118
166 / CHAPTER 20
unit comprising carbons 1 and 2 of a ketose onto the
aldehyde carbon of an aldose sugar. It therefore effects
the conversion of a ketose sugar into an aldose with two
carbons less and simultaneously converts an aldose sugar
into a ketose with two carbons more. The reaction re-
quires Mg
2+
and thiamin diphosphate(vitamin B
1
) as
coenzyme. Thus, transketolase catalyzes the transfer of
the two-carbon unit from xylulose 5-phosphate to ribose
5-phosphate, producing the seven-carbon ketose sedo-
heptulose 7-phosphate and the aldose glyceraldehyde
3-phosphate. Transaldolase allows the transfer of a
three-carbon dihydroxyacetone moiety (carbons 1–3)
from the ketose sedoheptulose 7-phosphate onto the al-
dose glyceraldehyde 3-phosphate to form the ketose
fructose 6-phosphate and the four-carbon aldose erythrose
4-phosphate. In a further reaction catalyzed by transke-
tolase,xylulose 5-phosphate donates a two-carbon unit
to erythrose 4-phosphate to form fructose 6-phosphate
and glyceraldehyde 3-phosphate.
In order to oxidize glucose completely to CO
2
via
the pentose phosphate pathway, there must be enzymes
present in the tissue to convert glyceraldehyde 3-phos-
phate to glucose 6-phosphate. This involves reversal of
glycolysis and the gluconeogenic enzyme fructose 1,6-
bisphosphatase.In tissues that lack this enzyme, glyc-
eraldehyde 3-phosphate follows the normal pathway of
glycolysis to pyruvate.
The Two Major Pathways for the
Catabolism of Glucose Have
Little in Common
Although glucose 6-phosphate is common to both
pathways, the pentose phosphate pathway is markedly
different from glycolysis. Oxidation utilizes NADP
rather than NAD, and CO
2
, which is not produced in
glycolysis, is a characteristic product. No ATP is gener-
ated in the pentose phosphate pathway, whereas ATP is
a major product of glycolysis.
Reducing Equivalents Are Generated
in Those Tissues Specializing
in Reductive Syntheses
The pentose phosphate pathway is active in liver, adipose
tissue, adrenal cortex, thyroid, erythrocytes, testis, and
lactating mammary gland. Its activity is low in nonlactat-
ing mammary gland and skeletal muscle. Those tissues in
which the pathway is active use NADPH in reductive
syntheses, eg, of fatty acids, steroids, amino acids via glu-
tamate dehydrogenase, and reduced glutathione. The
synthesis of glucose-6-phosphate dehydrogenase and
6-phosphogluconate dehydrogenase may also be induced
by insulin during conditions associated with the “fed
state” (Table 19–1), when lipogenesis increases.
Ribose Can Be Synthesized in Virtually
All Tissues
Little or no ribose circulates in the bloodstream, so tis-
sues must synthesize the ribose required for nucleotide
and nucleic acid synthesis (Chapter 34). The source of
ribose 5-phosphate is the pentose phosphate pathway
(Figure 20–2). Muscle has only low activity of glucose-
6-phosphate dehydrogenase and 6-phosphogluconate
dehydrogenase. Nevertheless, like most other tissues, it
is capable of synthesizing ribose 5-phosphate by reversal
of the nonoxidative phase of the pentose phosphate
pathway utilizing fructose 6-phosphate. It is not neces-
sary to have a completely functioning pentose phosphate
pathway for a tissue to synthesize ribose phosphates.
THE PENTOSE PHOSPHATE PATHWAY
& GLUTATHIONE PEROXIDASE PROTECT
ERYTHROCYTES AGAINST HEMOLYSIS
In erythrocytes, the pentose phosphate pathway pro-
vides NADPH for the reduction of oxidized glu-
tathione catalyzed by glutathione reductase,a flavo-
protein containing FAD. Reduced glutathione removes
H
2
O
2
in a reaction catalyzed by glutathione peroxi-
dase,an enzyme that contains the seleniumanalogue
of cysteine (selenocysteine) at the active site (Figure
20–3). This reaction is important, since accumulation
of H
2
O
2
may decrease the life span of the erythrocyte
by causing oxidative damage to the cell membrane,
leading to hemolysis.
GLUCURONATE, A PRECURSOR OF
PROTEOGLYCANS & CONJUGATED
GLUCURONIDES, IS A PRODUCT OF
THE URONIC ACID PATHWAY
In liver, the uronic acid pathwaycatalyzes the conver-
sion of glucose to glucuronic acid, ascorbic acid, and
pentoses (Figure 20–4). It is also an alternative oxidative
pathway for glucose, but—like the pentose phosphate
pathway—it does not lead to the generation of ATP.
Glucose 6-phosphate is isomerized to glucose 1-phos-
phate, which then reacts with uridine triphosphate
(UTP) to form uridine diphosphate glucose (UDPGlc)
in a reaction catalyzed by UDPGlc pyrophosphorylase,
as occurs in glycogen synthesis (Chapter 18). UDPGlc is
oxidized at carbon 6 by NAD-dependent UDPGlc de-
hydrogenase in a two-step reaction to yield UDP-glu-
curonate. UDP-glucuronate is the “active” form of glu-
curonate for reactions involving incorporation of
glucuronic acid into proteoglycans or for reactions in
which substrates such as steroid hormones, bilirubin, and
a number of drugs are conjugated with glucuronate for
excretion in urine or bile (Figure 32–14).
130
THE PENTOSE PHOSPHATE PATHWAY & OTHER PATHWAYS OF HEXOSE METABOLISM
/ 167
PENTOSE
PHOSPHATE
PATHWAY
NADPH
+
H
+
NADP
+
FAD
GLUTATHIONE
REDUCTASE
Se
S
S
2G
SH
G
G
GLUTATHIONE
PEROXIDASE
2H
2
O
H
2
O
2
2H
Figure 20–3.
Role of the pentose phosphate pathway in the glutathione peroxidase re-
action of erythrocytes. (G-S-S-G, oxidized glutathione; G-SH, reduced glutathione; Se, sele-
nium cofactor.)
Glucuronate is reduced to
L
-gulonate in an NADPH-
dependent reaction;
L
-gulonate is the direct precursor of
ascorbatein those animals capable of synthesizing this
vitamin. In humans and other primates as well as guinea
pigs, ascorbic acid cannot be synthesized because of the
absence of
L
-gulonolactone oxidase.
L
-Gulonate is me-
tabolized ultimately to
D
-xylulose 5-phosphate, a con-
stituent of the pentose phosphate pathway.
INGESTION OF LARGE QUANTITIES
OF FRUCTOSE HAS PROFOUND
METABOLIC CONSEQUENCES
Diets high in sucrose or in high-fructose syrups used in
manufactured foods and beverages lead to large amounts
of fructose (and glucose) entering the hepatic portal vein.
Fructose undergoes more rapid glycolysis in the liver than
does glucose because it bypasses the regulatory step cat-
alyzed by phosphofructokinase (Figure 20–5). This allows
fructose to flood the pathways in the liver, leading to en-
hanced fatty acid synthesis, increased esterification of fatty
acids, and increased VLDL secretion, which may raise
serum triacylglycerols and ultimately raise LDL choles-
terol concentrations (Figure 25–6). A specific kinase,
fructokinase,in liver (and kidney and intestine) catalyzes
the phosphorylation of fructose to fructose 1-phosphate.
This enzyme does not act on glucose, and, unlike glucoki-
nase, its activity is not affected by fasting or by insulin,
which may explain why fructose is cleared from the blood
of diabetic patients at a normal rate. Fructose 1-phos-
phate is cleaved to
D
-glyceraldehyde and dihydroxyace-
tone phosphate by aldolase B,an enzyme found in the
liver, which also functions in glycolysis by cleaving fruc-
tose 1,6-bisphosphate.
D
-Glyceraldehyde enters glycolysis
via phosphorylation to glyceraldehyde 3-phosphate, cat-
alyzed by triokinase.The two triose phosphates, dihy-
droxyacetone phosphate and glyceraldehyde 3-phosphate,
may be degraded by glycolysis or may be substrates for al-
dolase and hence gluconeogenesis, which is the fate of
much of the fructose metabolized in the liver.
In extrahepatic tissues, hexokinase catalyzes the
phosphorylation of most hexose sugars, including fruc-
tose. However, glucose inhibits the phosphorylation of
fructose since it is a better substrate for hexokinase.
Nevertheless, some fructose can be metabolized in adi-
pose tissue and muscle. Fructose, a potential fuel, is
found in seminal plasma and in the fetal circulation of
ungulates and whales. Aldose reductaseis found in the
placenta of the ewe and is responsible for the secretion
of sorbitol into the fetal blood. The presence of sor-
bitol dehydrogenase in the liver, including the fetal
liver, is responsible for the conversion of sorbitol into
fructose. This pathway is also responsible for the occur-
rence of fructose in seminal fluid.
GALACTOSE IS NEEDED FOR THE
SYNTHESIS OF LACTOSE, GLYCOLIPIDS,
PROTEOGLYCANS, & GLYCOPROTEINS
Galactose is derived from intestinal hydrolysis of the
disaccharide lactose,the sugar of milk. It is readily con-
verted in the liver to glucose. Galactokinasecatalyzes
the phosphorylation of galactose, using ATP as phos-
phate donor (Figure 20–6A). Galactose 1-phosphate re-
acts with uridine diphosphate glucose (UDPGlc) to
form uridine diphosphate galactose (UDPGal) and glu-
cose 1-phosphate, in a reaction catalyzed by galactose
1-phosphate uridyl transferase. The conversion of
UDPGal to UDPGlc is catalyzed by UDPGal 4-epim-
erase.Epimerization involves an oxidation and reduc-
tion at carbon 4 with NAD
+
as coenzyme. Finally, glu-
cose is liberated from UDPGlc after conversion to
glucose 1-phosphate, probably via incorporation into
glycogen followed by phosphorolysis (Chapter 18).
Since the epimerase reaction is freely reversible, glu-
cose can be converted to galactose, so that galactose is
not a dietary essential. Galactose is required in the body
not only in the formation of lactose but also as a con-
stituent of glycolipids (cerebrosides), proteoglycans,
and glycoproteins. In the synthesis of lactose in the
mammary gland, UDPGal condenses with glucose to
yield lactose, catalyzed by lactose synthase (Figure
20–6B).
386
168 / CHAPTER 20
C
H
OH
OH
C
C
H
OH
C
H
HO
H
H
CH
2
O
P
O
α-
D
-Glucose
6-phosphate
C
O
C
O
NADPH
+
H
+
PHOSPHO-
GLUCOMUTASE
D
-XYLULOSE
REDUCTASE
*
C
C
H
OH
C
C
H
OH
C
H
HO
H
H
CH
2
OH
O
P
O
Glucose
1-phosphate
*
C
UDPGlc PYRO-
PHOSPHORYLASE
C
H
OH
C
C
H
OH
C
H
HO
H
H
CH
2
OH
CH
2
OH
O
UDP
O
Uridine diphosphate
glucose (UDPGlc)
*
C
UTP
PP
i
UDPGlc
DEHYDROGENASE
C
H
OH
C
C
H
OH
C
C
H
HO
H
H
O
UDP
O
Uridine diphosphate
glucuronate
*
C
2NAD
+
+
H
2
O
2NADH
+
2H
+
H
2
O
O
O
–
C
H
OH
C
C
H
OH
C
C
H
HO
H
H
OH
O
O
D
-Glucuronate
*
C
NADP
+
NADPH
+
H
+
O
O
–
C
H
C
C
H
OH
C
HO
HO
C
H
HO
H
L
-Gulonate
L
-Gulonolactone
2-Keto-
L
-gulonolactone
O
O–
UDP
L
-Dehydroascorbate
Oxalate
[2H]
NAD
+
NADH
+
H
+
*
CH
2
OH
C
C
C
H
C
HO
HO
C
H
HO
L
-Ascorbate
O
*
O
CH
2
OH
C
C
H
C
C
H
HO
O
O
C
O
*
CH
2
OH
Xylitol
C
C
H
OH
C
H
OH
HO
H
CH
2
OH
NADH
+
H
+
NAD
+
C
H
C
H
OH
C
HO
C
H
HO
3-Keto-
L
-gulonate
O
O–
*
C
O
CH
2
OH
CH
2
OH
CO
2
C
H
OH
C
H
HO
L
-Xylulose
*
Glucuronides
Proteoglycans
H
2
O
Oxalate
Glycolate
Glycolaldehyde
D
-Xylulose 1-phosphate
D
-Xylulose 5-phosphate
Pentose phosphate pathway
O
2
CO
2
B
L
O
C
K
I
N
P
R
I
M
A
T
E
S
A
N
D
G
U
I
N
E
A
P
I
G
S
B
L
O
C
K
I
N
H
U
M
A
N
S
B
L
O
C
K
I
N
P
E
N
T
O
S
U
R
I
A
NADP
+
CH
2
OH
*
CH
2
OH
C
C
H
OH
HO
H D-Xylulose
CH
2
OH
*
Mg
2
+
ADP
ATP
Diet
Figure 20–4.
Uronic acid pathway. (Asterisk indicates the fate of carbon 1 of glucose; , PO
3
2–.)
P
90
THE PENTOSE PHOSPHATE PATHWAY & OTHER PATHWAYS OF HEXOSE METABOLISM
/ 169
HEXOKINASE
HEXOKINASE
PHOSPHOFRUCTOKINASE
ALDOLASE A
ALDOLASE B
PHOSPHO-
TRIOSE
ISOMERASE
ALDOLASE B
TRIOKINASE
FRUCTOSE-1,6-
BISPHOSPHATASE
ATP
Glycogen
Glucose 6-phosphate
Fructose 6-phosphate
Fructose 1,6-bisphosphate
Glyceraldehyde 3-phosphate
2-Phosphoglycerate
Pyruvate
Fatty acid synthesis
D
-Glyceraldehyde
D
-Glucose
GLUCOKINASE
GLUCOSE-6-PHOSPHATASE
ALDOSE
REDUCTASE
NADPH
+
H
+
NADH
+
H
+
NADP
+
NAD
+
D
-Sorbitol
D
-Fructose
Fructose 1-phosphate
Dihydroxyacetone-phosphate
Diet
BLOCK IN ESSENTIAL
FRUCTOSURIA
BLOCK IN HEREDITARY
FRUCTOSE INTOLERANCE
FRUCTOKINASE
SORBITOL
DEHYDROGENASE
ATP
*
ATP
ATP
ATP
PHOSPHOHEXOSE
ISOMERASE
Fatty acid
esterification
Figure 20–5.
Metabolism of fructose. Aldolase A is found in all tissues, whereas aldolase B is
the predominant form in liver. (*, not found in liver.)
Glucose Is the Precursor of All
Amino Sugars (Hexosamines)
Amino sugars are important components of glycopro-
teins(Chapter 47), of certain glycosphingolipids(eg,
gangliosides) (Chapter 14), and of glycosaminoglycans
(Chapter 48). The major amino sugars are glucosa-
mine, galactosamine, and mannosamine and the
nine-carbon compound sialic acid.The principal sialic
acid found in human tissues is N-acetylneuraminic acid
(NeuAc). A summary of the metabolic interrelationships
among the amino sugars is shown in Figure 20–7.
CLINICAL ASPECTS
Impairment of the Pentose Phosphate
Pathway Leads to Erythrocyte Hemolysis
Genetic deficiency of glucose-6-phosphate dehydrogen-
ase, with consequent impairment of the generation of
NADPH, is common in populations of Mediterranean
and Afro-Caribbean origin. The defect is manifested as
red cell hemolysis (hemolytic anemia)when suscepti-
ble individuals are subjected to oxidants, such as the an-
timalarial primaquine, aspirin, or sulfonamides or when
109
170 / CHAPTER 20
Galactose
GALACTOKINASE
GLYCOGEN SYNTHASE
PHOSPHORYLASE
GLUCOSE-
6-PHOSPHATASE
LACTOSE
SYNTHASE
PHOSPHOGLUCOMUTASE
PHOSPHOGLUCOMUTASE
GALACTOSE
1-PHOSPHATE
URIDYL TRANSFERASE
URIDINE
DIPHOSPHOGALACTOSE
4-EPIMERASE
URIDINE
DIPHOSPHOGALACTOSE
4-EPIMERASE
UDPGlc
PYROPHOSPHORYLASE
ATP
ADP
Galactose
1-phosphate
Glucose
1-phosphate
UDPGal
UDPGlc
UDPGlc
A
Mg
2
+
NAD
+
NAD
+
Glycogen
P
Glucose 1-phosphate
Glucose 6-phosphate
Glucose
BLOCK IN
GALACTOSEMIA
Glucose
PP
HEXOKINASE
ATP
ADP
Glucose 6-phosphate
Glucose 1-phosphate
Glucose
B
Mg
2
+
UDPGal
Lactose
i
i
Figure 20–6.
Pathway of conversion of (A)galactose to glucose in the liver and (B)glucose to lactose in
the lactating mammary gland.
they have eaten fava beans (Vicia fava—hence the term
favism). Glutathione peroxidase is dependent upon a
supply of NADPH, which in erythrocytes can be
formed only via the pentose phosphate pathway. It re-
duces organic peroxides and H
2
O
2
as part of the body’s
defense against lipid peroxidation (Figure 14–21).
Measurement of erythrocyte transketolaseand its acti-
vation by thiamin diphosphate is used to assess thiamin
nutritional status (Chapter 45).
Disruption of the Uronic Acid Pathway Is
Caused by Enzyme Defects & Some Drugs
In the rare hereditary disease essential pentosuria,con-
siderable quantities of
L
-xylulose appear in the urine
because of absence of the enzyme necessary to reduce
L
-xylulose to xylitol. Parenteral administration of xylitol
may lead to oxalosis,involving calcium oxalate deposi-
tion in brain and kidneys (Figure 20–4). Various drugs
markedly increase the rate at which glucose enters the
uronic acid pathway. For example, administration of
barbital or of chlorobutanol to rats results in a signifi-
cant increase in the conversion of glucose to glu-
curonate,
L
-gulonate, and ascorbate.
Loading of the Liver With Fructose
May Potentiate Hyperlipidemia
& Hyperuricemia
In the liver, fructose increases triacylglycerol synthesis
and VLDL secretion, leading to hypertriacylglyc-
erolemia—and increased LDL cholesterol—which can
be regarded as potentially atherogenic (Chapter 26). In
addition, acute loading of the liver with fructose, as can
occur with intravenous infusion or following very high
fructose intakes, causes sequestration of inorganic phos-
phate in fructose 1-phosphate and diminished ATP
synthesis. As a result there is less inhibition of de novo
purine synthesis by ATP and uric acid formation is in-
Documents you may be interested
Documents you may be interested
