Metabolism of monosaccharides and disaccharides

1
Metabolism of monosaccharides and disaccharides

• UNIT II
• Intermediary Metabolism

2
Figure 12.1. Galactose and fructose metabolism as
part of the essential pathways of energy
metabolism.
3
Overview

• Although many monosaccharides have been
  identified in nature, only a few sugars appear as
  metabolic intermediates or as structural
  components in mammals.
• Gluc is the most common monosacch consumed by
  humans, its metabolism has been discussed
• However, two other monosacchs, fructose
  galactose, occur in significant amounts in the
  diet, make important contributions to energy
  metabolism
• In addition, galactose is an important component
  of cell structural CHOs

4

• II. Fructose metabolism
• 10 of the calories contained in Western diet
  are supplied by fructose ( 50g/day).
• The major source of fructose is the disaccharide
  sucrose, which, when cleaved in intestine,
  releases equimolar amounts of fructose glucose
• Fructose is also found as a free monosacch in
  high-fructose corn syrup (55 fructose/45
  glucose, which is used to sweeten most cola
  drinks), in many fruits, in honey.
• Entry of fructose into cells is not
  insulin-dependent (unlike that of glucose into
  certain tissues), in contrast to glucose,
  fructose does not promote secretion of insulin

5

• A. Phosphorylation of fructose
• For fructose to enter pathways of intermediary
  metabolism, it must 1st be phosphorylated. This
  can be accomplished by either hexokinase or
  fructokinase (a.k.a ketohexokinase)
• Hexokinase phosphorylates gluc in all cells of
  the body, several additional hexoses can serve
  as substrates for this enz. However, it has a low
  affinity (high Km) for fructose. Therefore,
  unless intracellular conc. of fructose becomes
  unusually high, the normal presence of saturating
  concs of gluc means that little fructose is
  converted to F-6-P by hexokinase
• Fructokinase provides the primary mechanism for
  fructose phospho. It is found in the liver (which
  processes most of dietary fructose), kidney,
  small intestinal mucosa, converts fructose to
  F-1-P, using ATP as the P donor
• Note these 3 tissues also contain aldolase B

6

• B. Cleavage of fructose 1-phosphate
• F 1-P is not converted to F 1,6-BP as F-6-P, but
  is cleaved by aldolase B (a.k.a fructose
  1-phosphate aldolase) to DHAP glyceraldehyde
• Note both aldolase A (found in all tissues)
  aldolase B cleave F 1,6-BP produced during
  glycolysis to DHAP GA-3P.
• - DHAP can directly enter glycolysis or
  gluconeogenesis, whereas glyceraldehyde can be
  metabolized by a number of pathways

7

• C. Kinetics of fructose metabolism
• The rate of fructose metabolism is more rapid
  than that of gluc because the trioses formed from
  F-1-P bypass PFK, the major rate-limiting step in
  glycolysis
• Note loading the liver with fructose, e.g., by
  intravenous infusion, can significantly elevate
  the rate of lipogenesis caused by enhanced
  production of acetyl CoA

8

• D. Disorders of fructose metabolism
• A deficiency of one of the key enzs required for
  the entry of fructose into intermediary metabolic
  pathways can result in either a benign condition
  (fructokinase deficiency ? essential
  fructosuria), or a severe disturbance of liver
  kidney metabolism as a result of aldolase B
  deficiency (hereditary fructose intolerance,
  HFI-fructose poisoning) which is estimated to
  occur in 120,000 live births
• The 1st symptoms appear when a baby is weaned
  begins to be fed food containing sucrose or
  fructose. F-1-P accumulates, ATP Pi levels
  fall significantly, with adenine being converted
  to uric acid, causing hyperuricemia

9

• The decreased availability of hepatic ATP affects
  gluconeogenesis (causing hypoglycemia with
  vomiting), protein synthesis (causing a
  decrease in blood clotting factors other
  essential proteins)
• If fructose ( therefore, sucrose) is not removed
  from diet, liver failure death can occur
• Diagnosis of HFI can be made on basis of fructose
  in urine, or by a RFLP test

10
(No Transcript)
11

• E. Conversion of mannose to fructose 6-phosphate
• Mannose, the C-2 epimer of gluc, is an important
  component of glycoproteins
• Hexokinase phosphorylates mannose ? mannose 6-P,
  which in turn, is (reversibly) isomerized to
  F-6-P by phosphomannose isomerase
• Note there is little mannose in dietary CHOs.
  Most intracellular mannose is synthesized from
  fructose, or is pre-existing mannose produced by
  degradation of structural CHOs salvaged by
  hexokinase

12

• F. Conversion of glucose to fructose via sorbitol
• Most sugars are rapidly phosphorylated following
  their entry into cells. They are thereby trapped
  within cells, because organic Ps cant freely
  cross membs without specific transporters
• An alternate mechanism for metabolizing a
  monosacch is to convert it to a polyol by
  reduction of an aldehyde group, thereby producing
  an additional hydoxyl group

13

• 1. Synthesis of sorbitol
• Aldose reductase reduces glucose, producing
  sorbitol (glucitol). This enz is found in many
  tissues, including the lens, retina, Schwann
  cells of peripheral nerves, liver, kidney,
  placenta, RBCs, cells of the ovaries seminal
  vesicles.
• In cells of liver, ovaries, sperm seminal
  vesicles, there is a 2nd enz, sorbitol
  dehydrogenase, that can oxidize sorbitol to
  produce fructose.
• The 2-reaction pathway from gluc to fruc in
  seminal vesicles is for the benefit of sperm
  cells, which use fruc as a major CHO energy
  source.
• The pathway from sorbitol to fruc in liver
  provides a mechanism by which any available
  sorbitol is converted into a substrate that can
  enter glycolysis or gluconeogenesis

14
Figure 12.4. Sorbitol metabolism
15

• 2. The effect of hyperglycemia on sorbitol
  metabolism
• Because insulin is not required for entry of gluc
  into cells listed in previous paragraph, large
  amounts of gluc may enter these cells during
  times of hyperglycemia, e.g., in uncontrolled
  diabetes.
• Elevated intracellular gluc concs an adequate
  supply of NADPH cause aldose reductase to produce
  a sufficient increase in the amount of sorbitol,
  which cant pass efficiently through CMs ,
  therefore, remains trapped inside cell.
• This is exacerbated when sorbitol dehydrogenase
  is low or absent, e.g., in retina, lens, kidney
  nerve cells. As a result, sorbitol accumulates in
  these cells, causing strong osmotic effects ,
  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, vascular problems
  leading to nephropathy, retinopathy

16

• III. Galactose metabolism
• The major dietary source of galactose is lactose
  (galactosyl ß 1,4-glucose) obtained from milk
  milk products.
• Note digestion of lactose by ß-galactosidase
  (lactase) of the intestinal mucosal CM was
  discussed earlier
• Some galactose can also be obtained by lysosomal
  degradation of complex CHOs, such as
  glycoproteins glycolipids, which are important
  memb components.
• Like fructose, entry of galactose into cells is
  not insulin dependent
• A. Phosphorylation of galactose
• - Like fruc, galactose must be phosphorylated
  before it can be further metabolized. Most
  tissues have a specific enz for this purpose,
  galactokinase, which produces galactose 1-P. ATP
  is the P donor.

17

• B. Formation of UDP-galactose
• Galactose 1-P cant enter glycolytic pathway
  unless it is 1st converted to UDP-galactose. This
  occurs as an exchange reaction, in which UMP is
  removed from UDP-gluc (leaving behind G-1-P),
  is then transferred to the galactose 1-P,
  producing UDP-galactose. The enz which catalyzes
  this reaction is galactose 1-phosphate uridyl
  transferase
• C. Use of UDP-galactose as a carbon source for
  glycolysis or gluconeogenesis
• In order for UDP-galactose to enter the
  mainstream of gluc metabolism, it must 1st be
  converted to its C-4 epimer, UDP-gluc, by
  UDP-hexose 4-epimerase
• This new UDP-gluc (produced from the original
  UDP-galactose) can then participate in many
  biosynthetic reactions, as well as being used in
  uridyl transferase reaction described above,
  converting another galactose 1-P into
  UDP-galactose, releasing G-1-P, whose carbons
  are those of the original galactose

18
Figure 12.6. Structure of UDP-galactose.
19

• D. Role of UDP-galactose in biosynthetic
  reactions
• UDP-galactose can serve as the donor of galactose
  in a number of synthetic pathways, including
  synthesis of lactose, glycoproteins, glycolipids,
  glycosaminoglycans
• Note if galactose is not provided by the diet
  (e.g., when it cant be released from lactose as
  a result of a lack of ß-galactosidase in people
  who are lactose-intolerant), all tissue
  requirements of UDP-galactose can be met by the
  action of UDP-hexose 4-epimerase on UDP-glucose,
  which is efficiently produced from G-1-P

20

• E. Disorders of galactose metabolism
• Galactose 1-phosphate uridyltransferase is
  missing in individuals with classic galactosemia.
  In this disorder, galactose 1-P , therefore,
  galactose, accumulates in cells.
• Physiologic consequences are similar to those
  found in 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 enz that converts gluc to sorbitol
• Note a more benign form of galactosemia is
  caused by a deficiency of galactokinase

21
Figure 12.5. Metabolism of galactose.
22

• IV. Lactose synthesis
• Lactose is a disacch that consists of a molecule
  of ß-galactose attached by ß(1?4) linkage to
  gluc. Therefore, lactose is galactosyl
  ß(1?4)-glucose.
• Lactose, known as milk sugar, is produced by
  mammary glands of most mammals. Therefore, milk
  other dairy products are the dietary sources of
  lactose.
• Lactose is synthesized in the ER by lactose
  synthase (UDP-galactoseglucose
  galactosyltransferase), which transfers galactose
  from UDP-galactose to gluc, releasing UDP.

23

• This enz is composed of 2 proteins, A B.
  protein A is a ß-D-galactosyltransferase is
  found in a of body tissues. In tissues other
  than the lactating mammary gland, this enz
  transfers galactose from UDP-galactose to
  N-acetyl-D-glucoasamine, forming the same ß(1?4)
  linkage found in lactose, producing
  N-acetyllactosamine, a component of the
  structurally important N-linked glycoproteins
• In contrast, protein B is found only in lactating
  mammary glands. It is a-lactalbumin, its
  synthesis is stimulated by the peptide hormone,
  prolactin.
• Protein B forms a complex with the enz, protein
  A, changing specificity of that transferase so
  that lactose, rather than N-acetyllactosamine, is
  produced

24
Figure 12.7. lactose synthesis
25
Summary

• The major source of fructose is sucrose, which
  when cleaved releases equimolar amounts of
  fructose glucose.
• Entry of fruc into cells is insulin-independent.
  Fruc is 1st phosphorylated to F-1-P by
  fructokinase, then cleaved by aldolase B to
  DHAP glyceraldehyde. These enzs are found in
  liver, kidney, small intestinal mucosa.
• A deficiency of fructokinase causes a benign
  condition (fructosuria), but a deficiency of
  aldolase B causes hereditary fructose
  intolerance, in which severe hypoglycemia liver
  failure lead to death if the amount of fruc (and
  therefore, sucrose) in the diet is not severely
  limited.

26

• Mannose, an important component of glycoproteins,
  is phosphorylated by hexokinase to mannose-6-P,
  which is reversibly isomerized to F-6-P by
  phosphomannose isomerase.
• Gluc can be reduced to sorbitol (glucitol) by
  aldose reductase in many tissues, including the
  lens, retina, Schwann cells, liver, kidney,
  ovaries, seminal vesicles.
• In cells of liver, ovaries, seminal vesicles, a
  2nd enz, sorbitol dehydrogenase, can oxidize
  sorbitol to produce fructose.
• Hyperglycemia results in accumulation of sorbitol
  in those cells lacking sorbitol dehydrogenase.
  The resulting osmotic events cause cell swelling,
  may contribute to the cataract formation,
  peripheral neuropathy, nephropathy, retinopathy
  seen in diabetes

27

• The major dietary source of galactose is lactose.
  The entry of galactose into cells is not
  insulin-dependent.
• Galactose is 1st phosphorylated by galactokinase
  which produces galactose 1-P. this cpd is
  converted to UDP-galactose by galactose
  1-phosphate uridyltransferase, with the
  nucleotide supplied by UDP-gluc.
• A deficiency of this enz causes classic
  galactosemia. Galactose 1-P accumulates, excess
  galactose is converted to galactitol by aldose
  reductase. This causes liver damage, severe
  mental retardation, cataracts. Treatment
  requires removal of galactose ( therefore,
  lactose) from the diet.
• In order for UDP-galactose to enter the
  mainstream of gluc metabolism, it must be
  converted to UDP-gluc by UDP-hexose-4-epimerase.
  This enz can also be used to produce
  UDP-galactose from UDP-gluc when the former is
  required for synthesis of structural CHOs

28

• Lactose is a disacch that consists of galactose
  gluc. Milk other dairy products are the dietary
  sources of lactose.
• Lactose is synthesized by lactose synthase from
  UDP-galactose gluc in the lactating mammary
  gland. The enz has two subunits, protein A (which
  is a galatosyl transferase) found in most cells
  where it synthesizes N-acetyllactosamine)
  protein B (a-lactalbumin, which is found only in
  the lactating mammary glands, whose synthesis
  is stimulated by the peptide hormone, prolactin).
• When both subunits are present, the transferase
  produces lactose

29
Figure 12.8. Key concept map for metabolism of
fructose and galactose.