The Urea Cycle

Introduction

• Discussing the urea cycle
• Recap: Transamination and oxidative deamination
• Focus on alanine and alpha-ketoglutarate

Alanine in Muscle

• Alanine combines with alpha-ketoglutarate to form:
  • Pyruvate (from alanine)
  • Glutamate (from alpha-ketoglutarate)
• Enzyme involved: Alanine aminotransferase (ALT)
• Pathway is reversible

Glutamate to Liver

• Glutamate transported to liver via blood
• Inside liver cell:
  • Converts ADP+ to NADPH (reduction)
  • Oxidizes glutamate, releasing ammonia
  • Adds water, generates alpha-ketoglutarate
• Enzyme: Glutamate dehydrogenase
• NADPH used in free radical reactions and fatty acid synthesis

Toxicity of Ammonia

• Ammonia can convert to ammonium (NH4+)
• Dangerous in conditions with excessive protein breakdown (e.g., bodybuilders)
• Ammonium can affect the brain:
  • Astrocytes (brain cells)
  • Enzyme: Glutamine synthetase - Converts glutamate to glutamine using ammonium
  • Excessive glutamine causes cerebral edema (brain swelling)
  • Increases intracranial pressure and risk of coma
• Ammonium can also form glycine - Also can cause cerebral edema

Urea Cycle - Mitochondrial Steps

• Ammonium (NH4+) + 2 bicarbonate (HCO3-) + ATP → Carbamoyl phosphate
• Enzyme: Carbamoyl phosphate synthetase I
• Ornithine + Carbamoyl phosphate → Citrulline
• Enzyme: Ornithine transcarbamylase
• Citrulline + Aspartate → Argininosuccinate
• Enzyme: Argininosuccinate synthetase
• Argininosuccinate → Fumarate + Arginine
• Enzyme: Argininosuccinate lyase
• Arginine → Ornithine + Urea
• Enzyme: Arginase
• Urea transported to kidneys, excreted in urine

Clinical Implications

• Deficiencies in urea cycle enzymes (e.g., ornithine transcarbamylase) cause hyperammonemia
  • Leads to cerebral edema, glutamine, and glycine accumulation
• Treatment: Benzoate and phenylbutyrate
  • Bind glutamine and glycine, assisting in excretion via kidneys

Conclusion

• Importance of the urea cycle in managing ammonia levels in the body
• Potential complications from enzyme deficiencies and respective treatments