4 ammonia

• Ammonia is constantly being liberated in the metabolism of amino acids and other nitrogenous compounds
• At physiological pH


  Ammonia exists as ammonium (NH4+)
• Formation of ammonia


  1. Occurs from amino acids (transamination and deamination)

  2. Biogenic amines

  3. Amino group of purines and pyrimidines

  4. Action of intestinal bacteria on urea
• Despite a regular and constant production of NH3 from various tissues, its concentration in the circulation is surprisingly low
• Transport of ammonia


  Occurs mostly in the form of glutamine or alanine and not as free ammonia
• Alanine is important for NH3 transport from muscle to liver by glucose-alanine cycle
• Glutamine


  Storehouse of NH3 and present at the highest concentration in blood among amino acids
• Glutamine serves as a storage and transport form of NH3
• Glutamine synthesis mostly occurs in liver, brain, and muscle
• Ammonia is removed from the brain predominantly as glutamine
• Glutamine synthetase


  Mitochondrial enzyme responsible for the synthesis of glutamine from glutamate and ammonia
• Synthesis of glutamine


  Requires ATP and Mg2+ ions
• Functions of ammonia


  Involved in the synthesis of many compounds in the body including nonessential amino acids, purines, pyrimidines, amino sugars, asparagine
• Ammonium ions (NH4+) are very important to maintain acid-base balance of the body
• Types of organisms based on ammonia disposal

  • Ammoniotelic
  • Uricotelic
  • Ureotelic
• Ammoniotelic


  Aquatic animals dispose of NH3 into the surrounding water
• Uricotelic


  Ammonia is converted mostly to uric acid (e.g., reptiles and birds)
• Ureotelic


  Mammals including humans convert NH3 to urea
• Urea is a non-toxic and soluble compound, hence easily excreted
• Even a marginal elevation in blood ammonia concentration is harmful to the brain
• Ammonia accumulation results in slurring of speech, blurring of vision, tremors, coma, and death if not corrected
• Hyperammonemia


  Elevation in blood NH3 level may be genetic or acquired
• Impairment in urea synthesis due to a defect in any one of the five enzymes is described in urea synthesis
• All disorders lead to hyperammonemia and cause mental retardation
• Acquired hyperammonemia may be due to hepatitis, alcoholism, etc.
• Explanation for NH3 toxicity


  Reaction catalysed by glutamate dehydrogenase explains the toxic effects of NH3 in the brain
• 1. ketoglutarate is a key intermediate in TCA cycle and its depleted levels impair the TCA cycle
• The net result of NH3 toxicity is reduced production of energy (ATP) by the brain
• Trapping and elimination of ammonia


  Intravenous administration of sodium benzoate and phenyllactate is done
• These compounds can condense with glycine and glutamate to form water-soluble products that can be easily excreted
• In some instances of toxic hyperammonemia, hemodialysis may become necessary