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Urea Cycle Introduction: Urea is the major end product of nitrogen metabolism in humans and mammals. Ammonia, the product of oxidative deamination reactions, is toxic in even small amounts and must be removed from the body. The urea cycle or the ornithine cycle describes the conversion reactions of ammonia into urea. Since these reactions occur in the liver, the urea is then transported to the kidneys where it is excreted. The overall urea formation reaction is: 2 Ammonia + carbon dioxide + 3ATP ---> urea + water + 3 ADP The step wise process of the urea cycle is summarized in the graphic on the left. One amine group comes from oxidative deamination of glutamic acid while the other amine group comes from aspartic acid. Aspartic acid is regenerated from fumaric acid produced by the urea cycle. The fumaric acid first undergoes reactions through a portion of the citric acid cycle to produce oxaloacetic acid which is then changed by transamination into aspartic acid. Link to: Urea Cycle (move cursor over arrows) Jim Hardy, Professor of Chemistry, The University of Akron. Urea is routinely measured in the blood as: Blood Urea Nitrogen (BUN). BUN levels may be elevated (a condition called uremia) in both acute and chronic renal (kidney) failure. Various diseases damage the kidney and cause faulty urine formation and excretion. Congestive heart failure leads to a low blood pressure and consequent reduced filtration rates through the kidneys, therefore, BUN may be elevated. Urinary tract obstructions can also lead to an increased BUN. In severe cases, hemodialysis is used to remove the soluble urea and other waste products from the blood. Waste products diffuse through the dialyzing membrane because their concentration is lower in the dialyzing solution. Ions, such as Na+ and Cl- which are to remain in the blood, are maintained at the same concentration in the dialyzing solution - no net diffusion occurs. As stated previously, high ammonia levels are toxic to humans. A complete block of any step in the urea cycle is fatal since there is no known alternative pathway for the synthesis of urea. Inherited disorders from defective enzymes may cause a partial block in some of the reactions and results in hyperammonemia which can lead to mental retardation. Extensive ammonia accumulation leads to extensive liver damage and death. Liver cirrhosis caused by alcoholism creates an interference in the enzymes which produce carbamyl phosphate in the first step on the cycle.

Uric Acid Excretion: In animals that excrete urea, water is required to dissolve urea in urine. Actually, urea is a natural diuretic which insures the flow of urine. Animals such as birds and reptiles which must conserve water, excrete nitrogen as uric acid as a solid mixed with very small amounts of water. The conversion of ammonia and the synthesis of uric acid in birds and reptiles is a complicated energy requiring process. In humans, uric acid is not produced from ammonia but is synthesized from adenine and guanine found in various nucleotides. Uric acid is normally excreted in small amounts in the urine of humans. Uric acid concentrations may become elevated in kidney diseases and leukemia. Uric acid salts maybe deposited in the form of kidney and bladder stones. A painful arthritic disorder called gout results from the deposition of uric acid salts in cartilage in the joints. Gout is probably caused by a variety of inborn errors of metabolism resulting in excessive synthesis of uric acid. Gout can be controlled by diet and/or a drug called allopurinol which inhibits the enzyme which produces uric acid.

Ammonia Excretion: Animals such as fish that live in the water excrete ammonia. However, even fish do not have large concentrations of ammonia in the blood because it is excreted as the amide in glutamine. Glutamine is carried to a membrane in the gills near the surrounding water where a hydrolysis of the glutamine to glutamic acid releases the ammonia. Humans also excrete small amounts of NH3 which is converted by the acid in the urine to NH4+ (ammonium ions). Ammonia is excreted only as a defense against an acidosis condition because the neutralization of acid by ammonia has the effect of conserving bases in the blood.