Gluconeogenesis

This PPT contains content of Gluconeogenesis, Steps involved in Gluconeogenesis, (Gluconeogenesis from Pyruvate, Gluconeogenesis from lactate, Gluconeogenesis from amino acids, Gluconeogenesis from glycerol, Gluconeogenesis from Propionate), Regulation and significance of Gluconeogenesis

2. Gluconeogenesis
•The synthesis of glucose from noncarbohydrate
compounds is known as gluconeogenesis.
•The major substrates/precursors for
gluconeogenesisare:gluconeogenesisare:
Pyruvate
Lactate
Glucogenicamino acids
Propionate
Glycerol

3. •It mainly occurs in Cytosol, although some
precursor are produced in the mitochondria.
•It mostly takes place in liver and some extend •It mostly takes place in liver and some extend
in Kidney matrix.

4. Steps involved in Gluconeogenesis
•Gluconeogenesisclosely resembles the reversed
pathway of glycolysis, although it is not the complete
reversal of glycolysis. Essentially, 3 (out of 10) reactions
of glycolysisare irreversible.
•The seven reactions are common for both glycolysis•The seven reactions are common for both glycolysis
and gluconeogenesis. The three irreversible steps of
glycolysisare catalysedby the enzymes, namely
hexokinase, phosphofructokinaseand pyruvate
kinase. These three stages—bypassed by alternate
enzymes specific to gluconeogenesis—are discussed

5. Gluconeogenesisfrom PyruvateGluconeogenesisfrom Pyruvate

6. Conversion of pyruvateto
phosphoenolpyruvate
•Pyruvateis converted to oxaloacetateby “Pyruvate
carboxylase” in presence of ATP, Biotin and CO2.
•Oxaloacetateis synthesized in the mitochondrial matrix,
but due to membrane impermeability, oxaloacetatecannot but due to membrane impermeability, oxaloacetatecannot
diffuse out of the mitochondria. Therefore It is converted
to malateand then transported to the cytosol. Within the
cytosol, oxaloacetateis regenerated.
•It has to be transported to the cytosolto be used in
gluconeogenesis, where the rest of the pathway occurs.

7. •The reversible conversion of oxaloacetateand
malateis catalysedby malatedehydrogenase, an
enzyme present in both mitochondria and cytosol.
•In the cytosol, “phosphoenolpyruvate
carboxykinase” converts oxaloacetateto
phosphoenolpyruvatein presence of GTP and the phosphoenolpyruvatein presence of GTP and the
CO2 is liberated.
•For the conversion of pyruvateto phosphoenol
pyruvate, 2 ATP equivalents are utilized. This is in
contrast to only one ATP that is liberated in
glycolysisfor this reaction.

8. Conversion of fructose 1,6-bisphosphate
to fructose 6-phosphate
•Fructose 1,6-bisphosphateis converted to
Fructose 6-phosphateby
“fructose 1,6-
Fructose 6-phosphateby
“fructose 1,6-
bisphosphatase”
in presence of Mg2+ ions.

9. Conversion of glucose 6-phosphate to
glucose
•Glucose 6-phosphateis converted to Glucose
by “
Glucose 6-phosphatase
”.by “
Glucose 6-phosphatase
”.

10. Gluconeogenesisfrom lactate
(Cori cycle)(Cori cycle)

11. •Lactate produced by active skeletal muscle is a
major precursor for gluconeogenesis. Under
anaerobic conditions, pyruvateis reduced to
lactate by lactate dehydrogenase(LDH)lactate by lactate dehydrogenase(LDH)

12. •Lactate is a metabolic dead end in glycolysis,
since it must be reconverted to pyruvatefor its
further metabolism.
•Due to the absence of enzymes of
gluconeogenesisin muscles, namely: Glucose
6-phosphatase & Fructose 1,6-bisphosphatase, 6-phosphatase & Fructose 1,6-bisphosphatase,
lactate and pyruvateproduced in muscles
cannot be utilisedfor glucose synthesis.

13. •The plasma membrane is freely permeable to
lactate. Lactate is carried from the skeletal muscle
through blood and handed over to liver, where it
is oxidized to pyruvate.
•Pyruvate, so produced, is converted to glucose by
gluconeogenesis, which is then transported to the gluconeogenesis, which is then transported to the
skeletal muscle.
•The cycle involving the synthesis of glucose in
liver from the skeletal muscle lactate and the
reuse of glucose thus synthesized by the muscle
for energy purpose is known as Cori cycle.

14. Cori Cycle (Lactic Acid Cycle)
LIVER
Glucose
MUSCLE
Glucose
GlycolysisGluconeogenesis
Pyruvate
Lactate
Pyruvate
Lactate
GlycolysisGluconeogenesis
Lactate
Dehydrogenase
Lactate
Dehydrogenase
NAD+
NADH + H+
NADH + H+
NAD+

15. Gluconeogenesisfrom amino acidsGluconeogenesisfrom amino acids

16. •The glucogenicamino acids (all except leucine
and lysine) results in the formation of
pyruvateor the intermediates of citric acid
cycle.cycle.
•Which, ultimately, result in the synthesis of
glucose.

18. Gluconeogenesisfrom glycerolGluconeogenesisfrom glycerol

19. GlycerolGlycerol 3-phosphateDihydroxyacetone
phosphate.
•“Glycerokinase”
converts Glycerolto Glycerol 3-
phosphate.
•“Glycerol 3-phosphate dehydrogenase”
convertsGlycerol
•“Glycerol 3-phosphate dehydrogenase”
convertsGlycerol
3-phosphateto Dihydroxyacetonephosphate.
•Dihydroxyacetonephosphate is an intermediate in
glycolysiswhich can be conveniently used for glucose
production.

20. Gluconeogenesisfrom PropionateGluconeogenesisfrom Propionate

21. •Oxidation of odd chain fatty acids and the breakdown
of some amino acids (methionine, isoleucine) yields
PropionylCoA.
•PropionylCoAMethyl MalonylCoASuccinylCoA
•“PropionylCoAcarboxylase” converts PropionlyCOA
to Methyl MalonylCoAin presence of ATP and biotin.to Methyl MalonylCoAin presence of ATP and biotin.
•“B12 coenzyme” converts Methyl MalonylCoAto
SuccinylCoA.
•SuccinylCoAformed from PropionylCoAenters
gluconeogenesisvia Citric Acid Cycle.

22. Regulation of Gluconeogenesis
•Enzymes of gluconeogenesisare subjected to allostericregulation and
hormonal regulation. Pyruvatecarboxylaseand fructose 1, 6
biphosphataseregulate gluconeogenesisallosterically. Whereas, all the
key enzymes of gluconeogenesisare under hormonal Control
•Hormonal regulation: Insulin decreases the synthesis of key enzymes of
gluconeogenesis, thus inhibiting gluconeogenesis, whereas glucagon gluconeogenesis, thus inhibiting gluconeogenesis, whereas glucagon
and glucocorticoidfavourgluconeogenesis.
•Allostericregulation: Pyruvatecarboxylaseis an allostericenzyme,
acetyl CoAis its activator. Supply of glucose and fatty acid oxidation
generates acetyl CoA, this in turn activates the gluconeogenesis.
Fructose 1,6 biphosphataseis another allostericenzyme. AMP is its
allostericinhibitor. So when there is an energy crisis gluconeogenesisis
inhibited due to binding of AMP to F 1,6 biphosphatase.

23. Significance
•The major metabolic significance of gluconeogenesisis
the maintenance of blood glucose levels, especially in
starvation.
•The glycogen storage gets depleted in 12-18 of
prolonged starvation. This process enhances lipolysisprolonged starvation. This process enhances lipolysis
and protein catabolism so that blood glucose level is
maintained to normal

24. References:
•Biochemistry 5
th
Edition by Dr. U. Satyanarayana& Dr. U. Chakrapani
•Harper’s Illustrated Biochemistry, twenty-sixth edition by Robert K. Murray, Daryl K. Granner, Peter A. Mayes &
Victor W. Rodwell
•Lehninger, Principle of Biochemistry, Fourth edition by David L. Nelson and Michael M. Cox