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CONTROL OF GLUCONEOGENESIS

Control

of gluconeogenesis and glycolysis are reciprocal

When

gluconeogenesis is active, glycolysis is inactive


pathways are not highly active at the same time

Both

Cont.
When

there is sufficient energy, gluconeogenesis takes place

Reciprocal

regulation occurs at two (2) main points

1.
Fructose-6-phosphate

Fructose-1,6-bisphosphate
Glycolysis- Red Gluconeogenesis- yellow
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2.
Phosphoenol pyruvate Oxaloacetate pyruvate

Cont.
Pyruvate

is the starting point for gluconeogenesis.

The

first control point determines the fate of pyruvate.


first enzyme under control is pyruvate carboxylase.
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The

Phosphoenol pyruvate Oxaloacetate pyruvate Pyruvate carboxylase

Allosteric Control of Pyruvate Carboxylase


Acetyl-CoA

is a positive allosteric modulator of the enzyme.

At

the same time acetyl-CoA inhibits the pyruvate dehydrogenase complex.


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Gluconeogenesis (+) Pyruvate carboxylase Pyruvate (-) pyruvate dhase Acetyl- CoA

Citric acid cycle


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When

a cell has sufficient energy, oxidative phosphorylation decreases accumulates

NADH NADH

inhibits Citric acid cycle and Acetyl-CoA level rises


Acetyl-CoA levels indicate high energy levels.
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High

High

Acetyl-CoA levels indicate high energy levels.

Acetyl

CoA also acts as a biosynthetic precursor. Acetyl CoA concentration inhibits pyruvate dehydrogenase Acetyl CoA also stimulates pyruvate carboxylase
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Increased

Increased

Increased

Acetyl CoA also stimulates pyruvate carboxylase,

Pyruvate

carboxylase is the first step of gluconeogenesis, so


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Pyruvate

is channelled into gluconeogenesis to form glucose carboxylase is inhibited by

Pyruvate

ADP
When

ATP levels are falling, and ADP levels are rising, the ADP inhibits pyruvate carboxylase so more pyruvate will be channelled into citric acid cycle.
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Control of phosphoenol pyruvate carboxykinase (PEP C)

Phosphoenol pyruvate(PEP) PEP C Oxaloacetate pyruvate


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The

enzyme converts oxaloacetate to phosphoenol pyruvate

ADP

inhibits Phosphoenol pyruvate carboxykinase

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Reciprocal Control of Pyruvate Kinase (PK)

Phosphoenol pyruvate PK

Oxaloacetate pyruvate
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Cont.

Pyruvate kinase (PK) catalyses conversion of PEP to pyruvate in glycolysis PK is inhibited when energy levles are high and stimulated when energy levles are low

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PK is inhibited by ATP and stimulated by fructose-1,6-biphosphate PK is also stimulated by alanine

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2nd gluconeogenic step under control


Fructose-1,6-bisphosphatase(F-1,6-

bisPase) reaction.
This

enzyme catalyses the formation of fructose-6-phosphate (F-6-P) from fuctose-1,6-biphosphate (F-1,6-biP).


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2nd gluconeogenic step under control glucose Fructose-6-Phosphate

F-1,6 bisPase
Fructose-1,6-biphosphate Pyruvate
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The

fructose-1,6-biPase is another allosteric enzyme


is inhibited when energy levels are low and stimulated when energy levels are high is inhibited by AMP and stimulated by ATP and Citrate
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It

It

The

reverse reaction which forms F-1,6-biP from F-6-P is catalysed by Phosphofructokinase-1.

It

is inhibited by ATP and Citrate and stimulated by AMP and ADP


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Control of Gluconeogenesis by Hormones


Glycolysis

and gluconeogenesis are adjusted in the liver to maintain blood glucose. blood glucose levels decrease, glucagon rises.
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When

Glucagon stimulates gluconeogenesis by the following mechanism


Glucagon

stimulates adenyl cyclase

Adenyl

cyclase stimulates formation of 35 cyclic AMP from ATP stimulates cAMP dependent protein Kinase A
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cAMP

Protein

Kinase A phosphorylates a bifunctional protein.

The

bifunctional protein is made of one enzyme at one end and another enzyme at its other end.

The

enzymes are : phosphofructokinase-2 and (PFK-2) Fructose biphosphatase-2 (F biPase-2)


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Structure of bifunctional enzyme


1 32 250 470

Regulatory Phosphofructo Domain Kinase-2

Fructobiphos phatase-2

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The

protein Kinase A phosphorylates a serine residue on the bifunctional enzyme and this leads to activation of F biPase-2 and the inhibition of PFK-2
of F biPase-2 leads to breakdown of Fructose-2,6bisphosphate (F-2,6-biP) and a decreased levels of F-2,6-biP

Activation

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Low

levels of F-2,6-bisP inhibits glycolysis.

At

the same time low levels of F2,6-P will stimulate F-1,6-biPase and gluconeogenesis
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Summary Low blood glucose

glucagon
cAMP protein Kinase A
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Phosphorylation of PFK-2/ F-2,6-bPase protein activity of F-2,6-bPase F-2,6-bP activity of F-1,6-bPase


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Gluconeogenesis Increased blood glucose

The

control by glucagon also relies on the fact that F-2,6-bP stimulates PFK
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Control of gluconeogenesis at levels of Transcription


Glucagon

stimulates production of 2 gluconeogenic enzymes: Carboxykinase and

PEP

F-1,6-bPase
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Control of Production of Glucose in Gluconeogenesis

F-6-P F-1,6-bPase

F-1,6-bP
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F-6-P

is formed from F-1,6-bP

The

F-6-P is converted into glucose-6Phosphate (G-6-P)


is the last step in most tissues.

This

Unlike

glucose, G-6-P cannot be transported out of the cell


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Conversion

of G-6-P to glucose is controlled. This helps to maintain cellular glucose levels


of G-6-P to glucose is by control of the enzyme for the conversion; Glucose-6-Phosphatase (G-6-Pase)
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Control

G-6-Pase

is only present in Liver and Kidney- so only these organs can release glucose into the blood. of G-6-P into glucose takes place in the Lumen of endoplasmic reticulum (ER)

Conversion

Gluconeogenesis

takes place in the


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cytoplasm.

The

G-6-P formed is transported to the Lumen of the ER by a transport protein.

In

the lumen of the ER G-6-P is hydrolysed by membrane bound G-6Pase


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G-6-Pase

requires Ca2+ dependent stabilizing protein.

Glucose

and Pi are transported back to the cytoplasm by transport proteins


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Vigorous

exercise can lead to oxygen shortage (anaerobic conditions), and energy requirements must be met by increased levels of glycolysis. Under such conditions, glycolysis converts NAD to NADH, yet O2 is unavailable for regeneration of
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Under

such conditions, glycolysis converts NAD to NADH, yet O2 is unavailable for regeneration of NAD via cellular respiration.
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Instead, large amounts of NADH are reoxidized by the reduction of pyruvate to lactate. The lactate thus produced can be transported from muscle to the liver, where it is reoxidized by liver lactate dehydrogenase to yield pyruvate, which is converted eventually to glucose.
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In this way, the liver shares in the metabolic stress created by vigorous exercise. It exports glucose to muscle, which produces lactate, which can be processed by the liver into new glucose.

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This

is referred to as the Cori cycle. Liver, with a typically high NAD/NADH ratio (about 700), readily produces more glucose than it can use.

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Muscle

that is vigorously exercising will enter anaerobiosis and show a decreasing NAD/NADH ratio, which favours reduction of pyruvate to lactate.
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Glyoxylate Cylce
Occurs

in plants, invertebrates and some microorganisms

Involves

the conversion of Acetyl CoA into succinate


succinate can be converted into oxaloacetate and oxaloacetate into PEP
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The

The

PEP can be used to form glucose in gluconeogenesis. means that organisms which have the glyoxylate cycle can use acetyl CoA as a starting material for gluconeogenesis. do not have the glyoxylate
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This

Vertebrates

cycle.

Acetyl

CoA cannot be converted into pyruvate because the following reaction is irreversible: Pyruvate
pyruvate dehydrogenase complex Acetyl CoA
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There

is no NET conversion of acetyl CoA into oxaloacetate in the Citric acid cycle because;

for every 2 carbons that enter as Acetyl CoA, 2 carbons leave as Carbon dioxide.
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