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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..
8/18/2019 Biochem [Gluconeogenesis]
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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
@
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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
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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
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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
8/18/2019 Biochem [Gluconeogenesis]
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@
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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