Gluconeogenesis is the synthesis of glucose from non-carbohydrate precursors like lactate, glycerol, glucogenic amino acids, and pyruvate. It mainly occurs in the liver and kidney cytosol. The key steps involve converting pyruvate to phosphoenolpyruvate and overcoming the regulation of two irreversible glycolysis reactions through four unique gluconeogenic enzymes. Gluconeogenesis is regulated by hormones like insulin and glucagon that control the activity of the rate-limiting enzymes: glucose-6-phosphatase, fructose-1,6-bisphosphatase, and pyruvate carboxylase.

1. 2016

2. GLUCONEOGENESIS
DR. P.N. Ansil

3. • The synthesis of glucose from non-carbohydrate sources
• Site:
• Occurs mainly in cytosol – some precursors are
produced in mitochondria
• Notable precursors are
 Pyruvate
 Glycerol
 Lactate
 Propionate
 Glucogenic Amino acids
• Mostly takes place in liver (Approx.
1 kg glucose/day) & Kidney

4. Gluconeogenesis Net Reaction:
2 Pyruvate + 4 ATP + 2 GTP + 2 NADH + 2 H+ + 6 H2O
 Glucose + 4 ADP + 2 GDP+ 2 NAD+ + 6 Pi
Glycolysis Net Reaction:
Glucose + 2 ADP + 2 NAD+ + 2 Pi  2 Pyruvate + 2 ATP
+ 2 NADH + 2 H+ + 2 H2O

5. Why do we synthesize glucose?
 Need to maintain glucose levels within a narrow
range in blood.
 Brain, erythrocytes, testes & kidney medulla are
dependent on glucose for continuous supply of energy
 Skeletal muscles in exertion (anaerobic conditions)
use glucose at a rapid rate
 In fasting to meet the basal requirements of the body
for glucose –essential for the survival
 Effectively prevent the accumulation of certain
metabolites in blood. E.g. lactate, glycerol, propionate
etc.

6. PATHWAY
Gluconeogenesis:
 glycolysis going backwards
 3 places differ- control points in
glycolysis
 4 new enzymes (eukaryotes)
 Energy consumed
#3
#10
#1

7. 1, 3

8.  Total 6 ATP needed
 4 needed to
overcome barrier of
production of 2 mol
of PEP
Gluconeogenesis:

9. The Irreversible Steps
1) Pyruvate  PEP; reversing the pyruvate kinase step of glycolysis

10. Malate Shuttle

11. Gluconeogenesis:
 Irreversible steps II & III

12. 2) Fru-1,6-biP  Fru-6-P; reversing the PFK-1 step of glycolysis
 Absent in smooth muscle and heart muscle

13. 3) Glucose-6-P  Glucose; Glucose 6 phosphatase
 Mostly present in liver and kidney
 Absent in muscle and brain

14. Overlook
PFK 1

17. What is the major precursor?
• The major precursor for glucose biosynthesis is
pyruvate

18. What are the sources of pyruvate?
1. LACTATE
• Mostly from muscle.
• Lactate is produced in great quantities during
exertion.
• Lactate is released from the muscles to the blood
and travels to the liver for conversion to pyruvate
and, ultimately to glucose - Cori cycle.

19. Cori Cycle
• In MuscleGlucose
• In Liver
Lactate
Glucose

20. Significance:
• The lactate produced in the muscle is efficiently utilized
• It counteracts lactic acidosis

21. 2. GLUCOGENIC AMINO ACIDS
• Glucose is not readily available in D.M & starvation
• Carbon skeleton of Glucogenic amino acids results
in the formation of pyruvate or the intermediates of
TCA cycle
• It results in the formation of glucose

23. Glucose –Alanine Cycle (Cahill cycle)
• Alanine is transported to liver, transaminated to
pyruvate & converted to glucose glycolytic
pathway pyruvate transaminated to
alanine
• Significance:
• Increase blood sugar level using amino
acids(alanine) in special situations
• Muscle wastage in uncontrolled D.M explained by
this factor

24.  The liver can also use the amino acid
Alanine like Lactate
 Following transamination to pyruvate,
gluconeogenesis allows the liver to
convert it to glucose for secretion into
the blood

25. 3. GLYCEROL

26. • DHAP can be converted to glyceraldehyde-3-P by
triose phosphate isomerase
Glyceraldehyde -3-P
fructose -1,6-bisphosphate
glucose

27. Adipose tissue
Glycerol
Glycerol – 3 phosphate
Dihydroxy acetone-P
Glyceraldehyde-3-P
Gluconeogenesis
Glycerol to Glucose
Lipolysis by hormone dependent LPL
Glyceraldehyde 3 P dehydrogenase
Glycerol kinase
Triose isomerase
Reversal of glycolysis

28. 4. PROPIONYL CoA
• Propionyl CoA enters the pathway via TCA cycle
after conversion to Succinyl CoA
• In humans propionic acid is not synthesized but it
is formed as a metabolic intermediate.
• Eg: formed from oxidation of odd-chain fatty acids

30. Regulation
• RATE LIMITING ENZYMES:
Glucose 6 phosphatase
Fructose 1, 6 bisphosphatase
Pyruvate carboxylase

31. Glucose 6 phosphatase
• Allosteric regulation(metabolites):
glucose (-)
glucose 6 phosphate, acetyl CoA (+)
• Covalent modification(Hormones):
insulin (-)
glucagon (+)

32. Fructose 1, 6 bisphosphatase
• Allosteric regulation(metabolites):
ATP, acetyl coA(citrate) (+)
AMP, ADP, fructose 2,6 bisphosphate(-)
• Covalent modification(Hormones):
insulin (-)
glucagon (+)

33. Pyruvate carboxylase
Allosteric regulation(metabolites):
Acetyl CoA (citrate) (+)
AMP, ADP (-)
Covalent modification(Hormones):
insulin (-)
glucagon, epinephrine (+)

34. Pyruvate can go
“up” or “down”
depending upon
energy needs

35. Reciprocal
Regulation of
glycolysis and
gluconeogenesis

36. Important questions?
1. Define gluconeogenesis? What is its importance? What
are the precursors of glucose. State the steps involved
gluconeogenesis with a special notes on its regulation. (14
Marks)
1. Explain briefly gluconeogenesis? (8 Marks)
2. Define gluconeogenesis? Name the key gluconeogenic
enzymes (3 Marks)