Dirty Medicine's Biochemistry Series: The Urea Cycle

Overview

• The urea cycle is crucial for eliminating ammonia from the body by converting it into urea.
• Ammonia is a byproduct of protein breakdown (amino acids) and needs to be removed as it is toxic.
• The urea formed in the liver is transported to the kidneys for excretion.

The Urea Cycle Process

1. Ammonia Formation:

   • Ammonia is formed from amino acid catabolism.
   • Combines with CO2 to form carbamoyl phosphate.
   • Enzyme: Carbamoyl phosphate synthetase I (CPS I)

2. Carbamoyl Phosphate to Citrulline:

   • Combines with ornithine to form citrulline.
   • Enzyme: Ornithine transcarbamylase
   • Note: Reaction occurs in the hepatic mitochondria.

3. Citrulline to Argininosuccinate:

   • Citrulline combines with aspartate and ATP to form argininosuccinate.
   • Enzyme: Argininosuccinate synthetase

4. Argininosuccinate to Arginine:

   • Argininosuccinate breaks down to arginine, releasing fumarate.
   • Enzyme: Argininosuccinase

5. Arginine to Urea and Ornithine:

   • Arginine is converted back to ornithine, releasing urea.

Key Points

• Rate-limiting enzyme: Carbamoyl phosphate synthetase I (CPS I)
  • Mnemonic: CPS (like CVS pharmacy) where you get medicine to help with urination.

Enzyme Deficiencies

• Ornithine Transcarbamylase Deficiency:
  • Leads to a buildup of carbamoyl phosphate, converted to orotic acid (toxic).
  • Results in decreased citrulline and increased orotic acid.
  • X-linked recessive disorder.

Ammonia Toxicity

• High ammonia levels can cause serious symptoms:
  • Asterixis (negative myoclonus): Flapping tremor of the hands when held at 90-degree angle.
  • Cerebral Edema: Swelling in the brain, leading to symptoms like slurred speech, ataxia, altered mental status, blurred vision, and vomiting.

Treatment for Hyperammonemia

• Decrease dietary protein intake: Limits amino acid breakdown into ammonia.
• Medications:
  • Lactulose: Increases ammonia excretion via GI tract (causes diarrhea).
  • Rifaximin: Antibiotic that reduces ammonia production by killing colon bacteria.

Summary

• The primary goal of the urea cycle is ammonia detoxification by converting it into urea.
• Understanding the cycle, its enzymes, and related disorders is essential for managing conditions like hyperammonemia and enzyme deficiencies.