Urea Cycle

BIOSYNTHESIS OF UREA:
  • Urea is the major end product in Nitrogen metabolism in humans and mammals.
  • NH3, the product of oxidative deamination reaction, is toxic in even small amount and must be removed from the body.
  • Sources of the nitrogen in urea cycle are Aspartate and ammonia
  • Urea cycle a.k.a Ornithine cycle is the conversion reactions of NH3 into urea
  • This reaction occur in liver (certain occur in cytosol and mitochondria)
  • Enzymes for urea synthesis are present in Both Cytoplasm & Mitochondrial matrix
  • The urea is transported to the kidney where it is excreted.
  • The overall urea formation reaction is :-

2 NH3 + CO2 + 3ATP→urea + H2O + 3 ADP
  • One amine group comes from oxidative deamination of glutamic acid.
  • While, the other amino group come from aspartic acid.-Aspartic acid is generated from fumaric acid produced by the urea cycle
  • The fumaric acid first undergoes reactions through a portion of citric acid cycle (krebs cycle) to produce oxaloacetic acid which is then changed by transamination into aspartic acid.
STEPS IN UREA CYCLE:
  • First 2 steps of urea cycle occurs in mitochondria & rest 3 in cytoplasm 
 Synthesis of carbamoyl phosphate :
  • Carbamoyl phosphate synthase I (CPS l) of mitochondria catalyses the condensation of NH4+ ions withCO2 (1st Carbon to urea comes from CO2)to form carbamoyl phosphate. 
  • This step consumes 2 ATP and is irreversible, and rate-limiting. 
  • N acetylglutamate serve as allosteric actor of Carbamoyl phosphate synthetase I 
  • Another enzyme, carbamoyl phosphate synthase ll (CPS ll)- involved in pyrimidine synthesis-is present in cytosol. 
  • lt accepts amino group from glutamine and does not require N-acetylglutamate for its activity.
 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.
 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).
 Cleavage of arginosuccinate :
  • Arginosuccinase cleaves arginosuccinate to give arginine and fumarate.
  • Aspartate converted to fumarate in urea cycle
  • Arginine is the immediate precursor for urea. 
  • Fumarate liberated here provides a connecting link with TCA cycle, gluconeogenesis etc.
 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.
  • The urea in the brain is derived from Glutamine


ASSOCIATED DISORDERS:
  • Inherited hyperammonemia in Krebs-Henseleit urea cycle is a result of deficiency of N-acetyl glutamate synthetase
  • Ornithine transcarbamylase deficiency of the Krebs-Henseleit urea cycle is X-linked dominant in inheritance
Exam Question
  • Urea cycle linked to kreb's cycle by Fumarate
  • Sources of the nitrogen in urea cycle are Aspartate and ammonia
  • Urea cycle occurs in Liver
  • Inherited hyperammonemia in Krebs-Henseleit urea cycle is a result of deficiency of N-acetyl glutamate synthetase
  • Ornithine transcarbamylase deficiency of the Krebs-Henseleit urea cycle is X-linked dominant in inheritance
  • Number of ATP required for synthesis of 1 mole of urea is 3
  • Enzymes for urea synthesis are present in Both Cytoplasm & Mitochondrial matrix
  • N acetylglutamate serve as allosteric actor of Carbamoyl phosphate synthetase I 
  • Carbamoyl phosphate synthetase I is the rate limiting enzyme in urea synthesis
  • Urea is produced by the enzyme Arginase
  • Urea is mainly formed in liver and to small extent in Brain
  • First 2 steps of urea cycle occurs in mitochondria
  • Aspartate converted to fumarate in urea cycle
  • Ornithine-citrulline transporter aminoacids
  • The urea in the brain is derived from Glutamine
  • Amino acid involved in urea synthesis is Aspartic acid
  • In argininosuccinase deficiency, Arginine should be supplemented to continue the urea cycle
  • 1st Carbon to urea comes from CO2
  • Carbamoyl phosphate synthase - 1 acts in urea cycle

Don't Forget to Solve all the previous Year Question asked on Urea Cycle