urea cycle

November 3, 2013 [UREA CYCLE]

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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 CO2 and two molecules of NH3

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.

CO2 + NH3 + 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

Pi

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.

H2N C OPO32

O

HCO3 + NH3 + 2 ATP

+ 2 ADP + Pi

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 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

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 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.

urea cycle

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