Gluconeogenesis is the process for the synthesis of new glucose from the non-carbohydrate precursors. The precursors are as follows:

1. Lactate:- It is generated from pyruvate in glycolysis. It is then transferred to the liver by CORI’s cycle; and then is converted to glucose.
2. Glycerol:- It is formed in the adipose tissue by the hydrolysis of triacylglycerol. The generated glycerol is not used by the adipose tissue due to the poor content of glycerol kinase enzyme. So that’s why, glycerol is transported to liver where it is converted to glucose.
3. Glucogenic amino acid:- The carbon skeleton of glucogenic amino acid is converted into pyruvate which is then converted to glucose.
4. Intermediates of TCA cycle. 

Location:- Gluconeogenesis mainly occurs in the cytosol of the cell. Liver tissue is the main site for gluconeogenesis.

Characteristics of gluconeogenesis

• It involves glycolysis, TCA cycle an some other special reactions.
• Glycolysis and gluconeogenesis share the same pathway but in opposite direction
• Special reactions of gluconeogenesis are catalyzed by following enzymes:

1.  Pyruvate carboxylase
2.  Phospho-enol pyruvate carboxy kinase
3.  Fructose-1,6- bis phosphatase
4.  Glucose-6-phosphatase

Gluconeogenesis Pathway

The pathway for gluconeogenesis is described in below picture.

Special reaction of this pathway occurs in mitochondria.

1. Pyruvate carboxylate is converted to oxaloacetate by enzyme pyruvate carboxylase in presence of ATP, CO2 and vitamin biotin

2. The oxaloacetate in the mitochondria is impermeable to cross the mitochondrial membrane; so it is first converted into malate which leaves the mitochondria and enters the cytosol. The malate in cytosol is then again converted into oxaloacetate.

3. Decarboxylation of cytosolic oxaloacetate to form phospho-enol pyruvate (PEP) through  PEP carboxy kinase enzyme

4. PEP then enter the glycolysis cycle by reverse reaction to form fructose-1,6 bisphosphate

Regulation Of Gluconeogenesis

As glycolysis and gluconeogenesis share same pathway but in opposite direction, so they are regulated reciprocally. The rate of gluconeogenesis depends on-

• Availability of substrates, i.e- Substrate level regulation
• Changes in activity or concentration of some key enzymes; known as enzymatic regulation.

Substrate level regulation:- Gluconeogenesis is stimulated by the flow of its major substrates like:

1. Glycerol is released when the insulin level is low and high levels of glucagon
2. Lactate is produced by muscle during exercise
3. Amino acids are released during low insulin levels.

Hence, gluconeogenesis is stimulated during: fasting, prolonged exercise, high protein diet and during stress.

Enzymatic regulation:-  By four key enzymes

• Pyruvate carboxylase– It is an allosteric enzyme which is stimulated by acetyl-CoA and inhibited by ADP.
• PEP carboxy kinase
• Fructose-1,6 bis phosphatase:- it is allosterically stimulated by cAMD and inhibited by AMD.
• Glucose-6- phosphatase

Significance of Gluconeogenesis

1. Maintains blood glucose level when carbohydrate is not in the diet
2. During long starvation or when glycogen storage is completely depleted; glucose is continue supplied by gluconeogenesis to the brain, lens, cornea, kidney and medulla; as they regularly need glucose as the source of energy
3. It is used to clear products of the metabolism of other tissues from the blood like:- lactates which is produced by muscle and RBCs, glycerol which is produced by adipose tissue.

Multiple choice questions(MCQs)

1. Gluconeogenesis is used for the which type of metabolism?
A. Lipid metabolism

B. Nucleic acid metabolism

C. Carbohydrate metabolism

D. All of the above
2. Where does gluconeogenesis mainly occur?
A. Mitochondria

B. Cytosol

C. Ribosomes

D. Plasma membrane
3. Which process shares the same pathway as gluconeogenesis but in opposite direction?
A. Glycolysis

B. HMP shunt

C. TCA cycle

D. None of the above
4. From where is lactate generated?
A. Glucose

B. Fructose

C. Pyruvate

D. PEP
5. Match the following-
a. Pyruvate carboxylase 1. generated from pyruvate
b. Lactate 2. generated from adipose tissue
c. Glycerol 3. forms pyruvate
d. Glucogenic amino acids 4. converts and forms oxaloacetate
6. Which tissue forms the glycerol?
A. Areolar tissue

B. Epithelium

C. Adipose tissue

D. Elastic tissue
7. Which of the following is the precursor of gluconeogenesis?
A. Lactate

B. Glycerol

C. Intermediates of TCA cycle

D. All of the above
8. Which of the following statement is NOT true?
a. Gluconeogenesis is the process of synthesis of glucose from carbohydrate.
b. Adipose tissue forms the glycerol
c. Pyruvate carboxylase convert pyruvate carboxylate to oxaloacetate
d. Gluconeogenesis works opposite to glycolysis
9. Which enzyme catalyze the conversion of pyruvate to oxaloacetate?
A. Glucose-6-phosphate

B. Pyruvate kinase

C. Phopho-enol pyruvate kinase

D. Pyruvate carboxylase
10. When is gluconeogenesis inhibited?
A. Long starvation

B. Exercise

C. Low level of insulin

D. None of the above
11. What is the main function of gluconeogenesis?
A. Maintains blood calcium level

B. Maintain blood glucose level

C. Hydrolysis

D. All of the above
12. Where is pyruvate converted into oxaloacetate?
A. Cytosol

B. Outside the cell

C. Endoplasmic reticulum

D. Mitochondria
13. Which form of energy is required for the decarboxylation of cytosolic oxaloacetate to PEP?
A. ATP

B. ADP

C. GDP

D. NADH
14. Which hormone inhibit the gluconeogenesis?
A. Insulin

B. Glucagon

C. Growth hormone

D. None of the above
15. What stimulates the pyruvate carboxylase enzyme?
A. ATP

B. ADP

C. Acetyl-CoA

D. CO2

ANSWERS

1. Carbohydrate metabolism
2. Cytosol
3. Glycolysis
4. Pyruvate
5. a – 4 b – 1 c – 2 d – 3
6. Adipose tissue
7. All of the above
8. Gluconeogenesis is the process of synthesis of glucose from carbohydrate.
9. Pyruvate carboxylase
10. None of the above
11. Maintains blood glucose level
12. Mitochondria
13. GDP
14. Insulin
15. Acetyl-CoA

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REFERENCE:- Pankaja Naik- Biochemistry; 4^th edition; page no:- 177-182.