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Gluconeogenesis+

Evaluations

4/23/2003

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Overview of Glucose Metabolism

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Gluconeogenesis

Gluconeogenesis is the process whereby precursors

such as lactate, pyruvate, glycerol, and amino acids

are converted to glucose.

asting re!uires all the glucose to be synthesi"ed

#rom these non$carbohydrate precursors.

%ost precursors must enter the &rebs cycle at some

point to be converted to o'aloacetate.

('aloacetate is the starting material #or

gluconeogenesis

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)yruvate is converted to o'aloacetate be#ore

being changed to )hosphoenolpyruvate

*. )yruvate carbo'ylase catalyses the )$driven

#ormation o# o'aloacetate #rom pyruvate and -(2

2. )E) carbo'yinase )E)-& concerts o'aloacetate

to )E) that uses G) as a phosphorylating agent.

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)yruvate carbo'ylase re!uires biotin as a

co#actor

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Gluconeogenesis is not 1ust the reverse

o# glycolysis

everal steps are di##erent so that control o# one

pathway does not inactivate the other. owever

many steps are the same. hree steps are di##erent#rom glycolysis.

* )yruvate to )E)

2 ructose *,$ bisphosphate to ructose$$

phosphate

3 Glucose$$)hosphate to Glucose

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5iotin is an essential nutrient

here is hardly any de#iciencies #or biotin because it

is abundant and bacteria in the large intestine also

mae it.

owever, de#iciencies have been seen and are nearly

always lined to the consumption o# raw eggs.

6aw eggs contain vidin a protein that binds biotin

with a &d7 *0$*8that is one tight binding reaction9

:t is thought that vidin protects eggs #rom bacterial

invasion by binding bioitin and illing bacteria.

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)E) carbo'yinase

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cetyl$-o regulates pyruvate

carbo'ylase

:ncreases in o'aloacetate concentrations increase

the activity o# the &rebs cycle and acetyl$-o is a

allosteric activator o# the carbo'ylase. oweverwhen ) and ;

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ransport between the mitochondria

and the cytosol

Generation o# o'aloacetate occurs in the mito$

chondria only, but, gluconeogenesis occurs in the

cytosol. )E)-& is distributed between both

compartments in humans, while in mice, it is only#ound in the cytosol. :n rabbits, it is #ound in the

mitochondria. Either )E) must be transported

across the membranes or o'aloacetate has to be

transported. )E) transport systems are seen in the

mitochondria but o'aloacetate can not be trans$

ported directly in or out o# the mitochondria.

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ydrolytic reactions bypass )& and

e'oinase

he hydrolysis o# #ructose$*,$phosphate and

glucose$$ phosphate are separate en"ymes #rom

glycolysis. Glucose$$phosphatase is only #ound in

the liver and idney. he liver is the primary organ#or gluconeogenesis.

Glucose + 2;

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6egulators o# gluconeogenic en"yme activity

En"yme llosteric llosteric En"yme )rotein :nhibitors ctivators )hosphorylation ynthesis

PFK ATP, citrate AMP, F2-6P

FBPase AMP, F2-6PPK Alanine F1-6P nactivates

P!r" #arb" Acet!l#oA

P$P#K Gluco%on

PFK-2 #itrate AMP, F6P, Pi nactivates

FBPase-2 F6P Gl!cerol-&-P Activates

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ructose$$phosphate

PFK-2 PFK-2 F2,6Pase F2,6Pase

ructose$2,$bis)hosphate

ructose$*,$bis)hosphate

PP

)&$* 5)ase

+ $

cAMP-'e(en'ent (rotein )inase

AMP *+

ATP *-

#itrate *-

AMP *-

AMP *+

F-6-P *+

citrate *-

F-6-P *-

ormonal control of %l!col!sis an' %luconeo%enesis

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he glyo'ylate pathway

Onl! (lants .ave t.e abilit! to convert acet!l-#oA to

O/aloacetate 'irectl! wit.out (ro'ucin% re'ucin% e0uilivents

of A" T.is is 'one in t.e %l!o/!3ome, se(arate from t.e

mitoc.on'ria an' allows a re(lenis.ment of o/aloacetate"

socitrate l!ase - cleaves isocitrate into succinate an'

%l!o/!late" T.e succinate %oes to t.e mitoc.on'ria

Malate s!nt.ase ma)es malate from %l!o/!late an' Acet!l-

#oA"

T.e O/aloacetate can %o 'irectl! to carbo.!'rate s!nt.esis"

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Gl!co%en 4tora%e

5 Gl!co%en is a -%lucose (ol!mer5 *1 lin)a%es

5 *16 lin)e' branc.es ever! 7-1

resi'ues

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Gl!co%en Brea)'own or Gl!co%enol!sis

5 T.ree ste(s8Gl!co%en (.os(.or!lase

Gl!co%en + Pi 9-: %l!co%en + G1P*n resi'ues *n-1 resi'ues

8Gl!co%en 'ebranc.in%

8P.os(.ofructomutase

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Gl!co%en P.os(.or!lase

;e0uires

P!ri'o/al-P

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Gl!co%en ebranc.in% $n3!me

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P.os(.ofructomutase

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Gl!co%en 4!nt.eisis

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?P-%lucose P!ro(.or!lase

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Gl!co%en 4!nt.ase