VIII.

PENTOSE PHOSPHATE PATHWAY

In the irreversible oxidative reactions of the pathway, one carbon of glucose-6-phosphate is released as CO
2
;
NADPH is generated; and ribulose-5-phosphate is produced (Fig. 6.26).
Figure6.26 An overview of the pentose phosphate pathway.
NADPH is used for reductive biosynthesis (particularly of fatty acids) and for protection against oxidative
damage (e.g., by reduction of glutathione).
Ribulose-5-phosphate provides ribose-5-phosphate for nucleotide biosynthesis or generates pentose
phosphates, which enter the nonoxidative portion of the pathway.
In the reversible nonoxidative reactions, pentose phosphates produced from ribulose-5-phosphate are
converted to the glycolytic intermediates fructose-6-phosphate and glyceraldehyde-3-phosphate.
Because the nonoxidative reactions are reversible, they can be used to generate ribose-5-phosphate for
nucleotide synthesis from intermediates of glycolysis.
A. Reactions of the pentose phosphate pathway
1. The oxidative reactions (Fig. 6.27)
Figure6.27 The oxidative reactions of the pentose phosphate pathway. These
a. Glucose-6-phosphate is converted to 6-phosphogluconolactone, and NADP
+
is reduced to
NADPH + H
+
.
1. Enzyme: glucose-6-phosphate dehydrogenase
b. 6-Phosphogluconolactone is hydrolyzed to 6-phosphogluconate.
1. Enzyme: gluconolactonase
c. 6-Phosphogluconate undergoes an oxidation, followed by a decarboxylation. CO
2
is released,
and a second NADPH + H
+
is generated from NADP
+
. The remaining carbons form ribulose-5-
phosphate.
1. Enzyme: 6-phosphogluconate dehydrogenase
CLINICAL CORRELATES
A deficiency of glucose-6-phosphate dehydrogenase causes insufficient amounts of
NADPH to be produced under certain conditions (e.g., when antimalarial drugs are
being used). As a result, glutathione is not adequately reduced and, in turn, is not
available to reduce compounds that are produced by the metabolism of these drugs.
Red blood cells lyse, and a hemolytic anemia can occur. This is an X-linked disorder,
and individuals who inherit this mutation have protection against malaria.
2. The nonoxidative reactions (see Fig. 6.26)
a. Ribulose-5-phosphate is isomerized to ribose-5-phosphate or epimerized to xylulose-5-
phosphate.
b. Ribose-5-phosphate and xylulose-5-phosphate undergo reactions, catalyzed
bytransketolase and transaldolase, that transfer carbon units, ultimately forming fructose 6-
phosphate and glyceraldehyde-3-phosphate.
1. Transketolase, which requires thiamine pyrophosphate, transfers two-carbon units.
2. Transaldolase transfers three-carbon units.
3. Overall reactions of the pentose phosphate pathway (Fig. 6.28)
Figure6.28 A balanced sequence of reactions in the pentose phosphate pathway.

B. Functions of NADPH (see Fig. 6.26)
1. The pentose phosphate pathway produces NADPH for fatty acid synthesis. Under these
conditions, the fructose-6-phosphate and glyceraldehyde-3-phosphate generated in the pathway
reenter glycolysis.
2. NADPH is also used to reduce glutathione (-glutamylcysteinylglycine).
a. Glutathione helps to prevent oxidative damage to cells by reducing hydrogen peroxide (H
2
O
2
)
(see Chapter 4).
b. Glutathione is also used to transport amino acids across the membranes of certain cells by the -
glutamyl cycle.
C. Generation of ribose-5-phosphate (see Fig. 6.26)
1. When NADPH levels are low, the oxidative reactions of the pathway can be used to generate
ribose-5-phosphate for nucleotide biosynthesis.
2. When NADPH levels are high, the reversible nonoxidative portion of the pathway can be used
to generate ribose-5-phosphate for nucleotide biosynthesis from fructose-6-phosphate and
glyceraldehyde-3-phosphate.


VII. FRUCTOSE AND GALACTOSE METABOLISM
Although glucose is the most abundant monosaccharide derived from the diet, fructose and galactose are
usually obtained in significant quantities, mainly from sucrose and lactose.
After fructose and galactose enter the cells, they are phosphorylated on carbon 1 and converted to
intermediates in the pathways of glucose metabolism.
Fructose is metabolized mainly in the liver, where it is converted to fructose-1-phosphate and cleaved to
produce DHAP and glyceraldehyde, which is phosphorylated to glyceraldehyde-3-phosphate. These two
triose phosphates are intermediates of glycolysis.
Fructose can be produced from sorbitol, which is generated from glucose.
Galactose is phosphorylated to galactose-1-phosphate, which reacts with UDP-glucose. The products are
glucose-1-phosphate and UDP-galactose, which is epimerized to UDP-glucose. The net result is that galactose
is converted to the glucose moieties of UDP-glucose and glucose-1-phosphate, intermediates in the pathways
of glucose metabolism.
UDP-galactose is used in the synthesis of glycoproteins, glycolipids, and proteoglycans.
UDP-galactose reacts with glucose in the mammary gland to form the milk sugar lactose.
Galactose can be reduced to galactitol.
A. Metabolism of fructose
The major dietary source of fructose is the disaccharide sucrose in table sugar and fruit, but it is also
present as the monosaccharide in corn syrup, which is used as a sweetener.
1. Conversion of fructose to glycolytic intermediates (Fig. 6.23)
Figure6.23 Fructose metabolism (in red) and its relationship to glycolysis. In the liver
a. Fructose is metabolized mainly in the liver where it is converted to pyruvate or, under fasting
conditions, to glucose.
1. Fructose is phosphorylated by ATP to form fructose-1-phosphate. The enzyme is fructokinase.
2. Fructose-1-phosphate is cleaved by aldolase B to form DHAP and glyceraldehyde, which is
phosphorylated by ATP to form glyceraldehyde-3-phosphate. DHAP and glyceraldehyde-3-
phosphate are intermediates of glycolysis. (Aldolase B is the same liver enzyme that cleaves
fructose-1,6-bisphosphate in glycolysis.)
b. In tissues other than liver, the major fate of fructose is phosphorylation by hexokinase to form
fructose-6-phosphate, which enters glycolysis. Hexokinase has an affinity for fructose about one-
twentieth of that for glucose.
2. Production of fructose from glucose (the polyol pathway)
a. Glucose is reduced to sorbitol by aldose reductase, which reduces the aldehyde group to an
alcohol.
b. Sorbitol is then reoxidized at carbon 2 by sorbitol dehydrogenase to form fructose.
c. Fructose, derived from glucose in seminal vesicles, is the major energy source for sperm cells.
CLINICAL CORRELATES
There are two disorders associated with fructose metabolism. Fructokinase is
deficient inessential fructosuria; therefore, fructose cannot be metabolized as rapidly as normal.
Blood fructose levels rise, and fructose appears in the urine. The condition is benign. The more serious
disorder is hereditary fructose intolerance (HFI). In HFI, aldolase B, the primary liver isozyme of the
glycolytic enzyme aldolase, is defective. Under such conditions, aldolase B still functions normally in
glycolysis (and other isozymes of aldolase may participate in glycolysis) but not in fructose metabolism (only
aldolase B can cleave fructose- 1-phosphate). Fructose-1-phosphate accumulates and inhibits glucose
production, causing severe hypoglycemia if fructose is ingested. Dietary fructose (found mainly in
sucrose) must be avoided.
B. Metabolism of galactose
The disaccharide lactose, found in milk or milk products, is the major dietary source of galactose.
1. Conversion of galactose to intermediates of glucose pathways (Fig. 6.24)
Figure6.24 The conversion of galactose to intermediates of glucose metabolism
a. Galactose is phosphorylated by ATP to galactose-1-phosphate. The enzyme isgalactokinase.
b. Galactose-1-phosphate reacts with UDP-glucose and forms glucose 1-phosphate and UDP-
galactose. The enzyme is galactose 1-phosphate uridylyl transferase.
c. UDP-galactose is epimerized to UDP-glucose in a reaction that is readily reversible. The enzyme
is UDP-glucose epimerase.
d. Repetition of the above-mentioned three reactions results in conversion of galactose to UDP-
glucose and glucose-1-phosphate.
1. In the liver, these glucose derivatives are converted to blood glucose during fasting or to glycogen
after a meal. In various tissues, the glucose-1-phosphate forms glucose-6-phosphate and feeds into
glycolysis.
CLINICAL CORRELATES
Disorders associated with galactose metabolism give rise to galactosemias. The
appearance of high concentrations of galactose in the blood after lactose ingestion may
be due to a galactokinase deficiency or to a uridylyl transferase deficiency. In
both conditions, galactose accumulates and is reduced to galactitol, which
causescataracts. Uridylyl transferase deficiency is more severe, causing elevation
of galactose-1-phosphate, which inhibits phosphoglucomutase, interfering with
glycogen synthesis and degradation. Hypoglycemia can occur after ingestion of
galactose. Dietary galactose (found mainly in milk and milk products, but also in
artificial sweeteners and as a filler in some medications) must be avoided.
2. Other fates of UDP-galactose (Fig. 6.25)
Figure6.25 The metabolism of uridine diphosphate galactose (UDP-galactose). UDP
a. UDP-galactose can be produced either from galactose or from glucose via UDP-glucose and an
epimerase.
1. UDP-galactose supplies galactose moieties for the synthesis of glycoproteins, glycolipids,
and proteoglycans.
a. The enzyme that adds galactose units to the growing polysaccharide chains is galactosyl
transferase.
2. UDP-galactose reacts with glucose in the lactating mammary gland to produce the milk
sugar lactose.
a. The modifier protein, -lactalbumin, binds to galactosyl transferase, lowering its K
m
for glucose
so that glucose adds to galactose (from UDP-galactose), forming lactose.
3. Conversion of galactose to galactitol
a. Aldose reductase reduces the aldehyde of galactose to an alcohol, forming galactitol. Galactitol is a
C4 epimer of sorbitol