2. Presented to:- Sir Shehroz Khan
Presented to:- Benish Nasir Khan
Topic
Gluconeogensis its regulation
and significance
3. Gluoconeogenesis
• Is the formation of glucose from non-
carbohydrate sources e.g lactic acid ,amino
acids , glycerols and propionate.
• Site: liver and kidney.
4. Gluoconeogenesis
• 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
5. Gluoconeogenesis
• Gluconeogenesis begins with various substrates
converted into pyruvate.and this proceed
though what is essentially the reverse of
glycosis(except for a few committed steps).
• 3 and 4-carbon substrates can enter the
gluconeogenesis pathway. Lactate from
anaerobic exercise in skeletal muscle is easily
converted to pyruvate; this happens as part of
the Cori cycle.
6. Gluoconeogenesis
• Oxaloacetate (an intermediate in the citric acid cycle
can also be used for gluconeogenesis. Amino acids,
after their amino group has been removed, feed into
parts of the citric acid cycle, and can thus can generate
glucose in this pathway.
• Fatty acids cannot be turned into glucose, as they are
broken down into the two carbon acetyl CoA.
(However glycerol which is a part of all
triacylglycerides can be used in gluconeogenesis).
7. PHYSIOLOGICAL SIGNIFICANCE OF
GLUCONEOGENESIS
• Gluconeogenesis is particularly important in liver
control of blood glucose homeostasis.
• Gluconeogenesis allows synthesis of glucose for
times when liver glycogen reserves are
substantially depleted; during fasting (before
breakfast) and during starvation.
8. PHYSIOLOGICAL SIGNIFICANCE OF
GLUCONEOGENESIS
• Unlike most tissues, glucose can easily diffuse
out of hepatocytes into the blood.
• Because hepatocytes contain much more of the
glycolysis enzyme glucokinase (KM ~ 10mM)
than hexokinase (KM = 0.1mM) most glucose
synthesised in the liver is unlikely to be
converted to glucose 6-phosphate.
10. • (1) Pyruvate to phosphoenolpyruvate
• Pyruvate is first converted to oxaloacetate by the enzyme
pyruvate carboxylase.
• Oxaloacetate is then converted to phosphoenolpyruvate by
phosphoenolpyruvate carboxykinase.
GLUCONEOGENESIS: ‘By-Pass’ Reactions
COOH
|
C = O
|
CH3
pyruvic acid
COOH
|
C = O
|
CH2
|
COOH
oxaloacetic acid
COOH
|
C – O – PO
||
CH2
phosphoenolpyruvic
acid
CO2
ATP ADP + Pi
GTP GDP
CO2
11. GLUCONEOGENESIS: ‘By-Pass’ Reactions
(2) Fructose 1,6-bisphosphate to Fructose 6-
phosphate
Catalysed by fructose bisphosphatase.
OH
O
CH2O – PO
CH2O – PO
3
2
OH
HOH
H
H
α-D-fructose 1,6-bisphosphate
3
2
OH
O
CH2O – PO
CH2OH
3
2
OH
HOH
H
H
α-D-fructose 6-phosphate
H2O
Pi
12. GLUCONEOGENESIS: ‘By-Pass’ Reactions
(3) Glucose 6-phosphate to glucose
Catalysed by glucose 6-phosphatase.
H2O
Pi
O
CH2OH
HO
OH
OH
OH
α-D-glucose
HH
H
H
H
O
CH2O – PO
HO
OH
OH
OH
HH
H
α-D-glucose 6-phosphate
3
2
H
H
Glucose 6-phosphatase is chiefly found in liver cells where it is
important for producing glucose to ‘top-up’ blood glucose levels.
It is absent in muscle cells.
13. GLUCONEOGENESIS from lactate/pyruvate
The Cori Cycle
Glucose
pyruvate
lactate
Glucose
pyruvate
lactate
blood
blood
Muscle/ Erythrocytes Liver
glycolysis gluconeogenesis
14. Glycerol, from the breakdown of triglycerides can also
provide a raw material for gluconeogenesis.
glycerol glycerol 3-
phosphate
dihydroxyacetone
phosphate
glucose
gluconeogenesis
GLUCONEOGENESIS FROM TRIGLYCERIDES
Acetyl CoA, the main breakdown product of fatty acids,
cannot be used to feed gluconeogenesis.
15. Fructose 2,6-bisphosphate is the most important
regulator of glycolysis and gluconeogenesis.
REGULATION OF GLYCOLYSIS/GLUCONEOGENESIS
Fructose 2,6-bisphosphate is not an intermediate of either
pathway but is synthesised from fructose 6-phosphate by
a dual function enzyme known as phosphofructokinase-
2/fructose 2,6-bisphosphatase.
Fructose 2,6-bisphosphate
stimulates phosphofructokinase activity (glycolysis)
inhibits fructose bisphosphatase activity
(gluconeogenesis)
17. REGULATION OF GLYCOLYSIS/GLUCONEOGENESIS
Reversible phosphorylation of phosphofructokinase-2 /
fructose 2,6-bisphosphatase controls the activity of this
enzyme.
fructose 6-
phosphate
fructose 2,6-bisphosphate
concentration decreases
phosphofructokinase -2
activity inhibited
fructose 2,6-bisphosphatase
activity stimulated by
phosphorylation
Enables
gluconeogenesis
Effects of phosphorylation:
Inhibits
glycolysis
18. REGULATION OF GLYCOLYSIS/GLUCONEOGENESIS
Reversible phosphorylation of phosphofructokinase-2 /
fructose 2,6-bisphosphatase controls the activity of this
enzyme.
fructose 6-
phosphate
fructose 2,6-bisphosphate
concentration increases
phosphofructokinase-2
activity stimulated by
dephosphorylation
fructose 2,6-bisphosphatase
activity inhibited
Inhibits
gluconeogenesis
Stimulates
glycolysis
Effects of dephosphorylation:
19. Regulation of Glycolysis/Gluconeogenesis
Synthesis and degradation of the regulator fructose 2,6-
bisphosphate is controlled by reversible phosphorylation
of the enzyme phosphofructokinase-2 / fructose 2,6-
bisphosphatase by protein kinase A.
Phosphorylation turns on
phosphofructokinase-2 / fructose 2,6-bisphosphatase
activity
Dephosphorylation turns on:
phosphofructokinase-2 / fructose 2,6-bisphosphatase
activity