300
chapter 15
Carbohydrate Metabolism II: Gluconeogenesis, Glycogen Synthesis and Breakdown, and Alternative Pathways
salvage pathways (Chapter 27), generation of NADPH
for biosynthetic reactions in the cytosol, and interconver-
sion of pentoses and hexoses are more valuable processes.
Thus, the pathway provides a means for generating glu-
cose from ribose and other pentoses that can be converted
to ribose 5-phosphate.
The pentose phosphate pathway is active in a wide vari-
ety of cell types, particularly those which have a high rate
of nucleotide synthesis or which utilize NADPH in large
amounts. Nucleotide synthesis is greatest in rapidly divid-
ing tissues, such as bone marrow, skin, and gastric mu-
cosa. NADPH is needed in the biosynthesis of fatty acids
(liver, adipose tissue, lactating mammary gland), choles-
terol (liver, adrenal cortex, skin, intestine, gonads), steroid
hormones (adrenal cortex, gonads), and catecholamines
(nervous system, adrenal medulla) and in other reactions
that involve tetrahydrobiopterin. NADPH is also needed
for maintenance of a reducing atmosphere in cells exposed
to high concentrations of oxygen radicals including ery-
throcytes, lens and cornea of the eye, and phagocytic cells,
which generate peroxide and superoxide anions during the
process of killing bacteria.
Oxidative Phase
C O O “
C H
2
0 P 0 32“
1
H C O H
J r -
- O
I
\ f
\
?
2
°
H O C H
K ? H
h
) =
o
'
1
н о Ч Г
j T
H C O H
H
1
O H
H C O H
6-PhosphogIuconp-<5-lactone
H
2
C 0 P 0 32"
6
-P hosphoglucon ate
The equilibrium of this reaction lies far to the right.
In the third step, 6-phosphogluconate is oxidatively
decarboxylated to ribulose 5-phosphate in the presence
of NADP+, catalyzed by 6-phosphogluconate dehydroge-
nase:
N AD PT
N A D P H + H +
+
-
+
-,
C O O “
C O O -
C O j
1
j
+
HCOH
HCOH
C H 2OH
HOCH
1
c=o
Mn!+
C = 0
HCOH
'
1
HCOH
I
HCOH
HCOH
HCOH
HCOH
1
H2C 0 P 0 32-
1
H2C 0 P 0 32*
H2C O P 0 32'
The first reaction in this phase is the oxidation of
glucose-6-phosphate to 6-phosphoglucono-5-lactone and
reduction of NADP+ to NADPH, catalyzed by glucose-6-
phosphate dehydrogenase (G6PD):
G luco se
6
-p h o sp h ate
6-Phosphoglucono-
3-lactone
The equilibrium of the reaction lies far to the right.
Under physiological conditions, G6PD is a dimer of
identical subunits of M.W. 55,000. The active enzyme
contains a molecule of NADP+, removal of which causes
dissociation into inactive monomers. Enzymes from rat,
cow, and human are very similar, and active interspecies
hybrid enzymes can be formed
in vitro.
The enzyme is
inhibited by NADPH at the concentration normally found
in hepatocytes and erythrocytes, by ATP competing with
glucose-6-phosphate for binding, and by cyanate. A large
reserve capacity of G6PD activity exists in the red blood
cell and, presumably, in other tissues.
In the second step, 6-phosphoglucono-5-lactone is
hydrolyzed to 6-phosphogluconate by 6-phosphogluco-
nolactonase:
6
-P h o s p h o g lu co n ate
3-K eto -6-p h o sp h o g lu co n ate
o-R ibulose-5-phosphate
3-Keto-6-phosphogluconate is a probable intermediate.
The reaction is similar to those catalyzed by malic enzyme
(in gluconeogenesis) and by isocitrate dehydrogenase (in
the TCA cycle).
Nonoxidative Phase
In this phase, ribulose 3-phosphate is converted to
glucose-6-phosphate. Stoichiometrically, this requires the
rearrangement of six molecules of ketopentose phosphate
to five molecules of aldohexose phosphate (Figure 15-20).
It has been claimed that the pathway shown in Figure 15-20
occurs primarily in fat tissue and that a modified pathway
involving arabinose 5-phosphate and octulose 8-phosphate
occurs in liver cells. The overall scheme of the nonoxida-
tive phase should be considered tentative.
There are only four types of reactions in this part of the
pathway:
1. Interconversion of a keto sugar (ribulose 5-phosphate
or fructose-6-phosphate) and an aldo sugar (ribose
5-phosphate or glucose-6-phosphate) by an isomerase.
2. Inversion of the optical configuration of an optically
active carbon atom, as in a conversion of ribulose
5-phosphate to xylulose 5-phosphate by an
epimerase.
