BIOCHEMISTRY
UREA CYCLE
ASSIGNMENT CODE: 307
Supervised By:
DR. Sobia Iftikhar Ali
Prepared By:
Muhammad Asad ( 41 )
Muhammad Salman ( 23 )
Syed Rehan ( 36 )
Mustajab Hessan ( 37 )
Mahrukh Kashif ( 87 )
Iman Arshad ( 07 )
Fatima Rajput ( 49 )
Areeba Nasir ( 82 )
Anya Imran ( 31 )
Alishay Batool ( 74 )
UREA CYCLE
The urea cycle, also known as the ornithine cycle, is a
series of biochemical reactions that take place in many
animals to convert ammonia (NH3) into urea.
This process primarily occurs in the liver, with some
activity in the brain and renal tubules. The cycle uses one
molecule of CO2 and two molecules of NH3, requiring 3
ATP to form urea.
Urea is released into the bloodstream, where its
concentration is typically 20-40 mg/dl of serum.
It is then filtered by the kidneys and excreted in the urine,
with a daily excretion rate of 20-40 grams in a 24-hour urine
collection.
Urea is the primary end product of nitrogen metabolism in
humans, accounting for 80-90% of the nitrogen excreted.
The urea cycle consists of five reactions, each catalyzed by
a specific enzyme. The first two reactions occur in the
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mitochondria, while the remaining three take place in the
cytoplasm.
Five Enzymes of Urea Cycle:
1- Carbamoyl Phosphate Synthase 1
2- Ornithine Transcarboxylase (Citrulline Synthase)
3- Arginosuccinate Synthetase.
4- Argininosuccinic.
5- Arginase.
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Reactions (steps) of the Urea Cycle:
1. Formation of carbamoyl phosphate:
One molecule of ammonia combines with carbon
dioxide in the presence of two molecules of ATP to
form carbamoyl phosphate.
This reaction is catalyzed by carbamoyl phosphate
synthase. The equation for the reaction is:
C O2 + N H 3 +2 ATP → H 2 N−CO−OP +2 ADP + PI
2. Formation Of Citrulline:
The second reaction is also, mitochondrial. The
carbamoyl group is transferred to the NH2 group of
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ornithine by mitochondrial ornithine
transcarboxylase. Citrulline leaves the mitochondria
and further reaction are taking place in cytoplasm.
3. Formation Of Arginosuccinate:
Citrulline plus aspartate forms argino-succinate by
arginosuccinate synthase. This require ATP that
changes to AMP +PPI because the ureido group (-NH-
CO-NH2) is very stable and requires energy for
activation.
4. Formation of Arginine:
To form arginine and fumarate by argininosuccinic.
This enzyme is present in liver and kidney of humans.
5. Formation Of Urea:
Liver arginase enzyme hydrolytically cleaves arginine
to form urea and regenerates ornithine and thus
completes the urea cycle.
Link between Urea Cycle and Krebs
Tricarboxylic Acid Cycle:
1. The fumarate resulting from reaction number 4 (in
Krebs urea cycle) is an intermediate in citric acid
cycle. It could be converted in cytoplasm to aspartate
which is needed for urea cycle.
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2. The CO2 used in urea cycle comes mainly from Krebs
tricarboxylic acid cycle.
3. Aspartate in urea cycle may be generated from
oxaloacetate of citric acid cycle.
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Regulation of Urea Cycle:
1. Carbamoyl phosphate synthase 1 is the rate limiting
enzyme of urea cycle. It is active only in the presence
of N-acetyl glutamate.
2. Excess ammonia formation stimulates urea
formation.
3. High arginine level stimulates N-acetyl glutamate
synthase enzyme, thus increases urea formation.
4. High urea level inhibits carbamoyl phosphate
synthase (reaction 1), ornithine transcarboxylase
(reaction 2) and arginase enzymes (reaction 5).
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UREA CYCLE
Metabolic Disorders of Urea Cycle:
Deficiency of any of the urea cycle enzymes would result in
hyperammonemia.
There are five types of hyperammonemia
They affect children and manifested by vomiting, irritability,
ataxia, lethargy, and mental retardation.
1.Hyperammonemia Type 1:
It may be due to carbamoyl phosphate synthase I deficiency.
2.Hyperammonemia Type 2:
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It is due to ornithine transcarboxylase deficiency. There is
increased glutamine in blood, CSF and urine due to
increased glutamine synthesis as consequence of increased
tissue levels of ammonia.
3.Citrullinemia (Hyperammonemia Type 3):
It is due to lack of argininosuccinic synthase.
4.Argininosuccinic aciduria
(Hyperammonemia Type IV):
It is due to argininosuccinic deficiency. There is increase in
argininosuccinic acid in plasma, CSF and urine. It is
manifested at age of two years. It is usually ends in death
early in life.
5.Hyperargininemia Type V:
It is due to arginase deficiency. There is increase in arginine
in blood, CSF and urine. It affects children (1:30,000) leading
to mental retardation, coma and death.
Ammonia Intoxication:
It is defined as toxicity of the brain due to increase in NH3
level in the systemic blood. This increased ammonia will be
fixed to α ketoglutaric acid to form glutamic acid than
glutamine leading to interference with citric acid cycle so
decrease ATP production in brain cells.
Manifestations of Ammonia Intoxication:
1. Tremors
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2. Blurred vision
3. Slurred speech
4. Vomiting
5. Confusion followed by coma and death.
Treatment:
1. Restrict protein diet
2. Injection of glutamic acid and α-ketoglutaric acid: they
act as a carrier for NH3 and combine with it to form a
nontoxic material called glutamine. Glutamine passes to
the kidney and by glutaminase yielding glutamic acid
and NH3 excreted in urine as ammonium salt.
3. Sodium benzoate and phenylacetate are given to
conjugate with glycine and glutamine and rapidly the
conjugates are excreted in urine.
4. Removal of excess NH3 by dialysis in acute cases
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