Urea Cycle Lecture Notes

Overview

• Discusses the urea cycle, building on previous discussions of transamination and oxidative deamination.
• Focuses on the conversion of toxic ammonia into urea for excretion.

Key Processes and Enzymes

Alanine and Alpha-Ketoglutarate Reaction

• Alanine combines with alpha-ketoglutarate (keto acid) to form:
  • Pyruvate
  • Glutamate
• Enzyme involved: Alanine Aminotransferase (ALT)

Glutamate Transport and Conversion

• Glutamate travels to the liver.
• Converted into alpha-ketoglutarate and ammonia through:
  • Enzyme: Glutamate Dehydrogenase
  • By-products: NADPH, used in free radical reactions and fatty acid synthesis.

Ammonia Toxicity

• Ammonia is toxic; can become ammonium (NH4+), especially during excessive protein breakdown.
• Excessive amounts can lead to cerebral edema (brain swelling) due to water retention.
  • High intracranial pressure can lead to brain herniation or coma.

Astrocytes and Glutamine Synthetase

• Astrocytes in the brain help manage ammonia levels by turning glutamate into glutamine.
• Enzyme: Glutamine Synthetase
• Excess glutamine can cause water to be drawn into the brain, causing edema.

Urea Cycle Steps

Formation of Carbamoyl Phosphate

• Ammonium combines with bicarbonate in mitochondria, forming carbamoyl phosphate.
• Requires ATP and enzyme Carbamoyl Phosphate Synthetase I.

Citrulline Formation

• Carbamoyl phosphate combines with ornithine to form citrulline.
• Enzyme: Ornithine Transcarbamylase

Argininosuccinate and Arginine Formation

• Citrulline combines with aspartate to form argininosuccinate (enzyme: Argininosuccinate Synthetase).
• Argininosuccinate converts to arginine, releasing fumarate (enzyme: Argininosuccinate Lyase).

Urea Formation

• Arginine is converted back to ornithine, releasing urea.
• Enzyme: Arginase
• Urea is excreted by the kidneys.

Clinical Relevance

• Mutations or deficiencies in urea cycle enzymes can cause ammonia buildup, leading to toxic effects.
• Treatment for elevated ammonia levels includes Benzoate and Phenylbutyrate.
  • These compounds bind glutamine and glycine, promoting excretion via the kidneys.

Conclusion

• The urea cycle is crucial for detoxifying ammonia in the body.
• Understanding the enzymes and intermediates involved is key for diagnosing and treating related disorders.

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