Overview
This lecture explains the urea cycle, its connection to amino acid metabolism, the toxicity of ammonia, and how the body detoxifies and excretes nitrogenous waste.
Amino Acid Catabolism and Ammonia Production
- Transamination in muscles converts alanine and α-ketoglutarate into pyruvate and glutamate via alanine aminotransferase (ALT).
- Glutamate is transported to the liver, where glutamate dehydrogenase converts it into α-ketoglutarate and releases toxic ammonia (NH₃).
- Ammonia is produced in protein catabolism, and excess levels can lead to toxicity, especially in cases of high protein intake or certain metabolic conditions.
Ammonia Toxicity and Effects
- Ammonia can gain a proton to become ammonium (NH₄⁺), which is also toxic at high levels.
- In the brain, astrocytes use the enzyme glutamine synthetase to convert glutamate and ammonium into glutamine.
- Excess glutamine is osmotically active and draws water into brain tissue, leading to cerebral edema and increased intracranial pressure, possibly coma or brain herniation.
- Ammonium can also be used to produce glycine, contributing to neurotoxicity and tissue swelling.
The Urea Cycle
- The urea cycle detoxifies ammonia in the liver by converting it to urea, which is less toxic.
- Ammonium, bicarbonate, and ATP are combined by carbamoyl phosphate synthetase I to form carbamoyl phosphate in mitochondria.
- Ornithine and carbamoyl phosphate form citrulline via ornithine transcarbamylase.
- Citrulline combines with aspartate to form argininosuccinate via argininosuccinate synthetase.
- Argininosuccinate is split into fumarate and arginine by argininosuccinate lyase.
- Arginase converts arginine into ornithine and urea, completing the cycle; urea is excreted in urine.
- Deficiencies in urea cycle enzymes cause ammonia accumulation and related toxicity.
Clinical Management of Urea Cycle Disorders
- High ammonia levels with glutamine/glycine buildup are treated with benzoate or phenylbutyrate.
- These agents bind glutamine and glycine, which are then excreted by the kidneys, reducing ammonia toxicity.
Key Terms & Definitions
- Transamination — Transfer of an amino group from one molecule to another.
- Alanine Aminotransferase (ALT) — Enzyme that catalyzes transamination between alanine and α-ketoglutarate.
- Glutamate Dehydrogenase — Enzyme converting glutamate to α-ketoglutarate, releasing ammonia.
- Ammonia (NH₃) — Toxic byproduct of amino acid breakdown.
- Ammonium (NH₄⁺) — Protonated form of ammonia, also toxic.
- Glutamine Synthetase — Enzyme converting glutamate and ammonium to glutamine.
- Urea Cycle — Hepatic pathway converting toxic ammonia to urea for excretion.
- Carbamoyl Phosphate Synthetase I — First enzyme in urea cycle, forms carbamoyl phosphate.
- Ornithine Transcarbamylase — Enzyme converting ornithine and carbamoyl phosphate to citrulline.
- Argininosuccinate Synthetase/Lyase — Enzymes forming/fissioning argininosuccinate.
- Arginase — Enzyme converting arginine to ornithine and urea.
- Benzoate/Phenylbutyrate — Agents used to treat hyperammonemia by binding amino acids for excretion.
Action Items / Next Steps
- Review enzyme steps and intermediates in the urea cycle.
- Memorize key enzymes and their functions in amino acid and ammonia metabolism.
- Complete assigned readings on metabolic disorders involving the urea cycle.