CICLO DEL

CIDO CTRICO
CICLO DE KREBS

respiracin celular

El piruvato producido por gluclisis es oxidado completamente hasta

la formacin de H2O y CO2.

Esta fase aerobia del catabolismo es llamada respiracin celular.

Se refiere a aquellos organismos que toman O2 del ambiente y

liberan CO2.

La respiracin celular ocurre en tres grandes procesos.

Produccin de acetil coenzima A.

Oxidacin de acetil Coenzima A.

Transferencia electrnica y fosforilacin oxidativa.

602

produccin
The Citric Acid Cycle de
Acetil-CoA

Chapter 16

Amino Fatty
acids acids

Stage 1
Acetyl-CoA
production

Glucose

Glycolysis

e!

e!

Pyruvate

e!

pyruvate
dehydrogenase
complex

CO2
e!

Acetyl-CoA
Stage 2
Acetyl-CoA

FIGURE 16

three stages
glucose, and
of acetyl gro
electrons ar
FADH2 are
plasma mem
ultimately re
tion of ATP.

and other
and CO2
complex,
of three e
karyotic c
A care

e!

e!

e!

tion of ATP.

Pyruvate
pyruvate
dehydrogenase
complex

Oxidacin de Acetil-CoA
CO2

e!

Acetyl-CoA
Stage 2
Acetyl-CoA
oxidation

Oxaloacetate
e!

Citrate

Citric
acid cycle

e!
e!

CO2

NADH,
FADH2
(reduced e! carriers)

e!

CO2

Stage 3

and other
and CO2
complex,
of three e
karyotic ce
A care
warding in
sic, muchin which
bound to t
formed in
derived fro
anism. Th
illustrates
and alloste
flux throug
is the prot
plexes: !-k
cycle, and
nase, of th

e!
CO2

fosforilacin oxidativa
e!

CO2

NADH,
FADH2
(reduced e! carriers)
e!
Respiratory
(electron-transfer)
chain

ADP + Pi

ATP

Stage 3
Electron transfer
and oxidative
phosphorylation
2H+ + 12 O2
H2O

anism
illust
and
flux t
is the
plexe
cycle
nase
(see
tein
mech
a com

Pyruv

The
drog
an ir
grou

ylation

O2

ugars, fatty
oxidized to
the respiracle, the cardegraded to
n which the
amino acid
ough several

tein structure, cofactor requirements, and reaction

mechanisms of these three complexes doubtless reflects
a common evolutionary origin.

Produccin de
Pyruvate Is Oxidized
to Acetyl-CoA and CO
Acetil-CoA
2

The overall reaction catalyzed by the pyruvate dehydrogenase complex is an oxidative decarboxylation,
irreversible
oxidation
process inde
which
theaminocidos
carboxyl o
an
El piruvato
proveniente
de la degradacin
glucosa,
group
is removed
from
pyruvate
as a molecule
of CO
cidos grasos
es oxidado
mediante
la piruvato
deshidrogenasa
para
2
generar Acetil-CoA y CO2.

O!
O
M D
C
A
C PO
A
CH3
Pyruvate

CO2

CoA-SH
NAD"

TPP,
lipoate,
FAD

"
NADH

pyruvate dehydrogenase
complex (E1 " E2 " E3)

S-CoA
O
M D
C
A
CH3
Acetyl-CoA

#G$% & !33.4 kJ/mol

FIGURE 162 Overall reaction catalyzed by the pyruvate dehydrogenase complex. The five coenzymes participating in this reaction, and

5d_c16_601-630

1/27/04

8:54 AM

Page 603 mac76 mac76:385_reb:

Coenzima A
16.1

Production of Acetyl-CoA (Activated Acetate)

603

Reactive
thiol group

NH2
H
HS CH2

CH2

N C

#-Mercaptoethylamine

CH2

CH2

H CH3

N C C C

CH2

O!
O P

O P

O OH CH3
Pantothenic acid

O!
O

5"

CH2
4"

H
3"

O P

O
CH3

O
H
2"

Adenine

1"

OH

Ribose 3"-phosphate

O!

O!

C
S-CoA

Acetyl-CoA

Coenzyme A

3"-Phosphoadenosine diphosphate

FIGURE 16-3 Coenzyme A (CoA). A hydroxyl group of pantothenic

acid is joined to a modified ADP moiety by a phosphate ester bond,
and its carboxyl group is attached to !-mercaptoethylamine in amide
linkage. The hydroxyl group at the 3" position of the ADP moiety has
a phosphoryl group not present in free ADP. The OSH group of the
mercaptoethylamine moiety forms a thioester with acetate in acetyl-

rier in a number of metabolic reactions. Acyl groups are

covalently linked to the thiol group, forming thioesters.
Because of their relatively high standard free energies
of hydrolysis (see Figs 136, 137), thioesters have a
high acyl group transfer potential and can donate their

(E2), and dihydrolipoyl dehydrogenase (E3)each

present in multiple copies. The number of copies of each
enzyme and therefore the size of the complex varies
among species. The PDH complex isolated from mammals is about 50 nm in diametermore than five times
the size of an entire ribosome and big enough to be visualized with the electron microscope (Fig. 165a). In
the bovine enzyme, 60 identical copies of E2 form a pentagonal dodecahedron (the core) with a diameter of
about 25 nm (Fig. 165b). (The core of the Escherichia
coli enzyme contains 24 copies of E2.) E2 is the point of

E3-binding domain; and the inner-core acyltransferase

domain, which contains the acyltransferase active site.
The yeast PDH complex has a single lipoyl domain with
a lipoate attached, but the mammalian complex has two,
and E. coli has three (Fig. 165c). The domains of E2
are separated by linkers, sequences of 20 to 30 amino
acid residues, rich in Ala and Pro and interspersed with
charged residues; these linkers tend to assume their extended forms, holding the three domains apart.
The active site of E1 has bound TPP, and that of E3
has bound FAD. Also part of the complex are two reg-

Complejo piruvato
deshidrogenasa
50 nm

La deshidrogenacin y descarboxilacin del piruvato para

general Acetil-CoA
FIGURE 165 Structure of the pyruvate dehydrogenase complex
(a) Cryoelectron micrograph of PDH complexes isolated from bovine
requiere la accin secuencial de tres diferentes enzimas
y 5 coenzimas o grupos
kidney. In cryoelectron microscopy, biological samples are viewed at
extremely low temperatures; this avoids potential artifacts introduced
prostticos.
by the usual process of dehydrating, fixing, and staining. (b) Threedimensional image of PDH complex, showing the subunit structure:
E1, pyruvate dehydrogenase; E2, dihydrolipoyl transacetylase; and E3,
dihydrolipoyl dehydrogenase. This image is reconstructed by analysis
of a large number of images such as those in (a), combined with crystallographic studies of individual subunits. The core (green) consists
of 60 molecules of E2, arranged in 20 trimers to form a pentagonal
dodecahedron. The lipoyl domain of E2 (blue) reaches outward to
touch the active sites of E1 molecules (yellow) arranged on the E2 core.
A number of E3 subunits (red) are also bound to the core, where the
swinging arm on E2 can reach their active sites. An asterisk marks the
site where a lipoyl group is attached to the lipoyl domain of E2. To
make the structure clearer, about half of the complex has been cut
away from the front. This model was prepared by Z. H. Zhou et al.
(2001); in another model, proposed by J. L. S. Milne et al. (2002), the
E3 subunits are located more toward the periphery (see Further Reading). (c) E2 consists of three types of domains linked by short polypeptide linkers: a catalytic acyltransferase domain; a binding domain, involved in the binding of E2 to E1 and E3; and one or more (depending
on the species) lipoyl domains.

El complejo piruvato descarboxilasa contiene las enzimas piruvato

deshidrogenasa (E1), dihidrolipoil transacetilasa (E2), y dihidrolipoil
deshidrogenasa (E3)cada una presente en mltiples copias.

Los grupos prosteticos son: Tiamina pirofosfato (TPP), Flavin adenin dinucletido
(FAD), coenzima A (CoA-SH),
Nicotn adenin dinucletido (NAD) y lipoato.
(a)
E1

*
E3

Number of lipoyl
domains varies by species.
E2

E. coli
(3)
N

10 nm

(b)

(c)

Mammals
(2)

Yeast
(1)

Flexible
polypeptide
linker
C

Binding domain
(involved in E2-E1
and E2-E3
binding)
Lipoyl
domain
Acyltransferase
domain
(inner core)

of pyruvate. Step 1 is essentially identical to the reacface of the enzyme complex. The five-reaction setion catalyzed by pyruvate decarboxylase (see Fig.
quence shown in Figure 166 is thus an example of
1413c); C-1 of pyruvate is released as CO2, and C-2,
substrate channeling. The intermediates of the
O leave the complex, and the
which in pyruvate has the oxidation state of an aldehyde,
multistep sequence never
is attached to TPP as a hydroxyethyl group. This first
local concentration of the substrate of E2 is kept very
3
CoA-SH CH3 C S- CoA
H
step is the slowest
therefore limits the rate ofCthe
O and O
O high. Channeling also prevents theft of the activated
overall reaction. It is also the point at which the PDH
acetyl group by other
enzymes that use this group as
Acetyl-CoA
C
C substrate specificity. In step 2
complexCH
exercises
substrate. As we shall see, a similar tethering mecha3 C its
the hydroxyethyl groupO
isoxidized to the level of a car- S nism for
channeling of substrate between active
3 theReduced

Pyruvate

SH

TPP

1
CH3
CO
2

Pyruvate

Hydroxyethyl
TPP

Acyl
lipoyllysine

OTPP

SCH

CHOH
O

CH13

CO2

Hydroxyethyl
TPP

CoA-SH

CH3
Lys

CHOH

transacetylase,
E2

FIGURE 166 Oxidative decarboxylation of pyruvate to acetyl-CoA

PDH complex.by The

fatecomplex.
of pyruvate
tracedis traced
in red.
In Instep
the PDH
The fate ofispyruvate
in red.
step
!
1 pyruvate
reacts with
the boundpyrophosphate
thiamine pyrophosphate
(TPP)of
of
uvate reacts with
the bound
thiamine
(TPP)
pyruvate dehydrogenase (E1), undergoing decarboxylation to the hye dehydrogenase
(E1), derivative
undergoing
decarboxylation to the hydroxyethyl
(see Fig. 1413). Pyruvate dehydrogenase also
!
2 , the transfer
of two electrons
and the acetylalso
group
hyl derivative carries
(see out
Fig.step1413).
Pyruvate
dehydrogenase
from TPP to the oxidized form of the lipoyllysyl group of the core enout step !
2 , the
transfer of two electrons and the acetyl group
zyme, dihydrolipoyl transacetylase (E2), to form the acetyl thioester of
PP to the oxidized
form lipoyl
of the
lipoyllysyl
of the core
enthe reduced
group.
Step !
3 is agroup
transesterification
in which
the
dihydrolipoyl transacetylase (E2), to form the acetyl thioester of
uced lipoyl group. Step !
3 is a transesterification in which the

SH
SH

Dihydrolipoyl
transacetylase,
Dihydrolipoyl
E2

E 166 Oxidative decarboxylation of pyruvate to acetyl-CoA

SH
NADH + H+

FAD

Reduced
lipoyllysine

Lys

Oxidized
lipoyllysine

CH3

S- CoA

Acetyl-CoA

Acyl
lipoyllysine
lipoyllysine

TPP

dehydrogenase,
E1

SH

H
SOxidized

TPP

Pyruvate
dehydrogenase,
E1 Pyruvate

lipoyllysine

FADH
2 + H+
NADH

FAD

NAD+

5
FADH2

Dihydrolipoyl
NAD+
dehydrogenase,
Dihydrolipoyl E
3

dehydrogenase,
E3

OSH group of CoA replaces the OSH group of E2 to yield a

OSH group of CoA replaces the OSH group of E2 to yield acetyl-CoA

and
the reduced
fully reduced
(dithiol)
form
ofInthe
and
the fully
(dithiol) form
of the lipoyl
group.
step lipoyl
!
4 di- group. In ste
hydrolipoyl
dehydrogenase
(E3) promotes (E
transfer
of two hydrogen
hydrolipoyl
dehydrogenase
transfer of two
3) promotes
atoms from the reduced lipoyl groups of E2 to the FAD prosthetic group
atoms from the reduced lipoyl groups of E2 to
the FAD prosthe
of E3, restoring the oxidized form of the lipoyllysyl group
of E2.
!
In of
step E
!
53, the
reduced FADH
E3 transfers a form
hydride ion
NADlipoyllysyl
,
restoring
the2 ofoxidized
of tothe
gro
forming NADH. The enzyme complex is now ready for another catIn step 5 the reduced FADH2 of E3 transfers a hydride ion
alytic cycle. (Subunit colors correspond to those in Fig. 165b.)

forming NADH. The enzyme complex is now ready for an

alytic cycle. (Subunit colors correspond to those in Fig. 16

16.2

607

Reactions of the Citric Acid Cycle

CICLO DEL CIDO CTRICO

Acetyl-CoA
1
Condensation

O
CH3

S-CoA

H2O
CoA-SH

citrate
synthase

HO

COO!

CH2

CH2

COO!

2a

COO!

CH2

COO!

Dehydration

Citrate

Oxaloacetate

Dehydrogenation

COO!

Citric acid
cycle

malate
dehydrogenase

H2O

aconitase

COO!
HO
Malate

COO!

CH

CH2

CH2

COO!

COO!

COO!

cis-Aconitate

7
Hydration

fumarase

NADH

H2O
2b

aconitase

Hydration

H2O
COO!
Fumarate

CH2

CH
FADH2

HC

COO!

HO

COO!

COO
succinate
dehydrogenase

isocitrate
dehydrogenase

6
Dehydrogenation

CH2
CH2
COO

CH2

COO!
succinyl-CoA
synthetase
!

CH2

Succinate

COO

!-ketoglutarate
dehydrogenase
complex

GTP
(ATP)
5
Substrate-level
phosphorylation

S-CoA

GDP O
(ADP) Succinyl-CoA
" Pi

FIGURE 167 Reactions of the citric acid cycle. The carbon atoms

COO!

Isocitrate

3
Oxidative
decarboxylation

CO2

CH2
C

COO!

CH2

CoA-SH

COO!

CoA-SH

!-Ketoglutarate

CO2
4
Oxidative
decarboxylation

reaction step corresponds to a numbered heading on pages 608612.

FORMACIN DE CITRATO

La primera reaccin del ciclo es la condensacin de Acetil-CoA con

oxaloacetato para formar citrato.

Reaccin catalizada por la citrato sintasa.

#G$! % 13.3 kJ/mol

N H

H2C

O
H
HC C S- CoA

COO

Oxaloacetate

Citrate synthase

Acetyl-CoA

Asp375

MECHANISM FIGURE 169 Citrate synthase. In the mammalian citThe thioester

in acetyl-CoA
the ordered
methyl rerate synthase
reaction, linkage
oxaloacetate
binds first,activates
in a strictly
375 abstracts a proton from the methyl
hydrogens,
and
Asp
action sequence. This binding triggers a conformation change that
group, forming an enolate intermediate.
opens up the binding site for acetyl-CoA. Oxaloacetetate is specifically
oriented in the active site of citrate synthase by interaction of its two
1
carboxylates with two positively charged
Arg residues (not shown here).
The detailsEl
of intermediario
the mechanism are
in the
figure.
Citrate
sedescribed
hidroliza
y regenera
la
Synthase Mechanism
CoA-SH
y produce
citrato.
The
intermediate
is stabilized
by hydrogen bonding to
274
and/or protonation by His (full protonation is shown).
H
274
N 274His
His

CoA-SH

H
HC HCOO
O
+
His320
H

HO C
HC COO
C S- CoA
N H O C COO

Enol intermediate
H2C COO CH2 COO
Citrate
H
:

2O

H
N

His320

Asp375

Asp375

uently hydrolyzed, regenerating

The enol(ate) rearranges to attack the carbonyl carbon of
citrate.
274

Reactions
of the Citric
Acidestabiliza
Cycle
609bonding
TheElintermediate
is stabilized
by hydrogen
to
intermediario
se
por
la

274 (full protonation is shown).

and/or
protonation
The
intermediate
isby
stabilized
by hydrogen
bondingcon
to
formacin
de
unHis
puente
de hidrgeno
274 (full protonation is shown).
and/or protonation by His
la His 247.
H pro- 274
not dissociate from the active site. Aconitase can
His
N
mote the reversible addition of H2O to the doubleH
bond
His274
N

Althou
Althou
contain
contain
tion
is
tion is
consum
consum
steadysteady
sulfur
sulfur
ing
of t
ing of t
additio
additio

of enzyme-bound cis-aconitate in two different Nways,

one leading to citrate and
the other to isocitrate:N
H

H
N
O
H
"
H2O
H
H
O +
CH2 COO 320H2N
CH2 COO
O
His
+ N H O C COO HC
H C S- CoA
"
"
320

HO C COO His
C O
COO
intermediate
HC Enol
C SCoA
N H
H2C
C COO
COO aconitase
aconitase
H Enol intermediate
"
"
C COO
H C COO
H2C COO
H
O O
H
H
O O
375
Asp
cis-Aconitate
Citrate
375
CHAsp
COO"
2
The enol(ate) rearranges to attack the carbonyl
carbon of
"
274 positioned
H C COO
oxaloacetate,
with
His
to
abstract
the
El enolato
se rearregla
atacarcarbon
el proton
The enol(ate)
rearranges
to attackpara
the carbonyl
of
320 acts as a general acid.
274
it
had
previously
donated.
His
oxaloacetate,
with
His
positioned
to
abstract
the
proton
HO
C
H
carbono carbonilo del oxaloacetato.
it had previously donated. His320 acts" as a general acid.
COO
2
Isocitrate
2

His320

16.2

Although
at del
pH grupo
7.4 and 25 !C
Lathe
Aspequilibrium
375 extraemixture
un protn
containsmetilo
less than
10% isocitrate,
in the cell
the reacformando
un intermediario
enolato
tion is pulled to the right because isocitrate is rapidly
H lowering
consumed in the next step of the cycle,
His274 its
N
steady-state concentration. Aconitase contains
an iron+
sulfur center (Fig. 1610), which acts both
N in the binding of the substrate
at the active site and in the catalytic
H
H
N
addition or removal of HO2O.C COO

"

MECHAN
rate
synt
MECHAN

action
s
rate synt
opens
actionup
s
oriented
opens u
carboxyl
oriented
The
deta
carboxy
Synthase
The deta

#G$!
% 13.3 kJ/mol
The resulting condensation
generates
citroyl-CoA.
The resulting
condensation
Although the equilibrium
mixture
at pHgenerates
7.4 and citroyl-CoA.
25 !C
H
contains less than 10% isocitrate, in the cell theNreac-His274
H
His274
tion is pulled to the right because isocitrate is rapidly
N
N its
consumed in the next step of the cycle, lowering
H
steady-state concentration.
H Aconitase containsOanNironN
sulfur center (Fig. 1610),
which acts bothHin O
theHbindH
HC
C
S- CoA
320
N active
His at the
ing of the substrate
site and in H
the catalytic
N
S- CoA
C C
HO HC
COO
addition or removal
His320of H2O.N
HO

C
COO
CH2COO

Citroyl-CoA

CH2 COO
Asp375

Citroyl-CoA

Synthase

CoA-SH

CoA-SH
H2O

H2O

Asp375

La condensacin genera citroil-CoA

The thioester is subsequently hydroly

MECHANISM FIGURE 169 Citrate synthase. In the mammalian

citCoA-SH
and producing citrate.

The thioester is subsequently hydrol

Formacin de isocitrato
va cis-aconitato

La Enzima aconitasa (Aconitato hidratasa) cataliza la transformacin

reversible de citrato a isocitrato a travs de la formacin de un
intermediario de cido tricarboxlico (cis-aconitato).

Oxidacin de isocitrato a
-cetoglutarato y CO2.

La isocitrato deshidrogenasa cataliza la descarboxilacin oxidativa de isocitrato

para formar -cetoglutarato.

1- El Isocitrato se une a la enzima y es oxidado por transferencia de H+ a NAD+ o NADP+, dependiente de la

isocitrato deshidrogenasa.
2- La interaccin del oxigeno del grupo carbonilo con el Mn2+ incrementa la capacidad del grupo carbonilo para
para extraer un electrn y facilitar la descarboxilacin.
3- El rearreglo del enol intermediario genera el -cetoglutarato.

eration of NADPH, which is essential for reductive anabolic reactions.

OO"

H2

ron-sulfur center
es of the enzyme
of the carboxyl
with a hydroxyl
on the enzyme
on-sulfur center
ral properties of
Fig. 195).

d CO2 In the

Oxidacin
de -cetoglutarato
4 Oxidation of !-Ketoglutarate
to Succinyl-CoA and CO a
The next
step is anotherCoA
oxidative
decarboxylation,
in
succinil
y
CO
2.
which !-ketoglutarate is converted to succinyl-CoA
2

and CO2 by the action of the !-ketoglutarate dehy!

drogenase
serves asenelectron
accepEl
siguiente paso complex;
es otra reaccinNAD
de descarboxilacin
la cual el -cetoglutarato
se
en succinil
CoA ycarrier
CO2 por laof
accin
complejo -cetoglutarato
torconvierte
and CoA
as the
thedelsuccinyl
group. The
deshidrogenasa con NAD+ como aceptor de electrones y CoA como acarreador del
energy
of oxidation of !-ketoglutarate is conserved in
grupo
succinilo.
the formation of the thioester bond of succinyl-CoA:
CoA-SH

CH2

COO"

CH2
C

COO"
#-Ketoglutarate

NAD!

NADH

#-ketoglutarate
dehydrogenase
complex

CH2

COO"

CH2
C

! CO2

S-CoA

O
Succinyl-CoA

$G%& ' "33.5 kJ/mol

This reaction is virtually identical to the pyruvate

dehydrogenase reaction discussed above, and the

Conversin de succinilCoA
a Succinato.
5 Conversion
of Succinyl-CoA
to Succinate Succinyl-CoA,

16.2

(a)

like acetyl-CoA, has a thioester bond with a strongly

negative standard free energy of hydrolysis (!G"#
El siguiente paso en el ciclo del cido ctrico libera energa por la ruptura de un enlace
$36
In lathe
nextdestep
citric
acid
tioesterkJ/mol).
que se usa para
formacin
GTP oof
ATPthe
con una
ganancia
netacycle,
de -2.9 KJ/mol.
energy
released in the breakage of this bond is used to
El succinato se forma en el proceso.
drive the synthesis of a phosphoanhydride bond in eiLa enzima que cataliza la reaccin es la succinil CoA sintetasa.
ther GTP or ATP, with a net !G"# of only $2.9 kJ/mol.
Succinate is formed in the process:
CH2

COO$

CH2
C

S-CoA

O
Succinyl-CoA

GDP % Pi

GTP CoA-SH

COO$
CH2

succinyl-CoA
synthetase

CH2
COO$
Succinate

!G"# & $2.9 kJ/mol

The enzyme that catalyzes this reversible reaction is

called succinyl-CoA synthetase or succinic thioki-

His
Succinyl-CoA
synthetase

as ATP. There is no change in free energy for the nucleoside diphosphate kinase reaction; ATP and GTP are
energetically equivalent.

Oxidacin de succinato a
fumarato

6 Oxidation of Succinate to Fumarate The succinate

El succinato formado en la reaccin anterior es oxidado a fumarato
formed mediante
from succinyl-CoA
is oxidized
to fumarate by
la flavoprotena succinato
deshidrogenasa.
the flavoprotein succinate dehydrogenase:
COO&
CH2
CH2
COO

&

Succinate

FAD

FAD H2

succinate
dehydrogenase

OOC

&

C
C

COO&

Fumarate

"G#$ % 0 kJ/mol

In eukaryotes, succinate dehydrogenase is tightly bound

to the inner mitochondrial membrane; in prokaryotes, to

This e
tion o
doub
the re
rase i

Cycle

Hidratacin de fumarato
a malato

P) at the expense of
ve decarboxylation of
phosphorylation, like
ic reactions catalyzed
ydrogenase and pyruP formed by succinylinal phosphoryl group
le reaction catalyzed
ase (p. 505):

TP

La(formally,
reaccinfumarate
es catalizada
por la fumarasa.
hydratase).
The transition state
in this reaction is a carbanion:
H

OOC

&

C
C

COO&

OH

&

fumarase

C&
C

OOC

&

COO&
OH

Carbanion
transition state

Fumarate

"G#$ % 0 kJ/mol

of either isozyme of
nservation of energy
e energy for the nuon; ATP and GTP are

H!
fumarase

H
H

arate The succinate

ized to fumarate by
drogenase:

OOC

&

C
C

COO&
OH
H

Malate

"G#$ % &3.8 kJ/mol

H

COO&

COO

COO
L-Malate

D-Malate

Oxidacin de malato a
Oxidation of Malate
to Oxaloacetate In the last reaction
oxaloacetato.

8
of the citric acid cycle, NAD-linked L-malate dehy En la ltima reaccin del ciclo el NAD+ unido a la malato
drogenase
catalyzes the oxidation of L-malate to oxdeshidrogenasa cataliza la oxidacin de malato a oxaloacetato.
aloacetate:
COO& NAD!
HO C H
CH2
COO

&

L-Malate

NADH ! H

COO&

O
malate
dehydrogenase

C
CH2
COO&

Oxaloacetate

"G#$ % 29.7 kJ/mol

The equilibrium of this reaction lies far to the left under

Acetyl-CoA

Citrate
Oxaloacetate
NADH
Malate

Isocitrate
Citric
acid
cycle

CO2

NADH

-Ketoglutarate
CO2

NADH

Fumarate
Succinyl-CoA

FADH2
Succinate

GTP
(ATP)

o
o
p
tr
a
ro
!
m
p
th
th
(s
is

Acetyl-CoA

Citrate
Oxaloacetate
NADH
Malate

Isocitrate
Citric
acid
cycle

CO2

NADH

-Ketoglutarate
CO2

NADH

Fumarate
Succinyl-CoA

FADH2
Succinate

GTP
(ATP)

oxida
oxidi
plex
trans
as 32
round
! 30
maxi
plete
the s
the a
(see
is clo

Why

The other anaplerotic reactions shown in Table 162

are also regulated to keep the level of intermediates high
enough to support the activity of the citric acid cycle.
FIGURE
Biosynthetic
produced
by anctrico
incompletees deficiente
Cuando
elprecursors
ciclo del
cido
en oxaloacetato o
1614
Phosphoenolpyruvate (PEP) carboxylase, for example,
citric acid cycle in anaerobic bacteria. These anaerobes lack !intermediario
es carboxilado
paraintermediate
producirfructose 1,6is activated
by the glycolytic
ketoglutaratecualquier
dehydrogenase otro
and therefore
cannot carry el
out piruvato
the
bisphosphate, which accumulates when the citric acid
complete citric
acid cycle. !-Ketoglutarate
and succinyl-CoA serve as
oxaloacetato
.
cycle operates too slowly to process the pyruvate genprecursors in a variety of biosynthetic pathways. (See Fig. 1613 for
the normal direction of these reactions in the citric acid cycle.)
erated by glycolysis.

La adicin enzimtica del grupo carboxilo al piruvato requiere energa

del ATP.
Pyruvate

Glucose
pyruvate
carboxylase

Fatty acids,
sterols
Acetyl-CoA

PEP carboxykinase

Glutamine
Phosphoenolpyruvate
(PEP)

Serine
Glycine

PEP
carboxylase

Asparagine

Pyrimidines

Tyrosine

Malate

Citric
acid
cycle

Intermediates of the citric acid cycle are drawn off as

precursors in many biosynthetic pathways. Shown in red
are four anaplerotic reactions that replenish depleted cycle
intermediates (see Table 162).

-Ketoglutarate

Glutamate

malic
enzyme

Pyruvate

Succinyl-CoA

Tryptophan

FIGURE 1615 Role of the citric acid cycle in anabolism.

Proline
Arginine

Aspartate

Cysteine
Phenylalanine

Citrate

Oxaloacetate

Porphyrins,
heme

Purines

eactions.

activity decreases and phosphatase action removes the

phosphoryl groups from E1, activating the complex.
The PDH complex of plants, located in the mitochondrial matrix and in plastids, is inhibited by its products, NADH and acetyl-CoA. The plant mitochondrial

Regulacin del ciclo del cido

ctrico

cetyl-CoA by the Pyruvate

Complex Is Regulated by Allosteric
echanisms

ex of mammals is strongly inhibited by

yl-CoA and NADH, the products of the
d by the complex (Fig. 1618). The aln of pyruvate oxidation is greatly enng-chain fatty acids are available. AMP,
all of which accumulate when too litinto the citric acid cycle, allosterically
H complex. Thus, this enzyme activity
en ample fuel is available in the form

ulation of metabolite flow

lex through the citric
complex is allosterically
]/[ADP], [NADH]/[NAD"],
A] ratios are high,
-sufficient metabolic state.
ecrease, allosteric activation
n results. The rate of flow
d cycle can be limited by
citrate synthase substrates,
etyl-CoA, or of NAD",
its conversion to NADH,
AD-dependent oxidation
bition by succinyl-CoA,
slows the cycle by
. In muscle tissue, Ca2"
nd, as shown here,
lding metabolism to
umed by contraction.

Pyruvate

ATP, acetyl-CoA,
NADH, fatty acids

pyruvate
dehydrogenase
complex

AMP, CoA, NAD", Ca2"

Acetyl-CoA
NADH, succinyl-CoA, citrate, ATP
ADP
citrate
synthase

Citric
acid
cycle

Oxaloacetate

malate
dehydrogenase

Citrate

Isocitrate
isocitrate
dehydrogenase

ATP
Ca2", ADP

NADH

Malate

-Ketoglutarate
FADH2

!-ketoglutarate
dehydrogenase
complex

succinate
dehydrogenase

GTP
(ATP)

Succinyl-CoA

succinyl-CoA, NADH
Ca2"