5 Urea cycle

• Urea


  End product of protein metabolism (amino acid metabolism)
• Urea accounts for 80-90% of the nitrogen-containing substances excreted in urine
• Urea is synthesized in the liver and transported to kidneys for excretion in urine
• Urea cycle


  First metabolic cycle elucidated by Hans Krebs and Kurt Henseleit in 1932
• Urea has two amino (-NH) groups, one derived from NH3 and the other from aspartate
• Carbon atom is supplied by CO2 in the urea cycle
• Urea synthesis


  Five-step cyclic process with five distinct enzymes
• The first two enzymes are present in mitochondria while the rest are localized in cytosol
• Synthesis of carbamoyl phosphate

  Carbamoyl phosphate synthase (CPS I) catalyses condensation of NH3 ions with CO2
• This step consumes two ATP and is irreversible, and rate-limiting
• CPS I requires N-acetylglutamate for its activity
• CPS II is involved in pyrimidine synthesis 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
• Citrulline produced is transported to cytosol by a transporter system
• Synthesis of arginosuccinate


  Arginosuccinate synthase condenses citrulline with aspartate
• This step requires ATP which is cleaved to AMP and pyrophosphate (PPi)
• Cleavage of arginosuccinate


  Arginosuccinase cleaves arginosuccinate to give arginine and fumarate
• Arginine is the immediate precursor for urea
• Fumarate provides a connecting link with TCA cycle and gluconeogenesis
• Formation of urea


  Arginase cleaves arginine to yield urea and ornithine
• Ornithine is regenerated and enters mitochondria for reuse in the urea cycle
• Arginase is activated by Mn2+
• Ornithine and lysine compete with arginine (competitive inhibition)
• Arginase is mostly found in the liver
• Only the liver can ultimately produce urea
• The urea cycle is irreversible and consumes 4 ATP
• Two ATP are utilized for the synthesis of carbamoyl phosphate
• One ATP is converted to AMP and PPi to produce arginosuccinate which equals to 2 ATP
• Regulation of urea cycle

  The first reaction catalysed by carbamoyl phosphate synthase (CPS I) is rate limiting reaction or committed step in urea synthesis
• CPS I is allosterically activated by N-acetylglutamate (NAG)
• High concentrations of arginine increase NAG
• The consumption of a protein-rich meal increases the level of NAG in liver, leading to enhanced urea synthesis
• Carbamoyl phosphate synthase I and glutamate dehydrogenase are localized in the mitochondria
• They coordinate with each other in the formation of NH3 and its utilization for the synthesis of carbamoyl phosphate
• The remaining four enzymes of urea cycle are mostly controlled by the concentration of their respective substrates
• Urea produced in the liver freely diffuses and is transported in blood to kidneys for excretion
• A small amount of urea enters the intestine where it is broken down to CO2 and NH3 by the bacterial enzyme urease
• This ammonia is either lost in the feces or absorbed into the blood
• In renal failure, the blood urea level is elevated (uremia)