Summary of steps (important!)

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1. Generation of ammonia in periphery
2. Transportation of ammonia to liver
   1. In periphery
      • Transamination: amino acids + α-ketoglutarate ⇄ α-ketoacids + glutamate
   2. Transport to liver, by either
      • Glutamine cycle (most common)
        • Glutamate is negatively charged, it needs to get one more ammonia to form glutamine, to be able to get through membrane
        • Glutamate + NH₄⁺ + ATP → Glutamine + ADP + Pi
      • Alanine cycle (Cahill cycle)
        • Similar reason, glutamate gives ammonia to pyruvate to form alanine, to be able to get through membrane. This process is a reversed transamination.
        • Pyruvate + glutamate ⇄ alanine + α-ketoglutarate
   3. In liver
      • Convert back to glutamate, by either
        • Glutaminase: glutamine + H2O → glutamate + ammonium
        • Transamination: alanine + α-ketoglutarate ⇄ pyruvate + glutamate
      • Release ammonia (Deamination): glutamate + NAD(P)⁺ + H₂O ⇄ α-ketoglutarate + NH₄⁺ + NAD(P)H + H⁺
3. Excretion of ammonia
   • Urea cycle

Transamination

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• Description: transfer of an amino group from an AA to an α-ketoacid for breakdown, or to an α-ketoacid to form a nonessential AA
• E.g.
  • ALT:
  • AST: aspartate + α-ketoglutarate ⇄ oxalacetate + glutamate

Deamination

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• Description: reaction in which an amino group from an AA is released as ammonium

Cahill cycle and Cori cycle

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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.

Urea cycle

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• Location: primarily occurs in the cytosol and mitochondria of liver cells and also in kidney cells

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