gluconeogenisis fnll

8/4/2019 gluconeogenisis fnll

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PRESENTED BY

Dr.ABIRAMI



The process of transformation of non-carbohydrates toglucose .

Principal organsliver, kidney

Non-carbohydrates

glucogenic amino acids

lactate

glycerol

organic acids



Gluconeogenesis is not a reversal of glycolysis.

Irreversible steps in glycolysis is circumvented by 4

enzymes: Pyruvate carboxylase

Phosphoenol pyruvate carboxy kinase.

Fructose 1,6 bis phoshatase

Glucose 6 phosphatase.



Pyruvate Carboxylase (Gluconeogenesis) catalyzes:

pyruvate + HCO 3- + ATP oxaloacetate + ADP +

Pi

Pyruvate Carboxylase uses biotin

PEP Carboxykinase (Gluconeogenesis) catalyzes:

oxaloacetate + GTP PEP + GDP + CO2



Malate shuttle:

oxaloacetate transported from mitochondria to

cytosol Iso-enzyme :malate dehydrogenase.

Provide 1 NADH+ also.



Partial reversal of glycolysis:

Phosphoenolpyruvate converted to fructose1,6

bisphosphate.Fructose 1,6 bisphosphate is converted to fructose 6phosphate-fructose 1,6 bisphosphatase.

Fructose 6 phosphatase is isomeised to glucose 6

phosphate .



Glucose 6 phosphate is converted to glucose –glucose6 phosphatase.



Glyceraldehyde-3-phosphateDehydrogenase

Phosphoglycerate Kinase

Enolase

PEP Carboxykinase

glyceraldehyde-3-phosphate

NAD+ + Pi

NADH + H+

1,3-bisphosphoglycerateADP

ATP

3-phosphoglycerate

Phosphoglycerate Mutase

2-phosphoglycerate

H2O

phosphoenolpyruvate

CO2

+ GDP

GTP

oxaloacetate

Pi + ADP

HCO3-

+ ATP

pyruvate

Pyruvate Carboxylase

Gluconeogenesis



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

TriosephosphateIsomerase

(continued)



Glycolysis & Gluconeogenesis are bothspontaneous.If both pathways were simultaneously active in a cell, it

would constitute a "futile cycle" that would wasteenergy.

Glycolysis: glucose + 2 NAD+ + 2 ADP + 2 Pi

2 pyruvate + 2 NADH + 2 ATPGluconeogenesis: 2 pyruvate + 2 NADH + 4 ATP + 2 GTP

glucose + 2 NAD+ + 4 ADP + 2 GDP + 6 Pi



Glycolysis yields 2~P.

Gluconeogenesis expends 6 ~P.

A futile cycle of both pathways would waste 4~P per cycle .



The Cori Cycle operates during exercise.

For a brief burst of ATP utilization, muscle cells utilize

~P stored as phosphocreatine.Once phosphocreatine is exhausted, ATP is providedmainly by Glycolysis, with the input coming fromglycogen breakdown and from glucose uptake from

the blood.



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

The glucose may travel back to the muscle to fuelGlycolysis.

Cori Cycle

Liver Blood Muscle

Glucose Glucose

2 NAD+ 2 NAD+

2 NADH 2 NADH

6 ~P 2 ~P

2 Pyruvate 2 Pyruvate

2 NADH 2 NADH2 NAD

+2 NAD

+

2 Lactate 2 Lactate



The Cori cycle costs 6 ~P in liver for every 2 ~P madeavailable in muscle. The net cost is 4 ~P.

Although costly in ~P bonds, the Cori Cycle allowsthe organism to accommodate to large fluctuations inenergy needs of skeletal muscle between rest andexercise.

Cori Cycle

Liver Blood Muscle

Glucose Glucose

2 NAD+ 2 NAD+

2 NADH 2 NADH

6 ~P 2 ~P


2 NADH 2 NADH2 NAD

+2 NAD

+

2 Lactate 2 Lactate



The equivalent of the Cori Cycle also operatesduring cancer.

If blood vessel development does not keep pace withgrowth of a solid tumor, decreased O2 concentration within the tumor leads to activation

of signal processes that result in a shift to anaerobicmetabolism.



Energy dissipation by the Cori Cycle, which expends 6

~P in liver for every 2 ~P produced via Glycolysis forutilization within the tumor, is thought to contribute tothe weight loss that typically occurs in late-stage cancereven when food intake remains normal.

Liver Blood Cancer Cell

Glucose Glucose

2 NAD+ 2 NAD+

2 NADH 2 NADH6 ~P 2 ~P


2 NADH 2 NADH

2 NAD+ 2 NAD+

2 Lactate 2 Lactate



Substrates for gluconeogenesis LACTATE:

Lactate formed in muscle or RBC.

Through cori s cycle GLUCOGENIC AMINO ACIDS:

In case of starvation, diabetes mellitus.

Glucose -Alanine cycle

Alanine from muscle transported to liver-tranamminated to pyruvate ---glucose



Glucose enters glycolytic pathway- pyruvate-alanine

Starvation- for disposal of ammonia

GLYCEROLPROPIONYL CO A



HORMONAL REGULATION OFGLUCONEOGENISIS:

GLUCAGON, GLUCOCORTICOIDS –increase

INSULIN-inhibits

PHYSIOLOGICAL IMPORTANCE:

CONDITIONS OF STARVATION- 12-18Hrs .



CLINICAL SIGNIFICANCE:

Pyruvate carboxylase deficiency:

Inborm metabolism error Malignant hyperthremia

Halothane anasthesia- genetical abnormality incalcium channel-inapproriate release of calcium

Activation of heat producing processes.

Ethanol:

Inhibits gluconeogenesis.



THANK YOU

gluconeogenisis fnll

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