Urea Cycle
Detoxifying nitrogen. The urea cycle converts toxic ammonia (from protein breakdown) into non-toxic urea that can be safely excreted by the kidneys. This vital liver pathway prevents ammonia accumulation, which would otherwise cause brain damage. A critical but often overlooked process.
The Cycle Steps
1. Carbamoyl Phosphate
NH₃ + CO₂ + 2 ATP. In mitochondria. Rate-limiting step. CPS I enzyme.
2. Citrulline
Ornithine + carbamoyl phosphate. Exported from mitochondria.
3. Argininosuccinate
Citrulline + aspartate. In cytoplasm. Adds second nitrogen.
4. Arginine
Fumarate released. Important amino acid. Also makes nitric oxide.
5. Urea + Ornithine
Arginase cleaves arginine. Urea to kidneys. Ornithine recycles.
Result
2 NH₃ → 1 Urea. Safe, water-soluble. Excreted in urine.
Where Does Ammonia Come From?
Protein Metabolism
- Amino acid catabolism: Deamination releases NH₃
- Dietary protein: Excess amino acids broken down
- Muscle breakdown: Releases amino acids
- Glutamate dehydrogenase: Major source
Other Sources
- Gut bacteria: Produce ammonia from protein
- Nucleotide breakdown: AMP/GMP metabolism
- Kidney: Glutamine deamination
- Muscle: Purine nucleotide cycle
When Things Go Wrong
Urea Cycle Disorders
Genetic enzyme deficiencies. Ammonia builds up. Can cause brain damage. Often present in infancy.
Liver Failure
Can't convert ammonia. Hepatic encephalopathy. Confusion, coma. Medical emergency.
Hyperammonemia
High blood ammonia. Toxic to brain. Causes neurological symptoms.
Protein Overload
Very high protein intake may stress cycle. Usually only issue if liver compromised.
Reye's Syndrome
Aspirin + viral illness in children. Impairs urea cycle. Ammonia rises.
Valproic Acid
Seizure med can inhibit cycle. Monitor ammonia levels.
Nutrient Requirements
Arginine
Cycle intermediate. Semi-essential in some conditions. May need supplementation.
Ornithine
Cycle carrier. Made from arginine. Supplements may support cycle.
Citrulline
Cycle intermediate. Supplements bypass liver. Raises arginine effectively.
ATP
Uses 3 ATP per cycle. Energy-dependent process.
N-Acetyl Glutamate
Activates CPS I (first enzyme). Made from acetyl-CoA and glutamate.
Manganese
Cofactor for arginase. Required for final step.