Friday, June 4, 2021

Urea cycle steps - in detailed

1. Synthesis of carbamoyl phosphate : Carbamoyl phosphate synthase I (CPS I) of mitochondria catalyses the condensation of ions with CO2 to form carbamoyl phosphate. This step consumes two ATP and is irreversible, and rate-limiting. CPS I requires N-acetylglutamate for its activity. Another enzyme, carbamoyl phosphate synthase II (CPS II)— involved in pyrimidine synthesis—is present in cytosol. It accepts amino group from glutamine and does not require N-acetylglutamate for its activity.

2. Formation of citrulline : Citrulline is synthesized from carbamoyl phosphate and ornithine by ornithine transcarbamoylase. Ornithine is regenerated and used in urea cycle. Therefore, its role is comparable to that of oxaloacetate in citric acid cycle. Ornithine and citrulline are basic amino acids. (They are never found in protein structure due to lack of codons). Citrulline produced in this reaction is transported to cytosol by a transporter system. 

Urea-cycle-steps-in-detailed
Urea cycle steps - in detailed 

3. Synthesis of arginosuccinate : Arginosuccinate synthase condenses citrulline with aspartate to produce arginosuccinate. The second amino group of urea is incorporated in this reaction. This step requires ATP which is cleaved to AMP and pyrophosphate (PPi). The latter is immediately broken down to inorganic phosphate (Pi).

4. Cleavage of arginosuccinate : Arginosuccinase cleaves arginosuccinate to give arginine and fumarate. Arginine is the immediate precursor for urea.

Fumarate liberated here provides a connecting link with TCA cycle, gluconeogenesis etc.

5. Formation of urea : Arginase is the fifth and final enzyme that cleaves arginine to yield urea and ornithine. Ornithine, so regenerated, enters mitochondria for its reuse in the urea cycle. Arginase is activated by Co2+ and Mn2+. Ornithine and lysine compete with arginine (competitive inhibition).

Arginase is mostly found in the liver, while the rest of the enzymes (four) of urea cycle are also present in other tissues. For this reason, arginine synthesis may occur to varying degrees in many tissues. But only the liver can ultimately produce urea.


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