Control of Gluconeogenesis,Lecture 2

8/3/2019 Control of Gluconeogenesis,Lecture 2

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CONTROL OF GLUCONEOGENESIS

Control of gluconeogenesis andglycolysis are reciprocal

When gluconeogenesis is active,

glycolysis is inactive

Both pathways are not highly active at

the same time


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Cont.

When there is sufficient energy,gluconeogenesis takes place

Reciprocal regulation occurs at two (2)

main points


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1.

Fructose-6-phosphate

Fructose-1,6-bisphosphate

Glycolysis- Red

Gluconeogenesis- yellow


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2.

Phosphoenol pyruvate

Oxaloacetate

pyruvate


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Cont.

Pyruvate is the starting point forgluconeogenesis.

The first control point determines thefate of pyruvate.

The first enzyme under control ispyruvate carboxylase.


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Oxaloacetate

pyruvate Pyruvate

carboxylase


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Allosteric Control of Pyruvate Carboxylase

Acetyl-CoA is a positive allosteric

modulator of the enzyme.

At the same time acetyl-CoA

inhibits the pyruvate dehydrogenasecomplex.


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Gluconeogenesis

(+) Pyruvate carboxylasePyruvate

(-) pyruvate dhaseAcetyl- CoA

Citric acid cycle


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When a cell has sufficient energy,oxidative phosphorylation decreases

NADH accumulates

NADH inhibits Citric acid cycle andAcetyl-CoA level rises

High Acetyl-CoA levels indicate highenergy levels.


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High Acetyl-CoA levels indicate highenergy levels.

Acetyl CoA also acts as a biosyntheticprecursor.

Increased Acetyl CoA concentrationinhibits pyruvate dehydrogenase

Increased Acetyl CoA also stimulatespyruvate carboxylase


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Increased Acetyl CoA alsostimulates pyruvate carboxylase,

Pyruvate carboxylase is the firststep of gluconeogenesis, so


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Pyruvate is channelled intogluconeogenesis to form glucose

Pyruvate carboxylase is inhibited byADP

When ATP levels are falling, andADP levels are rising, the ADPinhibits pyruvate carboxylase so morepyruvate will be channelled into citricacid 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 Phosphoenolpyruvate carboxykinase


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Reciprocal Control of Pyruvate Kinase (PK)


PK

Oxaloacetate

pyruvate


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Cont.

Pyruvate kinase (PK) catalyses conversion ofPEP to pyruvate in glycolysis

PK is inhibited when energy levles are highand stimulated when energy levles are low


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PK is inhibited by ATP and stimulated byfructose-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-PhosphateF-1,6

bisPase

Fructose-1,6-biphosphate

Pyruvate


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The fructose-1,6-biPase is anotherallosteric enzyme

It is inhibited when energy levels

are low and stimulated whenenergy levels are high

It is inhibited by AMP andstimulated by ATP and Citrate


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The reverse reaction which forms

F-1,6-biP from F-6-P is catalysedby 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.

When blood glucose levels decrease,

glucagon rises.


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Glucagon stimulates gluconeogenesis by the

following mechanism

Glucagon stimulates adenyl cyclase

Adenyl cyclase stimulates formation of

35 cyclic AMP from ATP

cAMP stimulates cAMP dependent

protein Kinase A

P t i Ki A h h l t


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Protein Kinase A phosphorylates abifunctional protein.

The bifunctional protein is made of oneenzyme 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

Regulatory

DomainPhosphofructo

Kinase-2

Fructobiphos

phatase-2

1

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The protein Kinase Aphosphorylates a serine residue on

the bifunctional enzyme and thisleads to activation of F biPase-2 and

the inhibition of PFK-2

Activation of F biPase-2 leads tobreakdown of Fructose-2,6-bisphosphate (F-2,6-biP) and a

decreased levels of F-2,6-biP


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Low levels of F-2,6-bisP inhibitsglycolysis.

At the same time low levels of F-2,6-P will stimulate F-1,6-biPase

and gluconeogenesis

S


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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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The control by glucagon also relies

on the fact that F-2,6-bP stimulatesPFK

Gluconeogenesis

Increased blood glucose


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Control of gluconeogenesis at levels of

Transcription

Glucagon stimulates production of

2 gluconeogenic enzymes:

PEP Carboxykinase and

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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Conversion of G-6-P to glucose is

controlled. This helps to maintain

cellular glucose levels

Control of G-6-P to glucose is bycontrol of the enzyme for the

conversion; Glucose-6-Phosphatase

(G-6-Pase)


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G-6-Pase is only present in Liver andKidney- so only these organs can

release glucose into the blood.

Conversion of G-6-P into glucosetakes place in the Lumen ofendoplasmic reticulum (ER)

Gluconeogenesis takes place in thecytoplasm.


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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-6-Pase


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Vigorous exercise can lead to

oxygen shortage (anaerobicconditions), and energy

requirements must be met byincreased 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 unavailablefor regeneration of NAD via

cellular respiration.


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Instead, large amounts of

NADH are reoxidized by thereduction of pyruvate to lactate.The lactate thus produced can

be transported from muscle tothe liver, where it is reoxidized

by liver lactate dehydrogenaseto yield pyruvate, which isconverted 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 typicallyhigh NAD/NADH ratio (about

700), readily produces moreglucose than it can use.


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Muscle that is vigorously

exercising will enteranaerobiosis and show a

decreasing NAD/NADH ratio,which favours reduction of

pyruvate to lactate.

Gl l t C l


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Glyoxylate Cylce

Occurs in plants, invertebrates andsome microorganisms

Involves the conversion of Acetyl CoA

into succinate

The succinate can be converted into

oxaloacetate and oxaloacetate into PEP


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The PEP can be used to form glucose ingluconeogenesis.

This means that organisms which have

the glyoxylate cycle can use acetyl CoAas a starting material forgluconeogenesis.

Vertebrates do not have the glyoxylatecycle.


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Acetyl CoA cannot be converted

into pyruvate because the following

reaction is irreversible:

Pyruvate

pyruvate dehydrogenase

complexAcetyl 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.

Control of Gluconeogenesis,Lecture 2

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