1. Gluconeogenesis

2. What is the Gluconeogenesis?
Gluconeogenesis is making a new glucose from non-carbohydrate precursors
In other words:
Create new glucose from the products of its breakdown
Its main function is to supply blood glucose in cases of carbohydrate deficiency
(fasting, starvation and low carbohydrate diet).

3. Sites for gluconeogenesis
Cytoplasm and mitochondria of liver and kidney tissues due to presence of glucose-6-phosphatase and fructose-1,6-biphosphatase.
The production of glucose is necessary for use as a fuel source by the brain, testes, erythrocytes, kidney medulla, lens and cornea of the eye and exercising muscle.

4. Glycolysis pathway

5. The reactions of gluconeogenesis:
Synthesis of glucose from pyruvate utilizes many of the same enzymes as glycolysis.
Three Glycolytic reactions are essentially irreversible
Hexokinase (or Glucokinase)
Phosphofructokinase
Pyruvate Kinase.
These steps must be by passed in Gluconeogenesis.

6. First Bypass Reaction Convervsion of Pyruvate to Phosphoenolpyruvate
Enzymes involved:
- Pyruvate carboxylase
- PEP carboxykinase

7. In Mitochondria
Pyruvate carboxylase (PC) exists in the mitochondria of liver and kidney but absent in muscle
ATP, biotin, Mn++ and CO2 are required.

8. Transport of Oxaloacetate into cytosol as Malate

9. In cytosol

10. Summary of the first bypass

11. Second bypass reaction Conversion of Fructose 1,6- bisphosphate to Fructose 6-phosphate
The second glycolytic reaction (phosphorylation of fructose 6-phosphate by PFK) is irreversible.
Hence, for gluconeogenesis fructose 6-phosphate must be generated from fructose 1,6-bisphosphate by a different enzyme which is Fructose 1,6-bisphosphatase.
Fructose 1,6-bisphosphatase presents in liver and kidney.
This reaction is also irreversible.
Fructose 1,6-bisphosphate + H2O fructose 6-phosphate + Pi

12. Phosphofructokinase (In Glycolysis):
fructose-6-P + ATP  fructose-1,6-bisP + ADP
Fructose-1,6-bisphosphatase (In Gluconeogenesis):
fructose-1,6-bisP + H2O  fructose-6-P + Pi

13. Third bypass reaction Glucose 6-phosphate to Glucose
Because the hexokinase reaction is irreversible, the final reaction of gluconeogenesis is catalyzed by Glucose 6-phosphatase.
Glucose 6-phosphate + H2O glucose + Pi
Glucose 6-phosphatase is present in the liver, kidney and small intestine but absent in brain and muscle. Thus, glucose produced by gluconeogenesis in the liver, is delivered by the bloodstream to brain and muscle.

14. Hexokinase or Glucokinase (In Glycolysis):
glucose + ATP  glucose-6-phosphate + ADP
Glucose-6-Phosphatase (In Gluconeogenesis):
glucose-6-phosphate + H2O  glucose + Pi

15. Summary of Gluconeogenesis Pathway:
Gluconeogenesis enzyme names in red.
Glycolysis enzyme names in blue.

17. Substrates for gluconeogenesis
1- Lactate (Lactic acid):
In vigorous skeletal muscle activity, large amount of lactic acid produced pass to liver through blood stream converted into pyruvic and lastly to glucose reach muscle again through blood stream to provide energy (Cori cycle).

18. Lactate produced from pyruvate passes via the blood to the liver, where it may be converted to glucose.
The glucose travels back to the muscle to fuel Glycolysis.

19. Substrates for gluconeogenesis
2- Glucogenic amino acids:
Amino acids by deamination can be converted into keto acids as pyruvic, ketoglutaric and oxaloacetic acid.
Proteins are considered as one of the main sources of blood glucose especially after 18 hr due to depletion of liver glycogen.

20. Carbon sources for gluconeogenesis
Glucose-alanine cycle:
Glucose oxidation produces pyruvate which can undergo transamination to alanine in liver. This reaction is catalyzed by alanine transaminase (ALT).
Additionally, during fasting, skeletal muscle protein is degraded yielding high amount of alanine which then enters the blood stream and is transported to the liver.
In liver, alanine is converted back to pyruvate which is then a source of carbon atoms for gluconeogenesis. The newly formed glucose can then enter the blood for delivery back to the muscle.

23. Acetyl CoA can not produce glucose
Acetyl CoA cannot give rise to a net synthesis of glucose. This is due to the irreversible nature of the pyruvate dehydrogenase reaction, which converts pyruvate to acetyl CoA.
Pyruvate dehydrogenase
Pyruvate acetyl CoA + CO2
NAD NADH+H+

24. Importance of gluconeogenesis
1-Maintenance of blood glucose during starvation, fasting and prolonged exercise. 2- Removal of lactic acid. 3- Removal of glycerol produced by lipolysis.