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Urea cycle
The (urea cycle( also known as the ornithine cycle )is a cycle
of biochemical reactions occurring in many animals that
produces )urea( from (ammonia( NH3.
Urea is formed in the liver mainly, some in the brain and renal
tubules from one molecule of CO
2
and two molecules of NH
3
using 3 ATP.



It is released into the blood with a level of 20-40 mg/dl of
serum.
It is cleared by the kidney to the urine with a level of 20-
40 g/24 hours urine collection.
It is the major end product of nitrogen catabolism in
humans representing 80-90% of the nitrogen excreted.

Five reaction each of them utilizes specific enzyme in urea
cycle.
The first 2 reactions of urea cycle are mitochondrial and the rest
3 reactions are cytoplasmic.
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Five enzymes of urea cycle:
1- Carbamoyl Phosphate Synthase 1
2- Ornithine Transcarbamoylase (Citrulline Synthase)
3- Argininosuccinate Synthetase.
4- Argininosuccinase.
5- Arginase.



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Reactions (steps) of the urea cycle
1. Formation of carbamoyl phosphate
One molecule of ammonia condenses with CO2 in the
presence of two molecules of ATP to form carbamoyl
phosphate.
The reaction is catalyzed by carbamol phosphate synthase 1.
CO
2
+ NH
3
+ 2ATP H2N-CO-OP + 2ADP +PI

2. Formation Of Citrulline
The second reaction is also, mitochondrial. The
carbamoyl group is transferred to the NH2 group of
ornithine by mitochondrial ornithine transcarbamoylase.
Citrulline leaves the mitochondria and further reaction
are taking place in cytoplasm.


cytosol
mitochondrial matrix
carbamoyl phosphate
P
i

ornithine citrulline
ornithine citrulline
urea aspartate
arginine argininosuccinate
fumarate
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3. Formation Of Argininosuccinate:
Citrulline plus aspartate forms arginino-succinate by
argininosuccinate 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 argininosuccinase.
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 asprtate which is
needed for urea cycle.
2- The CO2 used in urea cycle comes mainly from krebs'
tricarboxylic acid cycle.
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3- Aspartate in urea cycle may be generated from
oxaloacetate of citric acid cycle.

Regulation of urea cycle
1- Carbamoylphosphate synthase 1 is the rate limiting enzyme
of urea cycle. It is active only in the presence of N-
acetylglutamate.






H
2
N C OPO
3
2
O
HCO
3

+ NH
3
+ 2 ATP
+ 2 ADP + P
i
Carbamoyl Phosphate
Synthase
carbamoyl phosphate
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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 carbamoylphosphate synthase
(reaction 1), ornithine transcarbamoylase (reaction 2) and
arginase enzymes (reaction 5).

Metabolic disorders of urea cycle:
Deficiency of any of the urea cycle enzymes would result in
hyperammonemia.
There are five types of hyperammonaemia
They affect children and manifested by vomiting, irritability,
ataxia, lethargy, and mental retardation.
1- Hyperammonaemia type 1:
it may be due to carbamoylphosphate synthase I deficiency.

2- Hyperammonaemia type II:
it is due to ornithine transcarbamoylase deficiency. There is
increased glutamine in blood, CSF and urine due to increased
glutamine synthesis as consequence of increased tissue levels
of ammonia.

3- Citrullinaemia (type III):
it is due to lack of argininosuccinic synthase.



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4- Argininosuccinic aciduria (type IV):
it is due to argininosuccinase 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- Hyperargininaemia (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
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
2- Blurred vision
3- Slurred speech
4- Vomiting
5- Confusion followed by coma and death.


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Treatment
1- Restrict protein diet
2- Injection of glutamic acid and -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 NH
3
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 NH
3
by dialysis in acute cases.