U01.01.103 Urea cycle

The urea cycle, also known as the ornithine cycle, is the metabolic pathway by which the body eliminates excess nitrogen produced during amino acid catabolism. It occurs primarily in the liver and converts nitrogen into urea, which is then excreted by the kidneys.

Overview of Amino Acid Catabolism

Process:
- Amino acid breakdown generates intermediates like pyruvate and acetyl-CoA, used as metabolic fuels.
- Excess nitrogen, a byproduct of this process, is toxic and must be safely eliminated.
Urea Formation:
- Excess nitrogen is converted into urea through the urea cycle.
- Urea is water-soluble and is excreted in urine.

The Urea Cycle Steps

Location	Enzyme	Substrates	Products	Key Notes
Mitochondria	Carbamoyl phosphate synthetase I (CPSI)	CO₂ + NH₃	Carbamoyl phosphate	Requires N-acetylglutamate as an allosteric activator.
	Ornithine transcarbamylase	Carbamoyl phosphate + Ornithine	Citrulline	Citrulline is transported out of mitochondria to the cytoplasm.
Cytoplasm	Argininosuccinate synthetase	Citrulline + Aspartate	Argininosuccinate	Uses ATP; links nitrogen from aspartate to the cycle.
	Argininosuccinate lyase	Argininosuccinate	Arginine + Fumarate	Fumarate enters the TCA cycle; arginine progresses in the urea cycle.
	Arginase	Arginine	Urea + Ornithine	Urea is excreted; ornithine re-enters mitochondria to continue the cycle.

Mnemonic for Urea Cycle

Ordinarily, Careless Crappers Are Also Frivolous About Urination
- O: Ornithine
- C: Carbamoyl phosphate
- C: Citrulline
- A: Aspartate
- A: Argininosuccinate
- F: Fumarate
- A: Arginine
- U: Urea

Points to Remember

Key Regulation:
- Carbamoyl phosphate synthetase I (CPSI) is the rate-limiting enzyme of the urea cycle.
- It requires N-acetylglutamate for activation.
Clinical Relevance:
- Defects in the urea cycle can lead to hyperammonemia, a condition characterized by elevated ammonia levels in the blood, causing neurotoxicity.
Energy Requirement:
- The urea cycle consumes 4 ATP equivalents, making it an energy-intensive process.
Interconnection with TCA Cycle:
- Fumarate generated in the urea cycle can feed into the tricarboxylic acid (TCA) cycle, demonstrating metabolic integration.

Bibliography

Berg JM, Tymoczko JL, Gatto GJ, Stryer L. Biochemistry. 8th ed.
Nelson DL, Cox MM. Lehninger Principles of Biochemistry. 7th ed.
Online medical resources: UpToDate, PubMed.

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