle
between active
muscle/RBC and liver
(glucagon/insulin reg.)
Liver gluconeogenesis
buffers the blood
glucose for use by
muscle, RBC’s and brain
(120 g/day)
*Note: the brain fully
oxidizes glucose, so it
does not funnel back
lactate
GN
GL
RBCs
22. The Alanine Cycle
The liver can also use the
amino acid Alanine similarly
to Lactate
Following transamination to
pyruvate, gluconeogenesis
allows the liver to convert it
to glucose for secretion into
the blood
24. Is Gluconeogenesis the Reverse of
Glycolysis?
Glycolysis (2ATPs Consumed)
Glucose Pyruvate
Gluconeogenesis
6ATPs consumed (4ATP +2GTP) costly
25. Not quite because
• Consider the three irreversible reactions of
glycolysis all have -∆G
• If you are reversing them by gluconeogenesis
the energy change would be +∆G which
cannot be overcome
26. Seven common enzymes in both
• Phosphohexose isomerase
• Triose phosphate isomerase
• Phosphoglycerate kinase
• Aldolase
• Glyceraldehyde 3-phospahete
• Phosphoglycerate mutase
• Enolase
27. Glycolysis summary
• Universal takes place in every living cell
• Ancient metabolic pathway elucidated
• 10 enzyme reactions
Glucose Pyruvate
(6C) (3C)
2phases
• Energy investment (5 enzymes, 2 irreversible
rxns, 3 reversible rxns, 2ATPs used)
