PROCESOS BIOLOGICOS

GLUCONEOGENESIS

Dr. ERWIN DE LA FUENTE ORTEGA

 Objetivos Clase:

1.  Reconocer las enzimas, sustratos de

la gluconeogénesis.
2.  Conocer principales mecanismos de
regulación de la vía.
 IMPORTANCIA DE LA GLUCOSA.
FUENTE DE ENERGÍA

o  Tejidos que dependen casi

exclusivamente de Glucosa:
Cerebro (sistema nervioso),
eritrocitos, testículos, médula
renal y tejidos embrionarios.

o  Sistema nervioso: 120 g de

glucosa diarios.

o  Nuestro cuerpo puede sintetizar

glucosa por la vía metabólica
GLUCONEOGÉNESIS.
En ayuno
 GLUCONEOGENESIS

o  Ocurre principalmente HIGADO

en hígado y en menor
grado en riñón.

o  Es activada por
hormonas de manera en GLUCOSA
periodos de ayuno.

o  Mantiene la homeostasis
de glucosa sanguínea
(80-110mg/dl).

Human phisiology, 12 ed,

Stuart Ira Fox
 LA CELULA OCUPA 7 ETAPAS REVERSIBLES DE GLICOLISIS
PARA GLUCONEOGENESIS 14.4 Gluconeogenesis 553

TABLE 14–2 Free-Energy Changes of Glycolytic Reactions in Erythrocytes

Glycolytic reaction step !G!" (kJ/mol) !G (kJ/mol)
1 Glucose $ ATP 88n glucose 6-phosphate $ ADP % 16.7 % 33.4
2 Glucose 6-phosphate 34 fructose 6-phosphate 1.7 0 to 25
3 Fructose 6-phosphate $ ATP 88n fructose 1,6-bisphosphate $ ADP % 14.2 % 22.2
4 Fructose 1,6-bisphosphate 34 dihydroxyacetone phosphate $ 23.8 % 6 to 0
glyceraldehyde 3-phosphate
5 Dihydroxyacetone phosphate 34 glyceraldehyde 3-phosphate 7.5 0 to 4
$ $
6 Glyceraldehyde 3-phosphate $ Pi $ NAD 34 1,3-bisphosphoglycerate $ NADH $ H 6.3 % 2 to 2
7 1,3-Bisphosphoglycerate $ ADP 34 3-phosphoglycerate $ ATP % 18.8 0 to 2
8 3-Phosphoglycerate 34 2-phosphoglycerate 4.4 0 to 0.8
9 2-Phosphoglycerate 34 phosphoenolpyruvate $ H2O 7.5 0 to 3.3
10 Phosphoenolpyruvate $ ADP 88n pyruvate $ ATP % 31.4 % 16.7

Note: !G"# is the standard free-energy change, as defined in Chapter 13 (pp. 491–492).
Glycolysis Gluconeogenesis !G is the free-energy change calculated from the actual concentrations of glycolytic
Glucose intermediates present under physiological conditions in erythrocytes, at pH 7. The gly-
ATP
LAS ETAPAS Pi
IRREVERSIBLES 1, 3 y 10 deben
colytic reactions bypassed in gluconeogenesis are shown in red. Biochemical equations
are not necessarily balanced for H or charge (p. 501).
hexokinase
ser desarrolladas por otras enzimas.
glucose 6-phosphatase

ADP Glucose 6-phosphate H2O

Conversion of Pyruvate to Phosphoenolpyruvate Requires
Two Exergonic Reactions
 GLUCONEOGÉNESIS.
Las tres reacciones (irreversibles de la glucolisis) son
rodeadas por otras enzimas

Glucolisis Glucosa Gluconeogénesis:

1. Hexoquinasa (o ΔG<0
Glucoquinasa) (enzima1).
o  Enzimas que “Rodean
3. Fosfofructoquinasa E1Su EB3 (Bypass)” de la glucolisis.
(PFK1) (enzima 3) E3 EB2 o  O Reacciones de rodeo.
10. Piruvato Quinasa E10 EB1
(enzima 10). 2ATP
Energía
Piruvato
 PRIMERA REACCIÓN DE RODEO
Dos etapas.
o  Transformación de piruvato en fosfoenolpiruvato (PEP)
CITOSOLICO

1era Etapa MITOCONDRIAA NADH

o  Enzima Piruvato Carboxilasa
o  Biotina VitB7, une Bicarbonato al piruvato.
o  ATP (activa al bicarbonato).
o  Enzima Mitocondrial.
o  NADH, para exportar oxalacetato al citosolo

2da Etapa
o  Enzima PEP Carboxiquinasa
o  GTP
o  Enzima Mitocondrial o Citosolica

Oxalacetato es mitocondrial, tb es intermediario del ciclo de Krebs.

 phosphate by PFK-1 (Table 14–2, step 3 ). Because this
reaction is highly exergonic and therefore irreversible
SEGUNDAinREACCIÓN DE RODEO.
intact cells, the generation of fructose 6-phosphate
from fructose 1,6-bisphosphate (Fig. 14–16) is catalyzed
2!
by a different enzyme, Mg -dependent fructose 1,6-
La Fructosa-1,6 bis-fosfato es transformada en Fructosa-6P por hidrólisis del fosfato-1
bisphosphatase (FBPase-1), which promotes the es-
sentially irreversible hydrolysis of the C-1 phosphate
(not phosphoryl group transfer to ADP):
o  Enzima: Fructosa-1,6-
bisfosfatasa (FBPasa-1). Fructose 1,6-bisphosphate ! H2O ¡
o  Cofactor Mg2+ fructose 6-phosphate ! Pi
o  Citosol ¢G¿° " #16.3 kJ/mol

FBPase-1 is so named to distinguish it from another,

similar enzyme (FBPase-2) with a regulatory role, which
we discuss in Chapter 15.

TABLE 14–3 Sequential Reactions in Gluconeogenesis St

Pyruvate ! HCO#3 ! ATP 88n oxaloacetate ! ADP ! Pi
Oxaloacetate ! GTP 34 phosphoenolpyruvate ! CO2 ! GD
refore unnecessary. After the pyru-
e lactate dehydrogenase reaction is The third bypass is the final reaction of gluconeogenesis,
TERCERA REACCION DE RODEO.
e mitochondrion, it is converted to the dephosphorylation of glucose 6-phosphate to yield
yruvate carboxylase, as described glucose (Fig. 14–16). Reversal of the hexokinase reac-
etate, however, is converted directly tion (p. 532) would require phosphoryl group transfer
Transformación de glucosa-6P en glucosa por hidrólisis del fosfato.
ondrial isozyme of PEP carboxyki- from glucose 6-phosphate to ADP, forming ATP, an ener-
s transported out of the mitochon- getically unfavorable reaction (Table 14–2, step 1 ). The
on the gluconeogenic path. The reaction catalyzed by glucose 6-phosphatase does not
ytosolic isozymesGlucosa-6-fosfatasa.
o  Enzima: of PEP carboxyki- require synthesis of ATP; it is a simple hydrolysis of a
separate genes inMg2+
o  Cofactor: the nuclear chro- phosphate ester:
g another
o  Se example
expresa en ofhepatocitos
two distincty riñón Glucose 6-phosphate ! H2O ¡ glucose ! Pi
the same reaction but
“GLUCONEOGENICOS” having differ-
¢G¿° " #13.8 kJ/mol
ns or metabolic roles (recall the
y epitelio intestino delgado que permite
ase). This Mg2!-activated enzyme is found on the lumenal side
la absorción de glucosa.
of the endoplasmic reticulum of hepatocytes, renal cells,
e 1,6-Bisphosphate to Fructose and epithelial cells of the small intestine (see Fig. 15–28),
o  NO SE EXPRESA EN but not in other tissues, which are therefore unable to
econd Bypass
MUSCULO NI CEREBRO. supply glucose to the blood. If other tissues had glucose
c reaction that cannot participate in 6-phosphatase, this enzyme’s activity would hydrolyze
the phosphorylation of fructose 6- the glucose 6-phosphate needed within those tissues for
(Table 14–2, step 3 ). Because this glycolysis. Glucose produced by gluconeogenesis in the
xergonic and therefore irreversible liver or kidney or ingested in the diet is delivered to
generation of fructose 6-phosphate these other tissues, including brain and muscle, through
sphosphate (Fig. 14–16) is catalyzed the bloodstream.
2!
me, Mg -dependent fructose 1,6-
FBPase-1), which promotes the es-
e hydrolysis of the C-1 phosphate
Gluconeogenesis Is Energetically Expensive, but Essential
catalyzed the bloodstream.
COSTO ENERGETICO DE LA GLUCONEOGENESIS
tose 1,6- Para sintetizar una molécula de glucosa.
es the es-
hosphate
Gluconeogenesis Is Energetically Expensive,but
o  SE NECESITAN 6 NUCLEOTIDOS TRIFOSFATO DE ALTA
Essential
ENERGIA (4ATP +2GTP).
The sum of the biosynthetic reactions leading from
o  Es un proceso costoso para asegurar que sea irreversible (ΔG’o<0).
pyruvate to free blood glucose (Table 14–3) is
phate ! Pi 2 Pyruvate ! 4ATP ! 2GTP ! 2NADH ! 2H ! 4H2O ¡ !

6.3 kJ/mol glucose ! 4ADP ! 2GDP ! 6Pi ! 2NAD! (14–9)

another, For each molecule of glucose formed from pyruvate, six

ole, which high-energy phosphate groups are required, four from
ATP and two from GTP. In addition, two molecules of
SUSTRATOS PRECURSORES PARA LA GLUCONEOGENESIS.

1. Sustratos precursores de Ciclo de Cori

3C (tres carbonos). ej
LACTATO,
PIRUVATO,
GLICEROL.

2. Amino-ácidos
gluconeogenicos.

3. Los mamíferos no son

capaces de convertir ácidos
grasos en glucosa.
 vate or to intermediates of the citric acid cycle. Such an esse
amino acids can therefore undergo net conversion to in adip
AMINO-ACIDOS GLUCONEOGENICOS.
glucose and are said to be glucogenic (Table 14–4).
Alanine and glutamine, the principal molecules that
and so
adipocy
Mayoría excepto Leucina
transport y Lisina.
amino groups from extrahepatic tissues to the nesis, kn
liver (see Fig. 18–9), are particularly important gluco- pyruvat
genic amino acids in mammals. After removal of their reaction

Glucosa Entrada a la via. the dihy

(see Fig

TABLE 14–4 Glucogenic Amino Acids, Grouped by

Site of Entry Glycolys
PEP Pyruvate Succinyl-CoA ScoA If glycol
Alanine Isoleucine* glucone
Cysteine Methionine cose) w
Piruvato Glycine Threonine rates, th
Serine Valine the prod
Piruvato Desh. Threonine
Tryptophan*
Fumarate F ase-1 ca
Acetil-CoA Phenylalanine*
ATP # fr
!-Ketoglutarate αC Tyrosine*

O Arginine
Glutamate
Oxaloacetate O
C Glutamine
Asparagine
Aspartate
Fructose
Histidine
Proline
The sum
M I Note: All these amino acids are precursors of blood glucose or liver glycogen, because

Ciclo Krebs they can be converted to pyruvate or citric acid cycle intermediates. Of the 20 common
amino acids, only leucine and lysine are unable to furnish carbon for net glucose
synthesis. These t
αC *These amino acids are also ketogenic (see Fig. 18–21). the two

F
S ScoA
 REGULACION
GLUCONEOGENESIS,
Esta coordinada con la
regulación de la glucólisis.
 REGULACION GLUCONEOGENESIS y GLUCOLISIS.

•  Ambas rutas no deben estar

activas al mismo tiempo de Glucosa
otra manera genera un “ciclo ΔG<0
Inútil”, lo que lleva a un E1Su EB3
desperdicio de energía. E3 EB2
E10 EB1
2ATP
o  Tipos de regulación: Energía
Alostérico, a través de sensar la energía
celular.
Hormonal, regulación fisiológica.
Piruvato
 lular signal that the cell is meeting its current needs for
energy-yielding metabolism by the oxidation of fats
and proteins.

High [ATP]
REGULACION ALOSTERICA
The corresponding step in gluconeogenesis is the
conversion of fructose 1,6-bisphosphate to fructose 6-
Regulación por concentración
phosphatede Nucleótidos
(Fig. 15–15). Theque determinan
enzyme nivel de Energía Celular.
that catalyzes
this reaction, FBPase-1, is strongly inhibited (allosteri-
cally) by AMP; when the cell’s supply of ATP is low (cor-
[ATP], Alta energía celular, inhibe glicolisis.
responding to high [AMP]), the ATP-requiring synthesis
[ADP], Baja energía, activa
of glucose slows. glicolisis.
Thus these opposing steps in the glycolytic and gluco-
[AMP], Baja energía
[Fructose 6-phosphate]
neogeniccelular, activaand
pathways—PFK-1 glicolisis
FBPase-1—are e inhibe
regulated gluconeogénesis.
(b) in a coordinated and reciprocal manner. In general, when
sufficient concentrations of acetyl-CoA or citrate (the
ATP AMP, ADP

Gluconeogenesis
- ! ATP Fructose 1,6- ! ADP
bisphosphate

ATP Fructose 6-phosphate Pi

citrate fructose 2,6-
bisphosphate ATP

(c)
PFK-1
PFK-1
ADP
FBPase-1
FBPasa
Fosfo-fructo-quinasa-11 AMP Fructosa-bi-fosfatasa
citrate
not only a substrate for PFK-1 but also an ADP Fructose 1,6-bisphosphate H2O
t of the glycolytic pathway. When high
P] signals that ATP is being produced
t is being consumed, ATP inhibits PFK-1 Glycolysis
o an allosteric site and lowering the affin- FIGURE 15–15 Regulation of fructose 1,6-bisphosphatase (FBPase-1)
nzyme for its substrate fructose 6-phos-
15–14). ADP and AMP, which increase ATP
and phosphofructokinase-1 (PFK-1). The important role of fructose
2,6-bisphosphate in the regulation of this substrate cycle is detailed in
ation as consumption of ATP outpaces subsequent figures.

X Inhibición.
Activación
 EFECTO LARGO PLAZO DE LA INSULINA
Sobre Gluconeogénesis y Glucólisis.

o  Se controla la
expresión genética a
nivel transcripcional
(síntesis de mRNA) Estimula
de varias enzimas de
glucolisis y
(+)
gluconeogénesis.
Inhibe
(-)
 FBPase-
!F26BPEFECTO RAPIDO INSULINA
20 "F26BP
Estas hormonas controlan a la enzima bi-funcional
0
PFK-2.
05 0.1 0.2 0.4 0.7 1.0 2.0 4.0 0 50
[Fructose 6-phosphate] (mM) [Fructose 1,6-bisphosphat
Estado (a) Estado
(b) de
Nutrición Gluconeogenesis Ayuno.
(Desayuno,
almuerzo, Cena)
ATP Fructose 6-phosphate Pi

INSULINA PFK-1 F26BP FBPase-1 GLUCAGON

Estimula Estimula
glucólisis ADP Fructose 1,6-bisphosphate H2 O gluconeogénesis.

Glycolysis
(c)

ctose 2,6-bisphosphate in regulation of gly- Thus F26BP activates PFK-1 by increasing its apparen
esis. Fructose 2,6-bisphosphate (F26BP) has tose 6-phosphate (see Fig. 15–14b). (b) FBPase-1 ac
zymatic activities of phosphofructokinase-1 by as little as 1 !M F26BP and is strongly inhibited by
me) and fructose 1,6-bisphosphatase (FBPase- sence of this inhibitor (blue curve) the K0.5 for fruc
RESUMEN:
La gluconeogénesis usa 7 pasos reversibles de la glucolisis y rodean (bypass) tres
etapas irreversibles.

La gluconeogénesis es un proceso anabólico que requiere de energía para cada

glucosa se necesitan 6 NTP (4ATP y 2GTP) y 2 NADH.

La gluconeogénesis se desarrolla en Hígado y Riñón para proveer de Glucosa al

cerebro, musculo y eritrocitos.

La gluconeogénesis usa sustratos derivados de 3 carbonos (Lactato, glicerol) y

amino-ácidos (de la degradación de proteínas) para la síntesis de glucosa.

La gluconeogénesis esta regulada de manera coordinada con la glucolisis.

Esto impide que se pierda energía.

La gluconeogénesis es regulada de manera Alostérica u Hormonal.

Las hormonas tienen dos efectos, i) regular la expresión de enzimas de la

gluconeogénesis y glicolisis ii) Controlar la concentración del modulador
alostérico F2,6BP.