The document discusses fructose and galactose metabolism, including how fructose must be phosphorylated by fructokinase before entering metabolic pathways. It also describes disorders that can occur due to deficiencies in enzymes involved in fructose or galactose metabolism, such as hereditary fructose intolerance. Additionally, the roles of sorbitol and galactose in metabolism are covered, as well as disorders related to the sorbitol pathway and galactose metabolism.
2. Fructose metabolism
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 (primarily in
disaccharides), and make
important contributions
to energy metabolism. In
addition, galactose is an
important component
of cell structural
carbohydrates
3. Phosphorylation of fructose
▪ For fructose to enter the pathways of intermediary
metabolism, itmust first be phosphorylated . This can be
accomplishedby either hexokinase or fructokinase (also
called ketohexo kinase).
▪ Hexokinase phosphorylates glucose in most 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, see for fructose. Therefore, unless the
intracellular concentration of
▪ fructose becomes unusually high, the normal presence of
saturatingconcentrations of glucose means that little
fructose is converted tofructose 6-phosphate by
hexokinase. Fructokinase provides the primaryfound 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.
4. Cleavage of fructose- 1 phosphate
▪ aldolase B (also called fructose 1-phosphate
aldolase) todihydroxy acetone phosphate
(DHAP) and glyceraldehyde.
▪ [Note:Humans express three aldolases, A, B
and C, the products of threedifferent genes.
Aldolase A (found in most tissues), aldolase
B (in liver), and aldolase C (in brain) all cleave
fructose 1,6-bisphosphateproduced during
glycolysis to DHAP and glyceraldehyde 3-
phosphate
▪ , but only aldolase B cleaves fructose 1-
phosphate.]
6. Synthesis of fructose via sorbitol
▪ Most sugars are rapidly phosphorylated following their entry
into cells. They are thereby trapped within the cells, because
organ phosphates cannot freely cross membranes without
specific transporter An alternate mechanism for metabolizing
a monosaccharide is to convert it to a polyol (sugar alcohol) by
the reduction of an aldehyde group, thereby producing an
additional hydroxyl group.
▪ 1. Synthesis of sorbitol:
▪ Aldose reductase reduces glucose, producing sorbitol 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, and seminal vesicles,
▪ there is a second enzyme, sorbitol dehydrogenase, which can
oxidize the sorbitol to produce fructose
▪ . 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.
7. Disorders of fructose metobolism
disorders
hereditory
fructosuria
essentialfructosur
ia
8. Disorders of fructose metobolism
▪ A deficiency of one of the key enzymes required for the entry
offructose into intermediary metabolic pathways can result in
either benign condition as a result of fructokinase deficiency
(essentiafructosuria), or a severe disturbance of liver and kidney
meas a result of aldolase B deficiency (hereditary fructose
intolerancHFI), which is estimated to occur in 1:20,000 live births
.
▪ Fructose 1-phosphate accumulates, resulting in a drop in the level
of inorganic phosphate (Pi) and, therefore, of ATP. ATP falls,
AMP rises. In the absence of Pi, AMP is degraded, causing
hyperuricemia . The decreased availability of hepatic ATP affects
gluconeogenesis (causing hypoglycemia with vomiting), and protein
synthesis (causing a decreasein blood clotting factors and other
essential proteins)
▪ Kidney function may also be affected. Diagnosis of HFI can be
made on the basis of fructose in the urine, enzyme assay or by
DNA-based testing
▪ With HFI, sucrose and sorbitol (a sugar alcohol),as well as
fructose, must be removed from the diet to prevent liver failure
9.
10. Disordes of sorbitol pathway
▪ 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
uncontrolled diabetes. Elevated intracellular glucose
concentrations and an adequate supply of NADPH cause
aldose reductase to produce asignificant increase in the
amount of sorbitol, which cannot pass efficiently
through cell membranes and, therefore, remains
trappedinside the cell .
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 swelling 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 microvascular
problems leading to nephropathy and retinopathy
11. Galactose metabolism
▪ The major dietary source of galactose
is lactose (galactosyl β-1,4-
glucosidase 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.
12. ▪ 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 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 . This occurs in an exchange reaction, in
which UDP-glucose reacts with galactose1-
phosphate, producing UDP-galactose and glucose 1-
phosphate
13. 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 hexose4-epimerase.
This “new” UDP-glucose (produced from the original UDP-
galactose) can then participate in many biosynthetic
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 , glycolipid, and glycosaminoglycans
If galactose is not provided by the diet (for example, when it
cannot be released from lactose as a result of a lack of β-
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
16. GALACTOKINASE
DEFICIENCY
▪ Rare autosomal recessive
disorder
▪ Causes elevation of galactose
in blood (galactosemia) and
urine (galactosuria)
▪ Causes galactitol accumulation
if galactose is present in the
diet.
▪ Elevated galactitol can cause
17. Classical galactosemia
▪ Galactose 1-phosphate uridyltransferase (GALT)
deficiency.
▪ Autosomal recessive disorder (1:30,000 births).
▪ Causes galactosemia and galactosuria, vomiting,diarrhea,
and jaundice.
▪ • Accumulation of galactose 1-phosphate and galactitol
in nerve, lens, liver, and kidney tissue causes liver
damage, severe mental retardation, and cataracts.
▪ Prenatal diagnosis is possible by chorionic villus
sampling. Newborn screening is available.
▪ Therapy: Rapid diagnosis and removal ofgalactose (and
therefore lactose) from the diet.
▪ Despite adequate treatment, at risk for
18.
19. Some brainy challenges
Following the intravenous injection of lactose into a
rat, none of the lactose is metabolized. However,
ingestion of lactose leads to rapid metabolism of this
disaccharide.The difference in these observations is
a result of:
A. the presence of lactase in the serum.
B. the absence of hepatic galactokinase.
C.the absence of maltase in the serum.
D.the presence of lactase in the intestine.
20. answer
correct answer = D
. Lactase and maltase are
intestinal enzymes not found in the serum.
Therefore, ingested lactose is degraded, but
injected lactose is not. If hepatic galactokinase
is absent, the galactose segment of the lactose
is not metabolized, but the glucose segment of
the lactose can still be metabolized.
21. female with classic galactosemia due to GALT
deficiency
is able to produce lactose in breast milk
because:
A. free (nonphosphorylated) galactose is the acceptor
of glucose transferred by lactose synthase in
the synthesis of lactose.
B. galactose can be produced from a glucose
metabolite by epimerization.
C. hexokinase can efficiently phosphorylate dietary
galactose to galactose 1-phosphate
D. the enzyme deficient in galactosemia is activated
by a hormone produced in the mammary gland.
E. galactose can be produced from fructose by isomerization
22. Correct answer = B.
UDP-hexose 4-epimerase
converts UDP-glucose to UDP-galactose, thus
providing the appropriate form of galactose for
lactose synthesis. UDP-galactose, not free
galactose, is the source of the galactose portion
of lactose. Galactose is not converted to galactose
1-phosphate by hexokinase. Galactosemia
is the result of a deficiency in GALT.
Isomerization of fructose to galactose does not
occur in the human body.
23. A 5-month-old boy is brought to his physician
because of vomiting, night sweats, and tremors.
History revealed that these symptoms began after
fruit juices were introduced to his diet as he was
being weaned off breast milk.The physical examination
was remarkable for hepatomegaly.Tests on the
baby’s urine were positive for reducing sugar but
negative for glucose.The infant most likely suffers
from:
A. aldolase B deficiency.
B. fructokinase deficiency.
C. galactokinase deficiency.
D. β-galactosidase deficiency.
E. glucose 6-phosphatase deficiency
24. Correct answer = A
.The symptoms suggest
fructose intolerance, a deficiency in aldolase B.
Deficiencies in fructokinase or galactokinase
result in relatively benign conditions characterized
by elevated levels of fructose or galactose
in the blood and urine. Deficiency in
β–galactosidase (lactase) results in a decreased
ability to degrade lactose (milk sugar).
Congenital lactase deficiency is quite rare and
would have presented much earlier in this baby,
and with different symptoms.Typical lactase
deficiency (adult hypolactasia) presents at a
later age.The symptoms of glucose 6-phosphatase
deficiency would result from fasting, and
would not be related to ingestion of fruit juice.
