Title: Metabolism of Monosaccharides and Disaccharides
1Metabolism of Monosaccharides and Disaccharides
2OVERVIEW
- Glucose is the most common monosaccharide
consumed by humans, and its metabolism has been
discussed extensively. - However, two other monosaccharidesfructose and
galactoseoccur in significant amounts in the
diet, and make important contributions to energy
metabolism. - In addition, galactose is an important component
of cell structural carbohydrates. - Figure shows the metabolism of fructose and
galactose as part of the essential pathways of
energy metabolism in the body.
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4FRUCTOSE METABOLISM
- About 10 of the calories contained in the
Western diet are supplied by fructose
(approximately 50 g/day). - The major source of fructose is the disaccharide
sucrose, which, when cleaved in the intestine,
releases equimolar amounts of fructose and
glucose. - Fructose is also found as a free monosaccharide
in many fruits, in honey, and in high-fructose
corn syrup (55 fructose/45 glucose), which is
used to sweeten soft drinks and many foods. - Entry of fructose into cells is not
insulin-dependent and in contrast to glucose,
fructose does not promote the secretion of
insulin.
5A. Phosphorylation of fructose
- For fructose to enter the pathways of
intermediary metabolism, it must first be
phosphorylated (Figure 12.2). - This can be accomplished by either hexokinase or
fructokinase (also called ketohexo-kinase). - Hexokinase phosphorylates glucose in all cells of
the body, and several additional hexoses can
serve as substrates for this enzyme. However, it
has a low affinity for fructose. - Therefore, unless the intracellular concentration
of fructose becomes unusually high, the normal
presence of saturating concentrations of glucose
means that little fructose is converted to
fructose 6-phosphate by hexokinase. - Fructokinase provides the primary mechanism for
fructose phosphorylation (Figure 12.2). - It is found in the liver (which processes most of
the dietary fructose), kidney, and the small
intestinal mucosa, and converts fructose to
fructose 1-phosphate, using ATP as the phosphate
donor. - Note These three tissues also contain aldolase
B, discussed below.
6B. Cleavage of fructose 1-phosphate
- Fructose 1 -phosphate is not phosphorylated to
fructose 1,6-bisphos-phate as is fructose
6-phosphate, but is cleaved by aldolase B (also
called fructose 1-phosphate aldolase) to
dihydroxy-acetone phosphate (DHAP) and
glyceraldehyde. - Note Both aldolase A (found in all tissues) and
aldolase B cleave fructose 1,6-bisphosphate
produced during glycolysis to DHAP and
glyceraldehyde 3-phosphate, but only aldolase B
cleaves fructose 1-phosphate R DHAP can directly
enter glycolysis or gluconeogene-sis, whereas
glyceraldehyde can be metabolized by a number of
pathways, as illustrated in Figure 12.3. - C. Kinetics of fructose metabolism
- The rate of fructose metabolism is more rapid
than that of glucose because the trioses formed
from fructose 1 -phosphate by pass
phos-phofructokinasethe major rate-limiting step
in glycolysis.
7D. Disorders of fructose metabolism
- A deficiency of one of the key enzymes required
for the entry of fructose into intermediary
metabolic pathways can result in either a benign
condition (fructokinase deficiency), or a severe
disturbance of liver and kidney metabolism as a
result of aldolase B deficiency (hereditary
fructose intolerance, HFI), which is estimated to
occur in 120,000 live births (Figure 12.3). - The first symptoms of HFI appear when a baby is
weaned and begins to be fed food containing
sucrose or fructose. Fructose 1-phosphate
accumulates, resulting in a drop in the level of
inorganic phosphate (Pi) and, therefore, of ATP
As ATP falls, AMP rises. In the absence of Pj,
AMP is degraded, causing hyperuricemia. - The decreased availability of hepatic ATP affects
gluconeogenesis (causing hypoglycemia with
vomiting), and protein synthesis (causing a
decrease in blood clotting factors and other
essential proteins). - Diagnosis of HFI can be made on the basis of
fructose in the urine, or by a restriction
fragment length polymorphism test (RFLP). - In HFI, sucrose as well as fructose, must be
removed from the diet to prevent liver failure
and possible death.
8E. Conversion of mannose to fructose 6-phosphate
- Mannose, the C-2 epimer of glucose, is an
important component of glycoproteins. - Hexokinase phosphorylates mannose, producing
mannose 6-phosphate, which, in turn, is
(reversibly) isomerized to fructose 6-phosphate
by phospho-mannose isomerase. - Note There is little mannose in dietary
carbohydrates. Most intracellular mannose is
synthesized from fructose, or is preexisting
mannose produced by the degradation of structural
carbohydrates and salvaged by hexokinase.
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10F. Conversion of glucose to fructose via sorbitol
- Most sugars are rapidly phosphorylated following
their entry into cells. - They are thereby trapped within the cells,
because organic phosphates cannot freely cross
membranes without specific transporters. - An alternate mechanism for metabolizing a
monosaccharide is to convert it to a polyol by
the reduction of an aldehyde group, thereby
producing an additional hydroxyl group.
- Synthesis of sorbitol
- Aldose reductase reduces glucose, producing
sorbitol (glucitol, Figure 12.4). - This enzyme is found in many tissues, including
the lens, retina, Schwann cells of peripheral
nerves, liver, kidney, placenta, red blood cells,
and in cells of the ovaries and seminal vesicles.
- In cells of the liver, ovaries, sperm, and
seminal vesicles, there is a second enzyme,
sorbitol dehydrogenase, that can oxidize the
sorbitol to produce fructose (Figure 12.4). - The two-reaction pathway from glucose to fructose
in the seminal vesicles is for the benefit of
sperm cells, which use fructose as a major
carbohydrate energy source. - The pathway from sorbitol to fructose in the
liver provides a mechanism by which any available
sorbitol is converted into a substrate that can
enter glycolysis or gluconeogenesis.
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122. The effect of hyperglycemia on sorbitol
metabolism
- Because insulin is not required for the entry of
glucose into the cells listed in the previous
paragraph, large amounts of glucose may enter
these cells during times of hyperglycemia, for
example, in uncontroller diabetes. - Elevated intracellular glucose concentrations and
a adequate supply of NADPH cause aldose reductase
to produce a significant increase in the amount
of sorbitol, which cannot pass efficiently
through cell membranes and, therefore, remains
trapped inside the cell (Figure 12.4). - This is exacerbated when sorbitol dehydrogenase
is low or absent, for example, in retina, lens,
kidney, and nerve cells. - As a result, sorbitol accumulates in these cells,
causing strong osmotic effects and, therefore,
cell swellin as a result of water retention. - Some of the pathologic alterations associated
with diabetes can be attributed, in part, to this
phenomenon, including cataract formation,
peripheral neuropathy, and vascular problems
leading to nephropathy and retinopathy.
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14III. GALACTOSE METABOLISM_
- The major dietary source of galactose is lactose
galactosyl ß-1,4-glucose) obtained from milk and
milk products. - Some galactose can also be obtained by lysosomal
degradation of complex carbohydrates, such as
glycoprotein and glycolipids, which are important
membrane components. - Like fructose, the entry of galactose into cells
is not insulin-dependent.
A. Phosphorylation of galactose Like fructose,
galactose must be phosphorylated before it can be
further metabolized. Most tissues have a specific
enzyme for this purpose, galactokinase, which
produces galactose 1-phosphate (Figure 12.5). As
with other kinases, ATP is the phosphate
donor. B. Formation of UDP- galactose Galactose
1-phosphate cannot enter the glycolytic pathway
unless it is first converted to UDP-galactose
(Figure 12.5). This occurs in an exchange
reaction, in which UDP-glucose reacts with
galactose 1-phosphate, producing UDP-galactose
and glucose 1-phosphate (Figure 12.6). The enzyme
that catalyzes this reaction is galactose
1-phosphate uridyltransferase.
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16- C. Use of UDP- galactose as a carbon source for
glycolysis or gluconeogenesis - For UDP- galactose to enter the mainstream of
glucose metabolism, it must first be converted to
its C-4 epimer, UDP-glucose, by UDP-hexose
4-epimerase. - This "new" UDP-glucose (produced from the
original UDP-galactose) can then participate in
many biosynthetic reactions, as well as being
used in the Uridyltransferase reaction described
above, converting another galactose 1 -phosphate
into UDP-galactose, and releasing glucose 1
-phosphate, whose carbons are those of the
original galactose. (Figure 12.5). - D. Role of UDP-galactose in biosynthetic
reactions - UDP-galactose can serve as the donor of galactose
units in a number of synthetic pathways,
including synthesis of lactose (see below),
glycoproteins, glycolipids, and
gly-cosaminoglycans. - Note If galactose is not provided by the diet
(for example, when it cannot be released from
lactose as a result of a lack of p-galactosidase
in people who are lactose- intolerant), all
tissue requirements for UDP-galactose can be met
by the action of UDP-hexose 4-epimerase on
UDP-glucose, which is efficiently produced from
glucose 1 -phosphate (Figure 12.5).
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18- E. Disorders of galactose metabolism
- Gatactose 1 -phosphate Uridyltransferase is
missing in individuals with classic galactosemia
(Figure 12.5). - In this disorder, galactose 1 -phosphate and,
therefore, galactose accumulate in cells. - Physiologic consequences are similar to those
found in essential fructose intolerance, but a
broader spectrum of tissues is affected. - The accumulated galactose is shunted into side
pathways such as that of galactitol production.
This reaction is catalyzed by aldose reductase,
the same enzyme that converts glucose to
sor-bitol (39). Note A more benign form of
galactosemia is caused by a deficiency of
galactokinase (see Figure 12.5).
19IV. LACTOSE SYNTHESIS__
- Lactose is a disaccharide that consists of a
molecule of ß -galactose attached by a ß(1-4)
linkage to glucose. - Therefore, lactose is galactosyl
ß(1-4)-glucose. Lactose, known as the "milk
sugar," is produced by the mammary glands of most
mammals. Therefore, milk and other dairy products
are the dietary sources of lactose. - Lactose is synthesized in the Golgi by lactose
synthase (UDP-galactoseglucose
galactosyltransferase), which transfers galactose
from UDP-galactose to glucose, releasing UDP
(Figure 12.7). - This enzyme is composed of two proteins, A and B.
Protein A is a ß-D-gatactosyltransferase, and is
found in a number of body tissues. In tissues
other than the lactating mammary gland, this
enzyme transfers galactose from UDP-galactose to
N-acetyl-o glucosamine, forming the same ß(1 -gt4)
linkage found in lactose, and producing
N-acetyllactosaminea component of the
structurally important N-linked-glycoproteins. - In contrast, protein B is found only in lactating
mammary glands. It is a-lactalbumin, and its
synthesis is stimulated by the peptide hormone,
prolactin. - Protein B forms a complex with the enzyme,
protein A, changing the specificity of that
transferase so that lactose, rather than
N-acetyllactosamine, is produced (Figure 12.7).
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