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GLUCONEOGENESIS
- is the biosynthesis of glucose from non-carbohydrate precursors at liver and kidney (very
small amount). Very little takes place in the brain, heart muscle or skeletal muscles.
- Most excess glucose from diet is stored in liver as glycogen. However glycogen stored in liver is
only a half day supply of glucose to the brain under fasting or starvation conditions.
- Liver can send glucose to various tissues, but not ATP.
-During prolonged fast hepatic glycogen stores are depleted and glucose is formed from precursors
such as lactate, pyruvate, glycerol and keto acids.
Glycerol enters the cycle as Dihydroxyacetone
Lactate is dehydrogenated to pyruvate
amino acids enter as pyruvate or oxaloacetate.
Reactions Unique to Gluconeogenesis
Seven of the reactions of glycolysis are reversible and are used in the synthesis of glucose from
lactate or pyruvate.
However three of the reactions are irreversible and must be bypassed by four alternate reactions
that energetically favor the synthesis of glucose.
A. Carboxylation of Pyruvate
In gluconeogenesis, pyruvate is first carboxylated by pyruvate carboxylase to oxaloacetate
(OAA).
B. transport of Oxaloacetate to the Cytosol
Since gluconeogenesis is carried out in cytosol (enzymes of gluconeogenesis are located in the
cytosol), the mitochondrial product, oxaloacetate, must be transported to cytosol.
However, oxaloacetate is unable to cross the inner mitochondrial membrane directly.
It must first be reduced to malate which can then be transported from the mitochondria to the
cytosol through the malate-aspartate shuttle.
In the cytosol, Malate is reoxidized to oxaloactate
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C. Decarboxylation of Cytosolic Oxaloacetate.
Oxaloacetate is decarboxylated and phosphorylated in the cytosol by PEP-carboxykinase. The
reaction is driven by hydrolysis of GTP
The combined action of pyruvate carboxylase and PEP carboxykinase provides an
energetically favorable pathway from pyruvate to PEP.
PEP then enters the reversed reactions of glycolysis until it forms fructose 1, 6- bisphosphate.
D. Dephosphorylation of fructose 1, 6 bisphosphate
Hydrolysis of fructose 1, 6-bisphosphate by fructose 1, 6-bisphosphatase passes the irreversible
PFK- 1 reaction and provides energetically favorable pathway for the formation of fructose 6-
phosphate.
This reaction is an important regulatory site of gluconeogenesis,
1. Regulation by energy levels within the cell:
Fructose1, 6 bisphosphatase is inhibited by elevated levels of AMP, which signal an energy
poor state in the cell
Conversely high levels of ATP and low concentrations of AMP stimulate gluconeogensis
2. Regulation by fructose 2,6- bisphosphate
Fructose1, 6-bisphosphatase is inhibited by fructose 2, 6-bisphosphate, an allosteric
modifier whose concentration is influenced by the level of circulating glucagons.
E. Dephosphorylation of glucose-6-phosphate
Hydrolysis of glucose 6-phosphate by glucose 6-phosphatase bypasses the irreversible
hexokinase reaction provides energetically favorable pathway for the formation of free glucose,
Glucose 6-phosphatase like pyruvate carboxylase, occurs in liver and kidney, but not in muscle.
Thus muscle cannot provide blood glucose from muscle glycogen.
Advantages of Gluconeogenesis
1) Gluconeogenesis meets the requirements of glucose in the body when carbohydrates are not
available in sufficient amounts.
2) Regulate Blood glucose level
3) Source of energy for Nervous tissue and Erythrocytes
4) Maintains level of intermediates of TCA cycle
5) Clear the products of metabolism of other tissues (Muscle)
Regulation of gluconeogenesis
1. Fructose-1,6-Bisphosphatase
• Allosterically regulated in a fashion opposite to phosphofructokinase.
• Fructose-2,6-bisphosphate (F-2,6-BP) inhibits
• High energy state (high ATP, citrate) stimulates the phosphatase and gluconeogensis.
• Low energy state (high AMP, low citrate) stimulates PFK and glycolysis.
• Hormonal regulation acts through F-2,6-BP.
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Hormonal Regulation of F-2.6-Bisphosphatase
• F-2,6-BP made by PFK-2 and F-2,6-BP degraded by F-2,6-BPase
• Both activities are on the same protein ie A bifunctional enzyme
• Hormonal stimulation results in phosphorylation of this protein.
In liver, phosphorylation activates F-2,6-BPase,inhibits PFK-2. (stimulating gluconeogenesis)
• In muscle, phosphorylation activates PFK-2, inhibits F-2,6-Bpase. (stimulating glycolysis)
2. Regulation of Hexokinase and Glucose-6-phosphatase
• Hexokinase is inhibited by glucose-6-phosphate
Glucose-6-phosphatase has a high Km for glucose-6-phosphate. Therefore gluconeogenesis
is favored by high concentrations of glucose-6-phosphate.
3. Regulation of pyruvate carboxylase and PEP carboxykinase
High acetyl-CoA stimulates the enzyme and favors pyruvate to oxaloacetate, either for
increased TCA activity or increased gluconeogenesis.
When acetyl-CoA is low, pyruvate is broken down by pyruvate dehydrogenase to form
more acetyl co A. (Low acetyl-CoA favors breakdown of PEP and pyruvate to form acetyl-
CoA). This does not favour gluconeogenesis.
High levels of GTP (equivalent to ATP) favour the formation of PEP from oxaloacetate
and consequently favouring gluconeogenesis.
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Gluconeogenesis pathway

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GLUCONEOGENESIS - is the biosynthesis of glucose from non-carbohydrate precursors at liver and kidney (very small amount). Very little takes place in the brain, heart muscle or skeletal muscles. - Most excess glucose from diet is stored in liver as glycogen. However glycogen stored in liver is only a half day supply of glucose to the brain under fasting or starvation conditions. - Liver can send glucose to various tissues, but not ATP. -During prolonged fast hepatic glycogen stores are depleted and glucose is formed from precursors such as lactate, pyruvate, glycerol and keto acids. • Glycerol enters the cycle as Dihydroxyacetone • • Lactate is dehydrogenated to pyruvate amino acids enter as pyruvate or oxaloacetate. Reactions Unique to Gluconeogenesis Seven of the reactions of glycolysis are reversible and are used in the synthesis of glucose from lactate or pyruvate. However three of the reactions are irreversible and must be bypassed by four alternate reactions that energetically favor the synthesis of glucose. A. Carboxylation of Pyruvate In gluconeogenesis, pyruvate is first carboxylated by pyruvate carboxylase to oxaloacetate (OAA). B. transport of Oxaloacetate to the Cytosol • Since gluconeogenesis is carried out in cytosol (enzymes of gluconeogenesis are located in the cytosol), the mitochondrial product, oxaloacetate, must be transported to cytosol. • However, oxaloacetate is unable to cross the inner mitochondrial membrane directly. • It must first be reduced to malate which can then be transported from the mitochondria to the cytosol through the malate-aspartate shuttle. • In the cytosol, Malate is reoxidized to oxaloactate C. Decarboxylation of Cytosolic Oxaloacetate. Oxaloacetate is decarboxylated and phosphorylated in the cytosol by PEP-carboxykinase. The reaction is driven by hydrolysis of GTP • • The combined action of pyruvate carboxylase and PEP carboxykinase provides an energetically favorable pathway from pyruvate to PEP. PEP then enters the reversed reactions of glycolysis until it forms fructose 1, 6- bisphosphate. D. Dephosphorylation of fructose 1, 6 bisphosphate Hydrolysis of fructose 1, 6-bisphosphate by fructose 1, 6-bisphosphatase passes the irreversible PFK- 1 reaction and provides energetically favorable pathway for the formation of fructose 6phosphate. This reaction is an important regulatory site of gluconeogenesis, 1. Regulation by energy levels within the cell: • Fructose1, 6 bisphosphatase is inhibited by elevated levels of AMP, which signal an energy poor state in the cell • Conversely high levels of ATP and low concentrations of AMP stimulate gluconeogensis 2. Regulation by fructose 2,6- bisphosphate • Fructose1, 6-bisphosphatase is inhibited by fructose 2, 6-bisphosphate, an allosteric modifier whose concentration is influenced by the level of circulating glucagons. E. Dephosphorylation of glucose-6-phosphate Hydrolysis of glucose 6-phosphate by glucose 6-phosphatase bypasses the irreversible hexokinase reaction provides energetically favorable pathway for the formation of free glucose, Glucose 6-phosphatase like pyruvate carboxylase, occurs in liver and kidney, but not in muscle. Thus muscle cannot provide blood glucose from muscle glycogen. Advantages of Gluconeogenesis 1) Gluconeogenesis meets the requirements of glucose in the body when carbohydrates are not available in sufficient amounts. 2) Regulate Blood glucose level 3) Source of energy for Nervous tissue and Erythrocytes 4) Maintains level of intermediates of TCA cycle 5) Clear the products of metabolism of other tissues (Muscle) Regulation of gluconeogenesis 1. Fructose-1,6-Bisphosphatase • Allosterically regulated in a fashion opposite to phosphofructokinase. • Fructose-2,6-bisphosphate (F-2,6-BP) inhibits • High energy state (high ATP, citrate) stimulates the phosphatase and gluconeogensis. • Low energy state (high AMP, low citrate) stimulates PFK and glycolysis. • Hormonal regulation acts through F-2,6-BP. Hormonal Regulation of F-2.6-Bisphosphatase • F-2,6-BP made by PFK-2 and F-2,6-BP degraded by F-2,6-BPase • Both activities are on the same protein ie A bifunctional enzyme • Hormonal stimulation results in phosphorylation of this protein. • In liver, phosphorylation activates F-2,6-BPase,inhibits PFK-2. (stimulating gluconeogenesis) • In muscle, phosphorylation activates PFK-2, inhibits F-2,6-Bpase. (stimulating glycolysis) 2. Regulation of Hexokinase and Glucose-6-phosphatase • Hexokinase is inhibited by glucose-6-phosphate • Glucose-6-phosphatase has a high Km for glucose-6-phosphate. Therefore gluconeogenesis is favored by high concentrations of glucose-6-phosphate. 3. Regulation of pyruvate carboxylase and PEP carboxykinase • High acetyl-CoA stimulates the enzyme and favors pyruvate to oxaloacetate, either for increased TCA activity or increased gluconeogenesis. • When acetyl-CoA is low, pyruvate is broken down by pyruvate dehydrogenase to form more acetyl co A. (Low acetyl-CoA favors breakdown of PEP and pyruvate to form acetylCoA). This does not favour gluconeogenesis. • High levels of GTP (equivalent to ATP) favour the formation of PEP from oxaloacetate and consequently favouring gluconeogenesis. Gluconeogenesis pathway Name: Description: ...
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