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chapter 15
Carbohydrate Metabolism II: Gluconeogenesis, Glycogen Synthesis and Breakdown, and Alternative Pathways
Gluconeogenic Pathway
Gluconeogenesis from pyruvate is essentially the reverse
of glycolysis, with the exception of three nonequilibrium
reactions (Figure 15-1). These reactions are
Glucose + ATP
>4-
hexokinase or glucokinase
(15.1)
glucose-6-phosphate2
+ ADP3
+ HH
Fructose-6-phosphate2- + ATP
fructose-1,6-bisphosphate4- + ADP3- + H+
(15.2)
4
_
6-phosphofructokinase
T,._i_ pyruvatekinase
Phosphoenolpyruvate
+ ADP3
+ H+ ------------4
pyruvate- + ATP4-
(15.3)
In gluconeogenesis, these reactions are bypassed by alter-
nate steps also involving changes in free energy and also
physiologically irreversible.
ATP +
co
2
+ h,o ■
ADP + R -
Pyruvate
Pyruvate carboxylase (in mitochondria)
Oxaloacetate
GTP-
GDP + CO,-
Phosphoenolpyruvate carboxykinase
(in mitochondria and cytosol)
Phosphoenolpyruvate
H,0—
2-Phosphoglycerate
3-Phosphoglycerate
A T P -
ADP-
1,3-Bisphosphoglycerate
NADH + H+-
NAD+"
Glyceraldehyde 3-phosphate
f;
Dihydroxyacetone phosphate
Fructose
6
-phosphate
Glucose
6
-phosphate
RO
'
GIucose-
6
-phosphatase (endoplasmic reticulum
Glucose
FIGURE 15-1
Pathway of gluconeogenesis from pyruvate to glucose. Only enzymes
required for gluconeogenesis are indicated; others are from glycolysis. The
overall reaction for the synthesis of one molecule of glucose from two
molecules of pyruvate is 2Pyruvate + 4ATP4“ + 2GTP4-
+
2NADH + 2H+ + 6H20 -> Glucose + 2NAD+ +
4 ADP3- + 2GDP3" +
6
Pf- + 4H+
Conversion of pyruvate to phosphoenolpyruvate in-
volves two enzymes and the transport of substrates and
reactants into and out of the mitochondrion. In glycoly-
sis, conversion of phosphoenolpyruvate to pyruvate results
in the formation of one high-energy phosphate bond. In
gluconeogenesis, two high-energy phosphate bonds are
consumed (ATP -* ADP + Pi; GTP —> GDP + Pj)
in reversing the reaction. Gluconeogenesis begins when
pyruvate, generated in the cytosol, is transported into the
mitochondrion—through the action of a specific carrier—
and converted to oxaloacetate:
acetyl-CoA, Mg2+
Pyruvate- + HCO- + ATP4------------------ >
pyruvate carboxylase
oxaloacetate2- + ADP3- + P2- + H+
Like many CC^-fixing enzymes, pyruvate carboxylase
contains
biotin
bound through the e-NPL of a lysyl residue
(Chapter 18).
The second reaction is the conversion of oxaloacetate
to phosphoenolpyruvate:
Oxaloacetate2
+ GTP4-(or ITP4-)
phosphoenolpyruvatecarboxylinase (PEPCK)
-------------------------------------------------------->
phosphoenolpyruvate3
+ CO
2
+ GDP3 (or IDP3 )
In this reaction, inosine triphosphate (ITP) can substitute
for guanosine triphosphate (GTP), and the CO
2
lost is the
one fixed in the carboxylase reaction. The net result of
these reactions is
Pyruvate + ATP + GTP (or ITP)
- 4
phosphoenolpyruvate + ADP + P; + GDP (or IDP)
Pyruvate carboxylase is a mitochondrial enzyme in an-
imal cells, whereas PEPCK is almost exclusively mito-
chondrial in some species (e.g., pigeons) and cytosolic in
others (e.g., rats and mice). In humans (and guinea pigs),
PEPCK occurs in both mitochondria and cytosol. An in-
teresting consequence of this species differences is that
quinolinate, an inhibitor of cytoplasmic PEPCK, causes
hypoglycemia in rats but is less active in humans and
guinea pigs.
In humans, oxaloacetate must be transported out of the
mitochondrion to supply the cytosolic PEPCK. Because
there is no mitochondrial carrier for oxaloacetate and its
diffusion across the mitochondrial membrane is slow, it
is transported as malate or asparate (Figure 15-2). The
malate shuttle carries oxaloacetate and reducing equiva-
lents, whereas the aspartate shuttle, which does not require
a preliminary reduction step, depends on the availability
of glutamate and a-ketoglutarate in excess of tricarboxylic
acid (TCA) cycle requirements.
