Rate limiting enzyme

Ornithine transcarbamylase deficiency

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• Definition: inherited genetic disorder characterized by the inability to excrete ammonia
• Epidemiology: most common urea cycle defect
• Inheritance: X-linked recessive (in contrast to the rest of urea cycle enzyme deficiencies which are all autosomal recessive)
• Pathophysiology
  • Defect in the enzyme ornithine transcarbamylase → impaired conversion of carbamoyl phosphate and ornithine to citrulline (and phosphate) → ammonia cannot be eliminated and accumulates
  • Conversion of excess carbamoyl phosphate to orotic acid occurs as part of the pyrimidine synthesis pathway
• Clinical features
  • Symptoms commonly manifest in the first days of life but can develop at any age.
  • Nausea, vomiting, irritability, poor feeding
  • Delayed growth and cognitive impairment
  • In severe cases, metabolic encephalopathy with coma and death
  • Does not cause megaloblastic anemia (as opposed to orotic aciduria)
• Diagnostics
  • Hyperammonemia (usually > 100 μmol/L)
  • ↑ Orotic acid in urine and blood
  • ↓ BUN
  • ↑ Carbamoyl phosphate and ↓ citrulline in the serum
  • Normal ketone and glucose levels

Transport of ammonia by alanine

1. In the liver, alanine is transaminated by alanine aminotransferase to pyruvate with the amino group being transferred to α-ketoglutarate to form glutamate. Almost all aminotransferase enzymes use α-ketoglutarate as the amino group acceptor.
2. Thus, amino groups are funneled into glutamate during protein catabolism.
3. Glutamate is further metabolized by the enzyme glutamate dehydrogenase, which liberates free ammonia and regenerates α-ketoglutarate.
4. Ammonia then enters the urea cycle to form urea, the primary disposal form of nitrogen in humans.
5. Urea subsequently enters the blood and is excreted in the urine.

Cori cycle & Cahill cycle

Lactate/alanine is transported to the liver, where it is converted into glucose. It is then transported back to the muscles for energy production.