Download METABOLISM OF MONOSACCHARIDES AND DISACCHARIDES

METABOLISM OF
MONOSACCHARIDES AND
DISACCHARIDES
DR. A. TARAB
DEPT. OF BIOCHEMISTRY
HKMU
OVERVIEW
• Glucose is the most common monosaccharide
consumed by humans, and its metabolism has
been discussed extensively
• However, two other monosaccharides fructose and galactose – occur in significant
amounts in the diet, and make important
contributions to energy metabolism
• In addition, galactose is an important
component of cell structural carbohydrates
FRUCTOSE METABOLISM
• 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, and in honey
• Entry of fructose into cells is not insulindependent (unlike that of glucose into certain
tissues), and, in contrast to glucose, fructose does
not promote the secretion of insulin
• A. Phosphorylation of fructose
• For fructose to enter the pathways of
intermediary metabolism, it must first be
phosphorylated
• This can be accomplished by either hexokinase
or fructokinase (also called ketohexokinase).
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 (that is, a high km)
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
• 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
• B. Cleavage of fructose 1-phosphate
• Fructose 1-phosphate is not converted to
fructose as is fructose 6-phosphate, but is cleaved
by aldolase B (also called fructose 1-phosphate
aldolase) to dihydroxyacetone phosphate
(DHAP) and glyceraldehyde
• DHAP can directly enter glycolysis or
gluconeogenesis, whereas glyceraldehyde can
be metabolized by a number of pathways
• C. 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 1:20,000 live births
• The first symptoms appear when a baby is
weaned and begins to be fed food containing
sucrose or fructose
• Fructose 1-phosphate accumulates, and ATP
and inorganic phosphate levels fall
significantly, with adenine being converted to
uric acid, causing hyperuricemia
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ESSENTIAL FRUCTOSURIA
- Lack of fructokinase
- Autosomal recessive (1 in 130,000 births)
- Benign, asymptomatic condition
- Fructose accumulates in the urine
• HEREDITARY FRUCTOSE INTOLERANCE
(“FRUCTOSE POISONING”)
• - Absence of aldolase B leads to intracellular
trapping of fructose 1-phosphate
• - Causes severe hypoglycemia, vomiting,
jaundice, haemorrhage, hepatomegaly and
hyperuricemia
• - Can cause hepatic failure and death
• Therapy: Rapid detection and removal of fructose
and sucrose from the diet
• D. Conversion of mannose to fructose 6phosphate
• 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 6phosphate by phosphomannose isomerase
GALACTOSE METABOLISM
• The major dietary source of galactose is lactose
(galactosyl β-1,4-glucose) obtained from milk and
milk products
• Some galactose can also be obtained by
lysosomal degradation of complex carbohydrates,
such as glycoproteins, 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
• 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
• This occurs in an exchange reaction, in which
UDP is removed from UDP-glucose (leaving
behind glucose 1-phosphate), and is then
transferred to the galactose 1-phosphate
producing UDP-galactose
Structure of UDP-Galactose
• The enzyme that catalyzes this reaction is
galactose 1-phosphate uridyltransferase
• C. Use of UDP-galactose as a carbon source
for glycolysis or gluconeogenesis
• In order for UDP-galactose to enter the
mainstream of glucose metabolism, it must
first be converted to its C-4 epimer, UDPglucose, 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
• 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,
glycoproteins, glycolipids, and
glycosaminoglycans
• E. Disorders of galactose metabolism
• Galactose 1-phosphate uridyltransferase is
missing in individuals with classic
galactosemia
• 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
CLASSIC GALACTOSEMIA
• Uridyltransferase deficiency
• Autosomal recessive disorder (1 in 23,000
births)
• It causes galactosemia and galactosuria,
vomiting, diarrhea and jaundice
• Accumulation of galactose 1-phosphate in
nerve, lens, liver and kidney tissues causes
liver damage, severe mental retardation and
cataracts
• Antenatal diagnosis is possible by chorionic
villus sampling
• Therapy: rapid diagnosis and removal of
galactose (therefore lactose) from the diet
LACTOSE SYNTHESIS
• Lactose is a disaccharide that consists of a
molecule of β-galactose attached by a β(1→4)
linkage to glucose
• Therefore, lactose is galactosyl β(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 endoplasmic
reticulum by lactose synthase (UDPgalactose:glucose galactosyltransferase),
which transfers galactose from UDP-galactose
to glucose, releasing UDP
• This enzyme is composed of two proteins, A
and B
• Protein A is a β-D-galactosyltransferase 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-D-glucosamine,
forming the same β(1→4) linkage found in
lactose, and producing N-acetyllactosamine—
a component of the structurally important Nlinked glycoproteins
• In contrast, protein B is found only in lactating
mammary glands
• It is α-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 Nacetyllactosamine, is produced