Urea cycle

  • Urea is considered as the end product of protein metabolism (amino acid metabolism).
  • The nitrogen of amino acids gets converted to ammonia which is toxic to the body.
  • It is then converted to urea and detoxified.
  • Such urea accounts for 80-90% of the nitrogen containing substances which is excreted in the urine.
  • It is synthesized in the liver and transported to the kidneys for excretion through urine.
  • The urea cycle is elucidated by Hans Krebs and Kurt Henseleit in 1932 which was the first metabolic cycle.
  • Due to this reason, this cycle is also called Krebs-Henseleit cycle.
  • However, the individual reactions were described later on by Ratner and Cohen.
  • Urea has two amino groups (-NH2), one derived from NH3 and the other from aspartate where carbon atom is supplied by CO2.
  • Urea synthesis is a five step cyclic process which is guided by five distinct enzymes.
  • The first two enzymes are present in mitochondria and the rest enzymes are localized in cytosol.
  • The various steps of urea cycle are given below.


A) Synthesis of carbamoyl phosphate

  •  Carbamoyl phosphate synthetase I (CPS I) of mitochondria catalyzes the condensation of NH4+ 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.
  • There is another enzyme CPS II, involved in pyrimidine synthesis (present in cytosol) which accepts amino group from glutamine and does not require N-acetylglutamate for its activity.


formation and degradation of N-acetyl glutamateको लागि तस्बिर परिणाम

B) Formation of citrulline

  • Citrulline is synthesized from carbamoyl phosphate and ornithine by ornithine transcarbamoylase.
  • Ornithine is again generated and used in urea cycle.
  • Therefore, its role can be compared to the role of oxaloacetate in citric acid cycle.
  • Ornithine and citrulline are basic amino acids which are never found in protein structure due to lack of codons.
  • A transporter system transports citrulline to the cytosol which is formed in this reaction.


C) Synthesis of argininosuccinate

  • Argininosuccinate synthetase 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 form AMP and pyrophosphate (PPi).
  • The latter is broken down immediately to inorganic phosphate (Pi).


D) Cleavage of argininosuccinate

  • Argininosuccinase cleaves argininosuccinate to give free arginine and fumarate.
  • Arginine is the immediate precursor for urea where fumarate liberated here provides a connecting link with TCA cycle, gluconeogenesis, etc.
  • This is the only reversible reaction of the urea cycle.


urea cycleको लागि तस्बिर परिणाम


E) Formation of urea

  • Arginase is the fifth and final enzyme that helps in cleaving arginine to yield urea and ornithine.
  • Ornithine produced again enters mitochondria for its reuse, in the urea cycle.
  • Arginase is activated by Co2+ and Mn2+.
  • Ornithine and lysine compete with arginine which is competitive inhibition.
  • Arginase is mostly found in the liver, while the rest of the enzymes are present in other tissues.
  • For this reason, arginine synthesis may occur to varying degrees in many tissues.
  • But it is the liver that can ultimately produce urea.


Overall reaction and energetics

  • The urea cycle is irreversible and consumes 4 ATP.
  • Two ATPs are utilized for the synthesis of carbamoyl phosphate.
  • One ATP is converted to AMP and PPi to produce arginino-succinate which equals to 2 ATP.
  • Hence 4 ATP are actually consumed.
  • However, the urea cycle also causes a net conversion of oxaloacetate to fumarate via aspartate.
  • The regeneration of oxaloacetate produces NADH in the malate dehydrogenase reaction.
  • Each NADH molecule can generate up-to 5ATP during mitochondrial respiration greatly reducing the overall cost of urea synthesis.

NH4+ + CO2 + Aspartate + 3ATP     →    Urea + Fumarate + 2ADP + 2Pi + AMP +PPi


i) https://www.ncbi.nlm.nih.gov/books/NBK513323/

ii) https://www.news-medical.net/health/The-Urea-Cycle-Step-by-Step.aspx

Urea cycle