Biochem [Gluconeogenesis]

8/18/2019 Biochem [Gluconeogenesis]

1/6

Chapter

9

GLUCOhIE,OGENE,SIS

Glycolysis

and

Gluconeogenesis

Glucose

occupies

a

central

role

in

metabolism,

both as

a

fuel and

as

precursor

of

other

biochemicals.

The

brain

and

the

red

blood cells

are

almost

completely

dependent on

glucose

as

an energy

source.

The

liver's

capacity

to store

glycogen

is only sufficient

to

supply

with

glucose

for

about

half a

day

under

fasting,

intense

exercise,

low

carbohydrate

diet or

starvation

conditions.(Degradation

of

glycogen

to

glucose

is

the other

way

of

maintaining

blood

glucose

levets).

ln these cases

the body's

needs

must be

met by

gluconeogenesis

(new

glucose

synthesis)

from

noncarbohydrate

precursorc.

Gluconeogenesis

occurs

in liver

(90%)

and,

to

a

smaller

extent

in kidney

(10%).

The noncarbohydrate

precursors

that

can

be converted

to

glucose

include

lactate,

pyrwate,

citric

acid

cycle

intermediates,

and

the

carbon

skeletons

of

most

amino

acids

(excluding

Leu

and Lys).

First, all

of

these

substrates

must be

converted

to oxaloacetate,

starting

substance

for

gtuconeogenesis. Gluconeogenesis

is highly

endergonic.

For

example,

the

pathway

leading

from

phosphoenolpyruvate

to

glucos+G-phosphate

requires

6 molecules

of

ATP.

Gtuconeogenesis

is

a

pathway

consisting

of eleven

enryme-catalyzed

reactions.

lt

can

begin

in

the

mitochondria or

cytoplasm,

depending

on

the substrate

being

used.

Many

of

the

readions

are

the

reversible

steps

found

in

glycolysis.

However,

gluconeogenesis is not reversible

process

contrary

to

glycolysis.

ln

glycolisis

thrce

reactions

occur,

catalyzed

by

pyruvate

kinase,

phosphofrucfose

kinase and

hexokinase,

which

are

absent

in

gluconeogenesis.

(Ihese

three

reactions

are

indicated

by

mark,

O, in

the

next slide..


2/6

GLUCONEOGENESIS

E

pyru

Ph

osp h o

e no lopy

ruv

ate car

bory

las e

fructose

-116-bis-P

#

phosphofructokinase

fructose-

fr 6

-bis

-phosphatase

fructose

-6- P

glucose

-6-

P

g

lu

c o

s e -6-p h os

p

h at os e

Carboxylation

of

pyruvate

ln course

of

gluconeogenesis

pyruvate

can

not

be

converted

to

phosphoenolpyruvate

indirectly. GluconCogeneiis

begins

in

the

mitochondria

with the

formation of

oxaloacetate through

carboxylation

of

pyrwate.

This reaction also

requires

one

molecule of

ATR and

is

catalyzed

by

pyruvate

carborylase.

This

enzyme

is

stimulated

by

high levels

of

acetyl-CoA

(produced in

F.

oxidation

in the

liver)

and

inhibiled

by

high

levels

of

ADP. ln

next

step

(afrer

transfening of

oxaloacetate

to

cytosol)

oxaloace{ate

is

converted

to

phosphoenolpyruvate.

This

way

the

irreversible

reaction catalyzed

by

pyruvate

kinase is omitted.

"(*

oxaloacetate

vde

carborylase

ooc'o'

I

H-C-H

I

C:O

I

oF-o-

oxaloacetate

A

#

T

hexnkinase

@


3/6

Transport

of

oxaloacetate

from

mitochondion

to

cytosol

Oraloacetate

generated

in

mitochondion

must

be

transferred

to

cytosol

where

the enrymes

that convert

phospatenolpyruvate

to

glucose

are

present.

OxaloacE{ate

is

tmnsported

across

milochondrial

membrane

in

twoways.

l.Oxatoacetate

must

be

converted

to

aspartate

to which

mitochondrial

transport

system

exist

(malat+aspartate shuttle).

This conversion

is

catalyzed

by

mitochondrial

asparate

aminotansfurase.

ln

cytosol

aspartate

is

converted

back to

oxaloacetate

by

cytosol aspante

aminotansfurase.

Next, oxaloacetate

is

converted

phospatenolpyruvate

.

2.Oxaloacetate

is

converted

to

malate

by

mitochondrial

malate

dehydrogenase,

which is

transferred

to

cytosol,

and

converted

back

to

oxaloacehte

by

cytosol

malate

dehydrogenase.

flhese

two

sepante

ways

are

shown on

nextslide).

3.Also possible

third

way of

transport

of oxaloacetate

from mitochondrion to cytosol via

citric

acid.

lt is

mainly

used

to

transport

citric

acid

generated

by

conversion

of

lactate.

Oxaloacetate

transport

from

mitochondion to cytosol

Oxaloacetate

is transfened

from

mitochondrion

to

cytosol

by

malate.

aspartate

shuttle.

First,

in

mitochondrion

oxaloacetate

must be

converted

to

aspartate

or malate

(or

citrate).

MITOCHONDRION

co,

14

v

Phosphoenolopyruv

1

=

pyruvate

carboxylase

2

=

malate

dehydrogenaso-

(mitochondrial)

3

=

malate dehydrogenase-

(cytosol)

4

=

phosphoenolopyruvate

carbo{ykinase

$

=

asparagate

aminotransferEs'

(mitochondrial)

$

=

asparagate

aminotransferase.

(cytosol)

7

=

scitrate synthase

I

=

citrate

ATP-lyase

acefyl

-SCoA

-

r?

lt

Eitrate

I

@

ll

rB*

I

UBU

rcim-l

@

yt.

Frar".e

I

\'

.1f

*V

cetyl

SGoAt"/

\

i

Z

,

*8Sii

*8**fr*ffi*]i

uuu

lt

uuuuilffiilt

lt

MDH+Ff

tcrrosoll


4/6

DECARBOXYLATION

OF OXALOACETATE

ln

cytosol

oxaloacetate

regenerated

is decaborylized

and

phosphatorylated

by

phoshoenolopyruvate

caborykinase.

ln this

reaction

GTP

is

energy's

donor.

Phoshoenolopyruvde

is

formed

which

(in

next step)

is

converted

to

fructos+1,6-bis-phosphate

in

reversed

reaction

of

glycolysis

catalyzed

by

enrymes

taking

part

in

this

process.

I

H_C-H

I

C=O

I

ooc-o'

oxaloacetate

phosfroenotopyruvafe

carrboxyklnase

H-C-H

il

Q:O-

I

o"c-o'

phoshoenolopyruvate

Dephosphorylation

of

fructose-l,6-bis-phosphate

This

reaction

is

catatyzed

by

ftucfos*1,&bis

phosphatase

and allows

to

omit

irrevercible step

of

glycolysis

(catalyzed

by

phosphofructokinase.f.

Activity

of

this

phosphohse

is

regulated

by

level of cell'energy.

High level

of

AMP

inhibits

the activity of

enryme,

when

the

high

level

of

ATP

together

with low

level

of

AMP

stimulate

gluconeogenesis.

This

enryme

is

also

inhibited by

fructose.2,6-blb-phoshate

(negative

allosteric

efector)

which

is

regulated

by

hormones.

H

'

./il

-C-O-

r

\..-/

C:O

I

HO-C-H

I

H-C-OH

I

H-C-OH

H-i-o-fil

I-\_/

H

fru ctose-l,6

-bis-p

hos

ph

ate

fru

ctose- 1, 6-b

i s-ph os ha tas

e

T

H-?-OH

?=o

HO-C-H

H-c:6r\

H-i\+r/

H-?-o-o

H

fructose6-phosphate


5/6

Dephosphorylation of

glucose-G-phosphate

Ftydmtysis

of

glucose-G-phosphate

catalyzed by

glucose6pfiosphahse

allorrus to omit inerenible

step of

glycohfsis

catalized

by

hexolcinase

or

glucokinase.

Generate

glucose

can be transfened

to

blood

and

transported

to

different

tissues .

Gluconeogenesis

is very

endoergic

process.

One

molecule

of

glucose

is formed

from

two

molecules

of

pyruvate

.

ln

this

process

*3=

6

energy

rich

bonds

are

decayed..

ln

gluconeogenesis

4ATP

+

2

GTP

and2

(NADH

+

H*)

pair

is

used.

2Pyruvate

+

4ATP

+

2GTP

+

2NADH

+

2H*

GIUCOSE

+

4ADP

+

zGDP

+

2NAD

+

6Pi

lntroduction of

propionyl

residue to

gluconeogenesis

FatS acids with

uneven number

of

carbon atoms are

converted

to

n

molecules

of

acetyl

-

S-GoA

and

one

molecule

of

propionyl-S-CoA.

Propionyl-

S-CoA

is formed

from

amino

acids

with branched

sidechains.

e.g.

Val

and

from

side chain

of cholesterol. Propionyl-

S.CoA

is

converted to methylmalonyl-S-CoA,

which

is

isomerised

to

succinyl-S-CoA,

which is

the

substrate

in

tricarborylic

acid

cycle

,

where

via

Nastgpnie

pzez

succinate,

fumarate

and

malate is

converted

to

oxaloacetate,

i.

e., a substrate

for

gluconeogenesis.

.

H.

,.O

c

I

H-C-OH

I

HO-C-H

I

H-C-OH

I

H-C-OH

H-i-o-{il

I-\_/

H

glucose6-phoshate

propionyl€-CoA

COz -

from carborybiotin

COB12

-

coenzyrne

Btz

o

il

C-S-CoA

C?,

ArP

AD

+

Pi

O

,-E;*'\\'tsscoA

H

r*rruu^yrc,lB

O"C_O-

H.

.,O

c

I

H-C-OH

I

HO-C-H

I

H-C-OH

+

I

H-C-OH

I

H-C-OH

I

H

glucose

giluceso-6-phoshatase

CoB12

methylmalonyl-S-CoA

,nuhse

o

il

C-S€oA

,-i-,

H_C_H

I

o"c-o-

succinyl-S-CoA

ethylomalonyl-S-CoA

l0


6/6

@

re

Cts

Regulation

of

gluconeogenesis

acetylo--S€oA

|

frustose-2,6-b'"@

I

AMP

t

fruaos-1,6-bis-

O

phoshoenolopyruvafe

carboxykinase

2

OXALOACETATE

FRUCTOSE.I,6-biS{P

FRUCTOSEf{

P

GLUCOSE6

t_

I@

Y

The

factors

(enzrymes)

that

regulate

the

particular

steps

of

gluconeogenesis

are

shown

in

BLTJE

stucos

*i,o-

f@

bL-pnospianase

l-_@

11

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