Gluconeogenesis

Gluconeogenesis is making a new glucose from non-carbohydrate precursors

In other words:

Create new glucose from the products of its breakdown

Its main function is to supply blood glucose in cases of carbohydrate deficiency

(fasting, starvation and low carbohydrate diet).

What is the Gluconeogenesis?

Sites for gluconeogenesis

Cytoplasm and mitochondria of liver and kidney tissues due to presence of glucose-6-phosphatase and fructose-1,6-biphosphatase.

The production of glucose is necessary for use as a fuel source by the brain, testes, erythrocytes, kidney medulla, lens and cornea of the eye and exercising muscle.

Glycolysis pathway

The reactions of gluconeogenesis:

Synthesis of glucose from pyruvate utilizes many of the same enzymes as glycolysis.

Three Glycolytic reactions are essentially irreversible Hexokinase (or Glucokinase) Phosphofructokinase Pyruvate Kinase.

These steps must be by passed in Gluconeogenesis.

First Bypass ReactionConvervsion of Pyruvate to Phosphoenolpyruvate

• Enzymes involved:

- Pyruvate carboxylase

- PEP carboxykinase

C

C

CH 2

O O

O PO 32

C

C

CH 3

O O

O

A T P A D P + P i C

CH 2

C

C

O

O O

O O

HC O 3

G T P G D P

CO 2

p y r u v a te o x a lo a c e ta te P E P

P y ru v a te C a rb o x y la s e P E P C a rb o x y k in a s e

In Mitochondria• Pyruvate carboxylase (PC) exists in the mitochondria of

liver and kidney but absent in muscle• ATP, biotin, Mn++ and CO2 are required.

Transport of Oxaloacetate into cytosol as Malate

In cytosol

Summary of the first bypass

Second bypass reactionConversion of Fructose 1,6- bisphosphate to Fructose

6-phosphate

• The second glycolytic reaction (phosphorylation of fructose 6-phosphate by PFK) is irreversible.

• Hence, for gluconeogenesis fructose 6-phosphate must be generated from fructose 1,6-bisphosphate by a different enzyme which is Fructose 1,6-bisphosphatase.

• Fructose 1,6-bisphosphatase presents in liver and kidney.• This reaction is also irreversible.

Fructose 1,6-bisphosphate + H2O fructose 6-phosphate + Pi

Phosphofructokinase (In Glycolysis): fructose-6-P + ATP fructose-1,6-bisP + ADP

Fructose-1,6-bisphosphatase (In Gluconeogenesis):fructose-1,6-bisP + H2O fructose-6-P + Pi

fructose-6-phosphate fructose-1,6-bisphosphate

Phosphofructokinase CH2OPO3

2

OH

CH2OH

H

OH H

H HO

O6

5

4 3

2

1 CH2OPO32

OH

CH2OPO32

H

OH H

H HO

O6

5

4 3

2

1ATP ADP

Pi H2O

Fructose-1,6-biosphosphatase

Third bypass reaction Glucose 6-phosphate to Glucose

• Because the hexokinase reaction is irreversible, the final reaction of gluconeogenesis is catalyzed by Glucose 6-phosphatase.

Glucose 6-phosphate + H2O glucose + Pi

• Glucose 6-phosphatase is present in the liver, kidney

and small intestine but absent in brain and muscle.

Thus, glucose produced by gluconeogenesis in the liver,

is delivered by the bloodstream to brain and muscle.

Hexokinase or Glucokinase (In Glycolysis):glucose + ATP glucose-6-phosphate + ADP

Glucose-6-Phosphatase (In Gluconeogenesis): glucose-6-phosphate + H2O glucose + Pi

H O

OH

H

OHH

OH

CH2OH

H

OH

HH O

OH

H

OHH

OH

CH2OPO32

H

OH

HH2O

1

6

5

4

3 2

+ Pi

glucose-6-phosphate glucose

Glucose-6-phosphatase

Glyceraldehyde-3-phosphate Dehydrogenase

Phosphoglycerate Kinase

Enolase

PEP Carboxykinase

glyceraldehyde-3-phosphate

NAD+ + Pi

NADH + H+

1,3-bisphosphoglycerate

ADP

ATP

3-phosphoglycerate

Phosphoglycerate Mutase

2-phosphoglycerate H2O

phosphoenolpyruvate

CO2 + GDP

GTP oxaloacetate

Pi + ADP

HCO3 + ATP

pyruvate

Pyruvate Carboxylase

Gluconeogenesis

Summary of Gluconeogenesis Pathway:

Gluconeogenesis enzyme names in red.

Glycolysis enzyme names in blue.

Glucose-6-phosphatase

Fructose-1,6-bisphosphatase

glucose Gluconeogenesis

Pi

H2O glucose-6-phosphate

Phosphoglucose Isomerase

fructose-6-phosphate

Pi

H2O fructose-1,6-bisphosphate

Aldolase

glyceraldehyde-3-phosphate + dihydroxyacetone-phosphate

Triosephosphate Isomerase (continued)

1- Lactate (Lactic acid):

• In vigorous skeletal muscle activity, large amount of lactic acid produced pass to liver through blood stream converted into pyruvic and lastly to glucose reach muscle again through blood stream

to provide energy (Cori cycle).

Substrates for gluconeogenesis

Lactate produced from pyruvate passes via the blood to the liver, where it may be converted to glucose.

The glucose travels back to the muscle to fuel Glycolysis.

2- Glucogenic amino acids:

• Amino acids by deamination can be converted into keto acids as pyruvic, ketoglutaric and oxaloacetic acid.

• Proteins are considered as one of the main sources of blood glucose especially after 18 hr due to depletion of liver glycogen.

Substrates for gluconeogenesis

Carbon sources for gluconeogenesis

Glucose-alanine cycle: Glucose oxidation produces pyruvate which can undergo

transamination to alanine in liver. This reaction is catalyzed by alanine transaminase (ALT).

Additionally, during fasting, skeletal muscle protein is degraded yielding high amount of alanine which then enters the blood stream and is transported to the liver.

In liver, alanine is converted back to pyruvate which is then a source of carbon atoms for gluconeogenesis. The newly formed glucose can then enter the blood for delivery back to the muscle.

Acetyl CoA can not produce glucose

• Acetyl CoA cannot give rise to a net synthesis of glucose. This is due to the irreversible nature of the pyruvate dehydrogenase reaction, which converts pyruvate to acetyl CoA.

Pyruvate dehydrogenase

• Pyruvate acetyl CoA + CO2

NAD+ NADH+H+

Importance of gluconeogenesis

1-Maintenance of blood glucose during starvation, fasting and prolonged exercise.

2- Removal of lactic acid.

3- Removal of glycerol produced by lipolysis.