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URONIC ACID PATHWAY

CHEM3119
Dr. Misbah Irshad Lecture - 06 Biometabolism

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 Key Concepts
• This is an alternative oxidative pathway for
glucose and is also known as glucuronic acid
pathway
• It is concerned with the synthesis of glucuronic
acid
• a sugar acid derived from glucose, with its sixth
carbon atom oxidized to a carboxylic acid.

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• a uronic acid that was first
isolated from urine (hence
the name).
• It is found in
many gums such as gum
arabic, xanthan,
and Kombucha gum arabic
tea and is important for
the metabolism of
microorganisms
plants and animals.
Kombucha is a fermented, slightly
alcoholic, lightly effervescent, sweetened
black or green tea drink commonly
consumed for its supposed health
benefits. 4
Synthesis of
• pentoses
• Vitamin
• ascorbic acid (except in
primates and guinea pigs).
• Dietary xylulose enters
uronic acid pathway through which it can
participate in other metabolisms.
• In most of the pathways of carbohydrate
metabolism, phosphate esters participate,
• in uronic acid pathway, the free sugars or sugar
acids are involved.
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Formation of UDP- glucuronate
• Glucose 6-phosphate converted
to glucose 1-phosphate.
• UDP-glucose is then synthesized
by the enzyme UDP-glucose
pyrophosphorylase.
• the reactions are the same as in
glycogenesis
• UDP-glucose dehydrogenase
oxidizes UDP-glucose to UDP-
glucuronate.

UDP-glucose
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UDP-glucose

UDP-glucuronate
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 UDP-glucuronate
• UDP-glucuronate is the metabolically active form of
glucuronate
• which is utilized for conjugation with many substances
like bilirubin, steroid hormones and certain drugs.
• Several insoluble compounds are converted to soluble
ones through conjugation and, further, the drugs are
detoxified. UDP-glucuronate is also required for the
synthesis of glycosaminoglycans and proteoglycans.
• long linear polysaccharides consisting of repeating
disaccharide units

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Conversion of UDP-
glucuronate to L-gulonate
UDP-glucuronate loses its UDP
moiety in a hydrolytic reaction and
releases D- glucuronate

UDP-glucuronate
D- glucuronate
D- glucuronate is reduced to L-
gulonate by an NADPH-dependent
reaction.

D- glucuronate L-gulonate

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Synthesis of ascorbic acid in
some animals :

L-Gulonate is the precursor for the L-Gulonate

synthesis of ascorbic acid (vitamin C)
in many animals.
The enzyme L-gulonolactone
oxidase—
which converts gulonate to ascorbic
acid—is absent in man, other primates
and guinea pigs.
Therefore, vitamin C has to be
supplemented in the diet for these
animals.

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 -H20

L-Gulonolactone
L-Gulonate
L-
Gulonolactone
02 oxidase

2-Keto-L-gulonolactone
ascorbic acid 12
Oxidation of L-gulonate :
• L-Gulonate is oxidized to 3-keto-
L-gulonate decarboxylated to a
pentose, L-xylulose.
• L-Xylulose is converted to xylitol
by a reduction (NADPH-
dependent)
• xylitol to D-xylulose by an
oxidation (NAD+-dependent)
reaction.
• D-xylulose (and not L-form) after
getting phosphorylated can
enter the hexose
monophosphate shunt, for
further metabolism.
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 - NADH + H +

3-Keto L-gulonate L-Gulonate

- CO2

L-Xylulose

- NADP+

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Xylulose 5-phosphate
- NADH + H +
Xylitol D-Xylulose
Effect of drugs on uronic acid pathway

 Administration of drugs (barbital, chlorobutanol)

significantly increases the uronic acid pathway
to achieve more synthesis of glucuronate from
glucose.

 Certain drugs (aminopyrine, antipyrine) were found to

enhance the synthesis of ascorbic acid in rats.

antipyrine aminopyrine 15
Essential pentosuria

• This is a rare genetic disorder related to the deficiency of an

NADP dependent enzyme xylitol dehydrogenase.

• Due to this enzyme defect, L-xylulose cannot be converted to

xylitol.
• The affected individuals excrete large amounts of L-xylulose
in urine.
• Essential pentosuria is asymptomatic and the individuals
suffer from no ill-effects.
• It has been reported that the administration of drugs
aminopyrine (analgesic, anti-inflammatory, and antipyretic
properties ) &
• antipyrine (analgesic and antipyretic) increases the excretion
of L-xylulose in pentosuric patients. 16
 METABOLISM OF GALACTOSE
• The disaccharide lactose, present in milk and milk products, is
the principal dietary source of galactose.
• Lactase (E-galactosidase) of intestinal mucosal cells hydrolyses
lactose to galactose and glucose.
• Galactose is also produced within the cells from the lysosomal
degradation of glycoproteins and glycolipids.
• As is the case for fructose, galactose entry into the cells is not
dependent on insulin.
• The specific enzyme, namely galactokinase, phosphorylates
galactose to galactose 1-phosphate.
• This reacts with UDP-glucose in an exchange reaction to
form UDP-galactose in presence of the enzyme galactose 1-
phosphate uridyltransferase UDP-galactose is an active donor

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• reactions involving the formation of compounds like
• lactose, glycosamino- glycans, glycoproteins, cerebrosides
and glycolipids.
• UDP-galactose can be converted to UDP-glucose by UDP
hexose 4-epimerase.
• In this way, galactose can enter the metabolic pathways of
glucose.
• It may be noted that galactose is not an essential nutrient
since UDP-glucose can be converted to UDP-galactose by the
enzyme UDP- hexose 4-epimerase.

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DISORDERS OF GALACTOSE METABOLISM
Classical galactosemia
Galactosemia (incidence 1 : 30000) is due to the deficiency of the
enzyme galactose 1- phosphate uridyltrans-ferase.
It is a rare congenital disease in infants, inherited as an autosomal
recessive disorder.
The salient features of galactosemia are
1. Galactose metabolism is impaired leading to increased
galactose levels in circulation (galactosemia) and urine
(galactosuria).
1. The accumulated galactose is diverted for the production of
galactitol (dulcitol) by the enzyme aldose reductase (the same
enzyme that converts glucose to sorbitol). Aldose reductase is
present in lens, nervous tissue, seminal vesicles. The conversion
of galactose to galactitol is insignificant in routine galactose
metabolism.
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• Galactitol (like sorbitol) has been implicated in the
development of cataract.
• The accumulation of galactose 1-phosphate and
galactitol in various tissues like liver, nervous tissue,
lens and kidney leads to impairment in their function.

galactitol :
is a sugar alcohol, the reduction product of galactose
Galactose:
It is a C-4 epimer of glucose

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• High levels of galactose 1-phosphate in liver results
in the depletion of inorganic phosphate
(sequestering of phosphate) for other metabolic
functions.
• Galactose 1-phosphate inhibits glycogen
phosphorylase resulting in hypoglycemia.
• The clinical symptoms of galactosemia are—loss of
weight (in infants) hepato- splenomegaly, jaundice,
mental retardation etc. In severe cases,
• Cataract : clouding of the lens of the eye which
leads to a decrease in vision
• ,

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• amino aciduria : urine contains abnormally high amounts
of amino acids, in the healthy kidney, the glomeruli filter
all amino acids out of the blood, and the renal
tubules then reabsorb over 95% of the filtered amino acids
back into the blood.
• Albuminuria: kidney disease and means that you have too
much albumin in your urine. Albumin is a protein found in
the blood. are also observed.

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• Diagnosis :
• Early detection of galactosemia is possible
(biochemical diagnosis) by measuring the activity of
galactose 1-phosphate uridyl- transferase in
erythrocytes.
• Treatment :
• The therapy includes the supply of diet deprived of
galactose and lactose.
• Galactokinase deficiency :
• The defect in the enzyme galactokinase, responsible
for phosphorylation of galactose, will also result in
• galactosemia : “galactose in the blood,”
• and galactosuria (is a condition of excess spilling of
galactose into the urine.)
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 Assignments

1. Draw the pathway for METABOLISM OF

FRUCTOSE.

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