Overview
This lecture reviews the urea cycle, the process by which toxic ammonia—produced from amino acid breakdown—is safely converted into urea for excretion, while highlighting key enzymes, biochemical steps, the impact of ammonia toxicity, and therapeutic interventions.
Amino Acid Catabolism & Ammonia Formation
- Alanine in muscle transfers its amino group to alpha-ketoglutarate, forming pyruvate and glutamate (via alanine aminotransferase, ALT).
- Glutamate moves to the liver for oxidative deamination, forming alpha-ketoglutarate, NADPH, and free ammonia (via glutamate dehydrogenase).
- Excess ammonia is toxic, especially if protein breakdown is high (e.g., in heavy protein diets).
Ammonia Toxicity & Brain Effects
- Ammonia can become ammonium (NH4+) in the blood, which is taken up by astrocytes in the brain.
- Astrocytes use glutamine synthetase to convert glutamate and ammonium into glutamine.
- Excess glutamine draws water into brain tissue, causing cerebral edema and increased intracranial pressure, possibly leading to coma and brain herniation.
- Ammonium can also lead to excess glycine, contributing to neurotoxicity.
Urea Cycle Steps
- Ammonium, bicarbonate (HCO3-), and ATP form carbamoyl phosphate (via carbamoyl phosphate synthetase I).
- Ornithine reacts with carbamoyl phosphate to form citrulline (via ornithine transcarbamylase).
- Citrulline combines with aspartate to make argininosuccinate (via argininosuccinate synthetase).
- Argininosuccinate is converted to arginine and fumarate (via argininosuccinate lyase).
- Arginine is split into ornithine and urea (via arginase); urea is excreted by the kidneys.
Enzyme Deficiencies & Treatment
- Defects in urea cycle enzymes cause ammonia buildup and toxic effects.
- Treatment includes benzoate or phenylbutyrate, which bind to glutamine/glycine, facilitating their excretion in urine.
Key Terms & Definitions
- Transamination — transfer of amino groups between amino acids and keto acids.
- Oxidative Deamination — removal of an amino group from glutamate to form ammonia.
- Urea Cycle — pathway converting ammonia to urea for excretion.
- Ammonia (NH3) / Ammonium (NH4+) — toxic metabolic waste from protein breakdown.
- Astrocytes — brain cells that detoxify ammonia by forming glutamine.
- Cerebral Edema — swelling of the brain due to excess water uptake.
- Carbamoyl Phosphate Synthetase I — enzyme catalyzing the first step of the urea cycle.
- Ornithine Transcarbamylase — enzyme forming citrulline from ornithine and carbamoyl phosphate.
- Arginase — enzyme that produces urea from arginine.
Action Items / Next Steps
- Review the steps and enzymes of the urea cycle.
- Memorize consequences of ammonia toxicity and associated treatments.
- Prepare for questions on enzyme deficiencies and their clinical impacts.