Gluconeogensis its regulation by Benish Akhtar

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Presented to:- Sir Shehroz Khan

Presented to:- Benish Nasir Khan

Topic

Gluconeogensis its regulation

and significance

Gluconeogensis its regulation

and significance

Gluoconeogenesis

• Is the formation of glucose from non-carbohydrate sources e.g lactic acid ,amino acids , glycerols and propionate.

• Site: liver and kidney.

Gluoconeogenesis

• Occurs in all animals, plants, fungi and microbes

• Occurs largely in the liver; some in renal cortex

• Of 10 enzymatic steps, 7 are reversals of glycolytic reactions

Gluoconeogenesis

• Gluconeogenesis begins with various substrates converted into pyruvate.and this proceed though what is essentially the reverse of glycosis(except for a few committed steps).

• 3 and 4-carbon substrates can enter the gluconeogenesis pathway. Lactate from anaerobic exercise in skeletal muscle is easily converted to pyruvate; this happens as part of the Cori cycle.

Gluoconeogenesis

• Oxaloacetate (an intermediate in the citric acid cycle can also be used for gluconeogenesis. Amino acids, after their amino group has been removed, feed into parts of the citric acid cycle, and can thus can generate glucose in this pathway.

• Fatty acids cannot be turned into glucose, as they are broken down into the two carbon acetyl CoA. (However glycerol which is a part of all triacylglycerides can be used in gluconeogenesis).

PHYSIOLOGICAL SIGNIFICANCE OF GLUCONEOGENESIS

• Gluconeogenesis is particularly important in liver control of blood glucose homeostasis.

• Gluconeogenesis allows synthesis of glucose for times when liver glycogen reserves are substantially depleted; during fasting (before breakfast) and during starvation.

PHYSIOLOGICAL SIGNIFICANCE OF GLUCONEOGENESIS

• Unlike most tissues, glucose can easily diffuse out of hepatocytes into the blood.

• Because hepatocytes contain much more of the glycolysis enzyme glucokinase (KM ~ 10mM) than hexokinase (KM = 0.1mM) most glucose synthesised in the liver is unlikely to be converted to glucose 6-phosphate.

glucose

glucose 6-phosphate

fructose 6-phosphate

fructose 1,6-bisphosphate

phosphoenolpyruvate

pyruvate

hexokinase

Phosphofructokinase-1

pyruvate kinase

fructose bisphosphatase

glucose 6-phosphatase

GLUCONEOGENESIS GLYCOLYSIS

oxaloacetate

pyruvate carboxylase

phosphoenolpyruvate carboxykinase

• (1) Pyruvate to phosphoenolpyruvate

• Pyruvate is first converted to oxaloacetate by the enzyme pyruvate carboxylase.

• Oxaloacetate is then converted to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase.

GLUCONEOGENESIS: ‘By-Pass’ Reactions

COOH |

C = O |

CH3

pyruvic acid

COOH |

C = O |

CH2

| COOH

oxaloacetic acid

COOH |

C – O – PO ||

CH2

phosphoenolpyruvic acid

CO2

ATP ADP + PiGTP GDP

CO2


(2) Fructose 1,6-bisphosphate to Fructose 6-phosphate

Catalysed by fructose bisphosphatase.

OH

O

CH2O – PO

CH2O – PO 3

2

OH

HOH

H

H

α-D-fructose 1,6-bisphosphate

3

2

OH

O

CH2O – PO

CH2OH3

2

OH

HOH

H

H

α-D-fructose 6-phosphate

H2O

Pi


(3) Glucose 6-phosphate to glucoseCatalysed by glucose 6-phosphatase.

H2O

Pi

O

CH2OH

HOOH

OH

OH

α-D-glucose

HH

H

HH

O

CH2O – PO

HOOH

OH

OH

HH

H

α-D-glucose 6-phosphate

3

2

HH

Glucose 6-phosphatase is chiefly found in liver cells where it is important for producing glucose to ‘top-up’ blood glucose levels.

It is absent in muscle cells.

GLUCONEOGENESIS from lactate/pyruvate

The Cori Cycle

Glucose

pyruvate

lactate

Glucose

pyruvate

lactate

blood

blood

Muscle/ Erythrocytes Liver

glycolysis gluconeogenesis

Glycerol, from the breakdown of triglycerides can also provide a raw material for gluconeogenesis.

glycerol glycerol 3-phosphate

dihydroxyacetone phosphate

glucosegluconeogenesis

GLUCONEOGENESIS FROM TRIGLYCERIDES

Acetyl CoA, the main breakdown product of fatty acids, cannot be used to feed gluconeogenesis.

Fructose 2,6-bisphosphate is the most important regulator of glycolysis and gluconeogenesis.

REGULATION OF GLYCOLYSIS/GLUCONEOGENESIS

Fructose 2,6-bisphosphate is not an intermediate of either pathway but is synthesised from fructose 6-phosphate by a dual function enzyme known as phosphofructokinase-

2/fructose 2,6-bisphosphatase.

Fructose 2,6-bisphosphate

stimulates phosphofructokinase activity (glycolysis)

inhibits fructose bisphosphatase activity

(gluconeogenesis)

glucose

glucose 6-phosphate



phosphoenolpyruvate

pyruvate

hexokinase

PFK-1

pyruvate kinase



stimulation

inhibition


PFK-2



Reversible phosphorylation of phosphofructokinase-2 / fructose 2,6-bisphosphatase controls the activity of this

enzyme.


fructose 2,6-bisphosphate concentration decreases

phosphofructokinase -2 activity inhibited

fructose 2,6-bisphosphatase activity stimulated by

phosphorylation

Enables gluconeogenesis

Effects of phosphorylation:

Inhibits glycolysis


Reversible phosphorylation of phosphofructokinase-2 / fructose 2,6-bisphosphatase controls the activity of this

enzyme.


fructose 2,6-bisphosphate concentration increases

phosphofructokinase-2 activity stimulated by

dephosphorylation

fructose 2,6-bisphosphatase activity inhibited

Inhibits gluconeogenesis

Stimulates glycolysis

Effects of dephosphorylation:

Regulation of Glycolysis/Gluconeogenesis

Synthesis and degradation of the regulator fructose 2,6-bisphosphate is controlled by reversible phosphorylation

of the enzyme phosphofructokinase-2 / fructose 2,6-bisphosphatase by protein kinase A.

Phosphorylation turns on

phosphofructokinase-2 / fructose 2,6-bisphosphatase activity

Dephosphorylation turns on:

phosphofructokinase-2 / fructose 2,6-bisphosphatase activity

glucose

glucose 6-phosphate



phosphoenolpyruvate

pyruvate

hexokinase

Phosphofructokinase-1

pyruvate kinase



AMP, Pi

ATP, citrate

AMP

stimulation

inhibition

AMP



The pancreatic hormone glucagon stimulates gluconeogenesis

glucagon

protein kinase A

PFK-2/fructose 2,6-bisphosphatase – OH

fructose 6-bisphosphate


PFK-2/fructose 2,6-bisphosphatase – P

Removal of fructose 2,6-bisphosphate stimulates gluconeogenesis and

inhibits glycolysis

G-protein / cAMP signalling cascade


The pancreatic hormone insulin inhibits gluconeogenesis

insulin

protein kinase APFK-2/fructose 2,6-

bisphosphatase – OH

fructose 6-bisphosphate


PFK-2/fructose 2,6-bisphosphatase – P

Presence of fructose 2,6-bisphosphate inhibits gluconeogenesis and

stimulates glycolysis

Thank you

Health & Medicine

Gluconeogensis its regulation by Benish Akhtar