Download Introduction: Dietary carbohydrates digestion give mainly

Introduction:
Dietary carbohydrates digestion give mainly three monosaccharides, namely glucose, fructose
and galactose, that are absorbed from the intestine into the portal vein and metabolized further in
the liver. Sucrose (table sugar) gives equal amounts of glucose and fructose, lactose (milk sugar)
gives equal amounts of galactose and glucose. In this part of carbohydrate metabolism we
discuss the uronic acid pathway, metabolism of fructose and galactose , their interrelationship
and their role in carbohydrate metabolism .
Contents :
o Overview of Uronic acid pathway, metabolism of fructose and galactose and their
interrelationship.
o Uronic acid Pathway
Fructose metabolism
Galactose metabolism
o
o
o
o
o
Definition
Importance : Biomedical ; Medical
Pathway
Significance : Intermediates of the pathway and their importance
Clinical Correlation :
Uronic acid pathway
: (1) Essential Pentosuria
Fructose metabolism
: (1) Fructosuria (2) Hereditary fructose Intolerance
Galactose metabolism : (1) Galactosemia
o Polyol pathway and its role in cataract formation.
Overview of Uronic acid pathway, metabolism of fructose and galactose and their
interrelationship.
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Definition : The uronic acid pathway is a pathway for the generation of the activated form of
glucuronate - UDP-glucuronate from glucose which is required for detoxificationof some
compounds and synthesis of mucopolysaccharides.
Biomedical importance : (Lehningher)
 Vital Intermediates of the pathway are – UDP Glucuronic acid, UDP Glucose, xylulose 5
phosphate, Vitamin C (in lower animals).
 Major significance of the pathway- synthesis of UDP Glucuronic acid for detoxification
of metabolites and foreign chemicals (xenobiotics) as glucuronides conjugates.
 Dietary D-Xylulose is metabolized by this pathway.
Medical importance:
 Essential pentosuria – is an inborn error of metabolism. L-Xylulose is excreted in
urine.
 Drugs such as barbiturates, chlorobutanol, aminopyrine induce the pathway leading to
increased availability of glucuronic acid for detoxification of these drugs.
(Lehningher)
 The glucuronate-drug conjugation system can, however, lead to drug tolerance.
Cause - chronic exposure to certain drugs.
Tissues
Subcellular site
Starting material
End product
: All Tissues; Liver ; adipose tissue
(high activity in starvation and diabetes mellitus (Devlin))
: Cytoplasm
: Glucose
: Xylulose 5 phosphate; Vitamin C (in lower animals); Oxalate
Pathway:
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Significance : Intermediates of the pathway and their importance
 UDP Glucuronic acid : Glucuronides are formed with substrates such as bilirubin, steroid and a
number of drugs for their excretion in urine or bile as glucuronide conjugates.
 UDP-glucuronate is the source of glucuronic acid for reactions involving its incorporation into
proteoglycans and glycosaminoglycans.
.
 Metabolism of dietary D-Xylulose and synthesis of Xylulose 5 phosphate – susbtrate for HMP
shunt pathway.
 Ascorbic acid : Glucuronate is reduced to L -gulonate, which is a precursor of ascorbate in those
animals capable of synthesizing this vitamin. In humans and other primates, as well as guinea
pigs, bats, and some birds and fishes, ascorbic acid cannot be synthesized because of the absence
of enzyme.
Clinical Correlation : Individuals in whom uronic acid pathway is blocked have no ill effects.
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(1) Essential Pentosuria: is a hereditary condition. The genetic defect is deficiency of L-xylulose
reductase leading to accumulation of L-xylulose (a pentose) and its excretion in urine. Large amounts of
pentose
is
excreted
in urine
especially
following
intake
of
glucuronic
acid.
It is a benign, symptomless condition, detected by routine urine test for reducing sugar (Benedict’s test).
Bials test is done to differentiate it from glucosuria of Diabetes mellitus.
Metabolism of Other Monosaccharides – Fructose and Galactose
Pentoses, Mannose, Amino sugars
FRUCTOSE METABOLISM
Introduction :
Fructose accounts for 30 – 60% of the total carbohydrate intake in mammals. It is predominantly
metabolized by the fructose pathway.
Sources of fructose : fruits, honey, corn syrup (sweetener in soft drinks), hydrolysis of sucrose
(by sucrase enzyme to glucose and fructose).
Metabolism of Fructose : Dietary fructose is absorbed into the portal circulation and enters
liver.
Fate of Fructose : In well fed condition, fructose is metabolized by glycolytic pathway in the
liver after conversion to a phosphorylated derivative. In starvation, it is metabolized to
intermediates of glycolysis, which by gluconeogenesis gives rise to glucose.
Synthesis of fructose in the body : Body synthesizes fructose in seminal vesicles from glucose
(fructose is present in semen and is the source of energy for sperms).
Biomedical importance :
 Fructose is readily metabolized via glycolysis or directly because it bypasses the
regulatory step catalyzed by phosphor fructo kinase.
 Fructose is metabolized rapidly in diabetics.
 Free fructose is found in seminal plasma and is secreted into the fetal circulation
(ungulates and whales), accumulates in amniotic and allantoic fluids - represents a
potential fuel source in these cases.
Medical Importance :
 Essential fructosuria
 Hereditary fructose intolerance leads to fructose accumulation and hypoglycemia.
 At high concentration fructose can cause depletion of adenine nucleotides (ATP) in liver
and hepatic necrosis.
Site of metabolism
Starting material
:
:
Liver
Fructose
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End product
: Glyceraldehyde 3 phosphate and Dihydroxy acetone phosphate.
Fate of the end products : Either enter glycolysis or get reconverted to glucose
(gluconeogenesis).
Pathway : There are 2 pathways for the metabolism of fructose :
(i) in muscle (extrahepatic tissue)
(ii) in liver.
In muscle (extrahepatic tissue), hexokinase phosphorylates fructose and it enters glycolysis. But
glucose inhibits the phosphorylation of fructose, since it is a better substrate for hexokinase.
Nevertheless, some fructose can be metabolized in adipose tissue and muscle.
In liver, fructokinase and Aldolase B enzymes convert fructose to intermediates of glycolysis.
In the fed state fructose, is metabolized by glycolysis and energy is produced. While in
starvation, fructose gives rise to intermediates of glycolysis which will be converted to glucose
by gluconeogenesis.
In liver, Fructose is metabolized by Fructokinase :
 Present in liver, kidney and intestine .
 has a high affinity for fructose.
 Independent of insulin / fasting.
 Phosphorylates fructose on position C1.
Fructose is more rapidly metabolized than glucose and galactose, since the glucokinase (GK)
and phosphofructokinase ( PFK) metabolic bottlenecks, are not encountered in fructose
metabolism.
However, excess fructose in the diet depletes Pi in the liver. The production of fructose 1
phosphate will be greater than the breakdown by Aldolase B resulting in accumulation of
Fructose 1 phosphate and depletion of Pi. Therefore ATP levels drop activating glycolysis and
lactate production.
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Fructose is deleterious for diabetics :
(i) Fructose rapidly enters tissues (Normal rate as compared to glucose). It is metabolized in the
liver by bypassing the PFK step. Hence fructose increases the flux of glycolytic pathway leading
to lipogenesis. Therefore fructose is lipogenic. [Glycerol 3 phosphate (intermediate of
glycolysis) is required for TAG synthesis]. Enhanced fatty acid synthesis- increases serum TAGIncreased LDL cholesterol – Atherogenic and harmful.
(iii) Fructose 1 phosphate accumulation inhibits glycogenolysis.
Clinical Correlation:
1. Essential fructosuria is a hereditary (inherited as autosomal recessive) condition.
Cause: Deficiency of fructokinase due to genetic defect in the enzyme.
It is benign, asymptomatic. This leads to accumulation of fructose and its excretion in urine.
It is detected by routine urine examination for reducing sugars.
2. Hereditary fructose intolerance : Hereditary condition.
Cause: Deficiency of Aldolase B due to genetic defect in the enzyme.
This leads to accumulation of fructose-1-P in liver after a dietary fructose load.
Fructose-1-P inhibits glycogen phosphorylase and induces hypoglycemia.
In addition, high fructose intake causes depletion of inorganic phosphate in liver cells which in
turn causes diminished ATP synthesis and consequently leading to hepatic cell necrosis and
cirrhosis of liver. Prolonged intake in children may lead to death.
Fructose induced hypoglycemia is seen in Hereditary fructose intolerance.
Polyol Pathway - Synthesis of Fructose from Glucose :
Site: active in brain, Lens of the eye and Seminal vesicles.
Fructose is found in seminal plasma and in the fetal circulation of ungulates and whales.
Aldose reductase is found in the placenta of the ewe and is responsible for the secretion of sorbitol into
the fetal blood. Fructose is preferred fuel molecule in semen for sperms, may be because other tissues
(penile urethra and vagina) that comes in contact with semen prefers glucose as fuel molecule.
Reactions:
Aldose reductase
D-Glucose
NADPH + H+
Sorbitol DeH
D- Sorbitol
NADP+
NAD+
D-Fructose
NADH + H+
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In diabetes, formation of sorbitol and fructose in the lens of the eye, maybe involved in the pathogenesis
of diabetic cataract. Sorbitol does not diffuse through the cell membrane and accumulates causing
osmotic damage.
GALACTOSE METABOLISM
Galactose, which is metabolized from the milk sugar, lactose (a disaccharide of glucose and
galactose), enters glycolysis by its conversion to glucose-1-phosphate (G1P).
Dietary D -Galactose

Hydrolysis of lactose, milk sugar, by lactase enzyme. Absorbed from the intestine.
Transported to the liver by the portal system and metabolized in the liver.

Absorbed by secondary active transport into the portal system and metabolized in the
liver

Synthesis in the body : synthesized in the mammary gland for synthesis of lactose in
milk.
BIOMEDICAL IMPORTANCE:
 It is readily converted to glucose in the liver - a test for hepatic function in the galactose
tolerance test.
 Galactose is a constituent of glycolipids (cerebrosides), proteoglycans, glycoproteins
 Synthesis of lactose in the mammary gland.
MEDICAL IMPORTANCE :
Galactosemia is a clinical condition associated with galactose metabolism. Failure to metabolize
galactose leads to cataracts.
Site of metabolism : Liver
Starting material : Galactose
End product : Glucose 6 phosphate (which enters glycolysis in fed state or gets converted
glucose by gluconeogenesis in starvation)
Pathway :
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Galactose Synthesis in Tissues:
Glucose is converted to galactose in many tissues for the synthesis of glycolipids,
glycosaminoglycans/proteoglycans, glycoproteins (in several tissues) and lactose (in
mammary gland).
UDP galactose-4-epimerase
Glucose
UDP-Glucose
Glucose
Lactose synthase
UDP-Galactose
Glycolipids, Glycoproteins and
glycosaminoglycans/Proteoglycans,
(Mammary gland) Lactose
Clinical Significance of Galactose Metabolism
Three inherited disorders of galactose metabolism have been delineated.
1. Classic galactosemia is a major symptom of two enzyme defects. One results from loss of the
enzyme galactose-1-phosphate uridyl transferase.
2. The second form of galactosemia results from a loss of galactokinase.
Manifestation : These two defects are manifested by
 a failure of neonates to thrive.
 Vomiting and diarrhea occur following ingestion of milk - hence individuals are termed
lactose intolerant.
 Include failure to thrive
 Mental retardation
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

Cataract formation and in some instances
Death from liver damage.
Clinical findings of these disorders include impaired liver function (which if left untreated leads
to severe cirrhosis), elevated blood galactose - hypergalactosemia, urinary galactitol
excretion and hyperaminoaciduria.
Circulating galactose is reduced to the sugar alcohol galacitol, by an NADPH-dependent
galactose reductase that is present in neural tissue and in the lens of the eye. At normal
circulating levels of galactose this enzyme activity causes no pathological effects.
However, a high concentration of galactitol in the lens causes osmotic swelling, with the
resultant formation of cataracts and other symptoms and CNS damage leading to mental
retardation.
{Unless controlled by exclusion of galactose from the diet, these galactosemias can go on to
produce blindness and fatal liver damage. Even on a galactose-restricted diet, transferasedeficient individuals exhibit urinary galacitol excretion and persistently elevated erythrocyte
galactose-1-phosphate levels. Blindness is due to the formation of galactitol}.
Treatment : The principal treatment of these disorders is to eliminate lactose from the diet.
Galactose free diets reverse most of the symptoms except mental retardation.
3. The third disorder of galactose metabolism result from a deficiency of UDP-galactose-4epimerase.
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