Gluconeogenesis

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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 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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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 ...
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