Gluconeogenesis

Gluconeogenesis is the biochemical process of formation of glucose form non-carbohydrate sources

Examples of non -carbohydrate sources involve in gluconeogenesis

 Pyruvate (From Lactate)

 Glycerol
 Glycogenic Amino acids; Alanine, Glutamine

Importance of gluconeogenesis
Some tissues almost all depends on glucose for energy production

Examples

 Red blood cells

 Brain and nervous system; need 120 g/ day (more than ½ of the glycogen store in liver)
 Cornea of the eye
 Testis
 Renal medulla
 Embryonic tissues

 Glucose is stored inside muscles and liver as glycogen

 During the fasting state or in the absence of carbohydrate diet
 Glycogen can be breakdown easily and thus can provide glucose
 Muscles utilize that glucose to produce energy inside the muscle cells
 Liver glycogen is involved in suppling glucose to the circulation
 Thus, liver glycogen is a main source of postprandial glucose
 But during the fasting state, this liver glycogen is sufficient only for 10-18 hours
 Glycogen stores are depleting during longer fasts, between meals and after vigorous exercises
 So, gluconeogenesis is important to provide glucose into the circulation
 So, it helps in maintaining blood glucose levels

Sites of gluconeogenesis in the cells

 Liver; major site
 Renal cortex

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Gluconeogenesis

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Pre-Med Online
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  As you can see the intermediate products involve in gluconeogenesis are almost similar to the
intermediates of glycolysis
 So, that glycolysis and gluconeogenesis is regulated in a reciprocal fashion (when glycolysis is
active, gluconeogenesis is inhibited and vice-versa) inside the cells
 If glycolysis and gluconeogenesis activate at the same time,
 Glucose would be converted to pyruvate by glycolysis
 Then pyruvate will be converted to glucose by gluconeogenesis again
 That will waste energy in the cell
 It is called a futile cycle or a substrate cycle
 That is prevented inside the cells, thus prevents the wasteful operation of both pathways at the
same time

How the futile cycle between glycolysis and gluconeogenesis is prevented inside
the cells?
Irreversible glycolytic steps are bypassed by different enzymes

 Conversion of pyruvate to PEP is done by Pyruvate carboxylase (PC) and Phosphoenolpyruvate

carboxykinase (PEPCK)
 Conversion of Fructose 1,6-bisphosphate to fructose-6-phosphate is done by Fructose-1,6-
bisphosphatase
 Conversion of Glucose-6-phosphate to Glucose is done by Glucose-6-phosphatase (G6Pase)

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 Conversion of pyruvate to PEP
 This is done by 2 irreversible steps
 First pyruvate is converted to oxaloacetate by Pyruvate carboxylase by adding a carbon dioxide
molecule
 Then oxaloacetate is converted to the PEP by PEPCK by releasing a carbon dioxide molecule

1
 Pyruvate carboxylase is a mitochondrial enzyme
 So, conversion of pyruvate to oxaloacetate irreversibly occurs inside mitochondria
 This reaction will consume one ATP
 Then oxaloacetate is converted reversibly to malate by malate dehydrogenase by using a NADH
 Malate is transported to the cytosol and reconverted to oxaloacetate inside the cytosol by
releasing NADH
 Then inside the cytosol oxaloacetate is converted irreversibly to PEP by cytosolic PEPCK
 This reaction consumes one GTP

2
 Pyruvate is converted to oxaloacetate inside the mitochondria irreversibly by PC
 Then oxaloacetate is converted irreversibly to PEP by mitochondrial PEPCK
 PEP is transported to the cytosol by a special transporter for PEP in the mitochondrial
membrane

Which pathway is used by the cell is decided by

 Availability of substrates ; during vigorous exercises lactate production is high

 Requirements for cytosolic NADH

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Regulation of conversion of pyruvate to PEP
This reaction is allosterically activated by Acetyl CoA

During aerobic respiration,

 Pyruvate is transported to mitochondria and converted into Acetyl CoA

 Acetyl CoA is used for TCA cycle
 Increase levels of Acetyl CoA will indicate that the TCA cycle is saturated
 Thus, gluconeogenesis is activated
 This time Glycolysis is inhibited

During fatty acid oxidation,

 Acetyl CoA is produced inside mitochondria

 This Acetyl CoA also allosterically activate PC

PC is allosterically inhibited by ADP

PEPCK is allosterically inhibited by ADP

Conversion of Fructose 1,6- bisphosphate into Fructose-6-phosphate

 This reaction is catalyzed by Fructose 1,6 bisphosphatase (FBP 1) enzyme
 This enzyme is a Mg dependent enzyme

This enzyme is allosterically activated by

 Citrate
 High ATP; high energy status
 Low AMP

Allosterically inhibited by

 Fructose ,6- bisphosphate

 High AMP; low energy status

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 Conversion of glucose-6-phosphate to glucose
 This is catalyzed by Glucose-6-phosphatase
 This enzyme is not present in brain and muscle cells
 So, that though glycogen is present in muscles, they are not involved in increasing glucose level
in blood

 Glucose-6-phosphatase is an endoplasmic reticulum enzyme

 So, that conversion of glucose-6-phosphate to glucose is done inside endoplasmic reticulum
 Then glucose is transported to the cytosol by a glucose transporter
 This glucose inside the liver cells, will be transported to blood via GLUT 2 transporters

Glucose-6- phosphatase deficiency

Free glucose will not be produced by

 Gluconeogenesis
 Glycogenolysis

Will cause severe fasting hypoglycemia

This is called Von Gierke’s disease or Type Ia glycogen storage disease

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 Hormonal regulation on Gluconeogenesis
During fasting state

 Insulin/Glucagon ratio decreases due to the presence of high levels of glycogen in blood
 Elevation of glycogen will result
1. Inhibition of glycolysis
 Binding of glucagon to glucagon receptors in liver and renal cortex (there are no glucagon
receptors in muscles)
 This will increase cAMP levels
 Thus, increase protein kinase activity
 Activated Protein kinase will phosphorylate pyruvate kinase
 Thus, inhibits the conversion of PEP to pyruvate
 Diverts PEP to gluconeogenesis
2. Lowers fructose ,6-bisphosphate levels
3. Induce PEP carboxykinase enzyme synthesis

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