Slides for educators and students. Can be used for MBBS, BDS, NURSING and general biochemistry classes.

1. Department of Biochemistry, KMC, DuwakotSunday, December
06, 2015
Rajesh Chaudhary 1

2. Sunday, December 06, 2015Rajesh Chaudhary2

3. Gluconeogenesis
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 Gluco: Glucose; Neo: New; Genesis: formation
 Sources: Non carbohydrate
Lactate,
pyruvate,
glycerol, amino
acids,
propionate
Glucose
Brain
Erythrocytes
Other
cells
gluconeogenesis

4. Gluconeogenesis
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Rajesh Chaudhary
How does gluconeogenesis affect a critically
ill patients?

5. 5

6. Blood glucose level regulation
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 Regulated in narrow limit
 Mammals: 4.5 – 5.5 mmol/L
 After carbohydrate diet: 6.5 – 7.2 mmol/L
 In starvation: 3.3 – 3.9 mmol/L
 Sudden decrease in glucose level in blood 
convulsions
 (Reason: Dependence of brain on glucose)
 In birds and ruminants

7. Maintenance of blood glucose level
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 Glucose is formed from two products:
 1. Those that undergo direct net conversion to
glucose including amino acids and propionate.
 2. Product of metabolism of glycolysis: lactate and
pyruvate

8. Maintenance of blood glucose level
(Cori cycle / lactic-acid cycle / glucose-alanine
cycle)
8

9. Energy requirement
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 Pyruvate carboxylase: 1 ATP
 Phosphoenol pyruvate carboxylase: 1 ATP
 Phosphoglycerate kinase: 1 ATP
 I.e. 3 ATP is required for production of ½ molecule of
glucose from 1 pyruvate
 I.e. 6 ATP for 1 glucose molecule.

10. Gluconeogenesis
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 Major gluconeogenic tissues: liver and kidney
 (Kidney contributes total 40% of glucose synthesis during
fasting state.)
 Involves 3 things:
 Glycolysis
 Citric acid cycle / TCA cycle
 Other special reactions
 Barriers: 3 barriers (thermodynamic barriers)
 1. Hexokinase (Step 1)
 2. Phosphofructosekinase (Step 2)
 3. Pyruvate Kinase (Step 3)

11. Gluconeogenesis
Enzymes necessary to overcome energy
barriers
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 1. Pyruvate carboxylase (mitochondrial)
 2. Phosphoenolpyruvate carboxykinase
 3. Fructose-1,6-bisphosphatase
 Present in: Liver & Kidney
 Absent in: Heart & smooth muscles
 4. Glucose-6-phosphatase
 Present in: Liver & Kidney
 Absent in: Muscle & adipose tissues
Cytoplasmic

12. Reactions unique to Gluconeogenesis
1st. Reaction: Carboxylation of Pyruvate
12
Malatedehydrogenase
enzyme

13. Reactions unique to Gluconeogenesis
2nd. Reaction: Transport of Oxaloacetate from
mitochondria to cytosol13
Malatedehydrogenase
enzyme

14. Reactions unique to Gluconeogenesis
3rd. Reaction: Decarboxylation of cytosolic
oxaloacetate
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Malatedehydrogenase
enzyme

15. Reactions unique to Gluconeogenesis
4th. Reaction: Dephosphorylation of fructose 1,6-
bisphosphate
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16. Control of glycolysis and
gluconeogenesis in LIVER16

17. Control of glycolysis and
gluconeogenesis in LIVER
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18. Reactions unique to Gluconeogenesis
5th. Reaction: Dephosphorylation of glucose 6-
phosphate
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 This process requires two proteins:
 1. glucose 6-phosphate translocase
 2. glucose 6-phosphatase (ER enzyme)
 Both of these enzymes are required for
gluconeogenesis as well as glycogenolysis.
 Type 1a glycogen storage disease and deficiency
of glucose 6-phosphatase.

19. Futile Cycle / Substrate cycle
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 When two metabolic pathways runs in opposite
direction at the same time.
 No overall net effect; no net production of ATP.
 In fact, ATP is used up in generating heat.
 Used in hibernating animals to produce heat, in brown
adipose tissues of young animals & to regulated
metabolic pathways.

20. Summary
Regulation of Gluconeogenesis
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Rajesh Chaudhary

21. Regulation of Glycolysis and
Gluconeogenesisgluconeogenesis
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 Both share same pathways (But, in opposite direction)
 Depends on 2 factors & 3 mechanisms:
 1. Substrate
 2. Hormones
 Mechanisms
 1. Change in rate of enzyme synthesis
 2. Covalent modification by reversible phosphorylation
 3. Allosteric effects

22. Regulation of gluconeogenesis
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 A. Glucagon
 1. Changes in allosteric effectors
 2. Covalent modification of enzyme activity
 3. Induction of enzyme synthesis
 B. Substrate availability
 C. Allosteric activation by Acetyl CoA
 D. Allosteric inhibition by AMP

23. Further clinical aspects
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 Glucosuria occurs when the renal threshold for glucose is
exceeded.
 The capacity of the tubular system to reabsorb glucose is
limited to a rate of about 2 mmol/min (350 mg/min).
 Fructose 1,6-bisphosphatase deficiency causes lactic
acidosis and hypoglycemia.
 Impairment of fatty acid oxidation is a cause of
hypoglycemia.

24. References24