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Chapter: Biochemistry: Protein Metabolism

Urea Cycle

Urea Cycle
Living organisms excrete the excess nitrogen resulting from the metabolic breakdown of amino acids in one of three ways.

Urea Cycle


Living organisms excrete the excess nitrogen resulting from the metabolic breakdown of amino acids in one of three ways. Many aquatic animals simply excrete ammonia. Where water is less, plentiful processes have evolved that convert ammonia to less toxic waste products which require less water for excretion. One such product is urea, which is excreted by most terrestrial vertebrates; another is uric acid, which is excreted by birds and terrestrial reptiles.

Accordingly, living organisms are classified as being either ammonotelic (ammonia excreting), urotelic (urea excreting) and uricotelic (uric acid excreting). Some animals can shift from ammonotelism to urotelism or uricotelism if their water supply becomes restricted.

Urea is synthesised in the liver by the enzymes of the urea cycle. It is then secreted into the blood stream and sequestered by the kidneys for excretion in the urine.The urea cycle reactions were elucidated by Hans Krebs and Kurt Henseleit. This cycle starts with the amino acid ornithine. The cycle is confined only to the mitochondria and cytoplasm of the cells of liver and it is found that the enzyme, arginase which is required in the final step of urea formation is present only in the liver and absent in all the other tissues.

Urea cycle occurs partially in the mitochondria and partially in the cytosol with ornithine and citrulline being transported across the mitochondrial membrane by specific membrane systems. The following are the various reactions in the process of urea formation.


1. Carbamoyl phosphate formation

Carbamoyl phosphate synthetase catalyses the condensation and activation of NH4+ and HCO3- to form carbamoyl phosphate.


2. Citrulline formation from ornithine

Ornithine transcarbamylase transfers the carbamoyl group of carbamoyl phosphate to ornithine, yielding citrulline.

The reaction occurs in the mitochondria so that ornithine, which is produced in the cytosol, must enter the mitochondria via a specific transport system. Like wise, since the remaining urea cycle reactions occur in the cytosol, citrulline must be transported from the mitochondria.


3. Argininosuccinate formation

Citrulline undergoes condensation with amino group of aspartate to form arigininosuccinate this reaction requires ATP, Mg2+ and the enzyme argininosuccinate synthetase.


4. Formation of arginine and fumarate

The enzyme argininosucccinase catalyses the elimination of arginine from the aspartate carbon skeleton forming fumarate


5. Formation of urea

The fifth and the final reaction in the urea cycle is the hydrolysis of arginine by the enzyme arginase to yield urea and ornithine.

Ornithine is then returned to the mitochondria for another round of the cycle.


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