15.5C: Urea Cycle
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Urea is the chief nitrogenous waste of mammals. Most of our nitrogenous waste comes from the breakdown of amino acids. This occurs by deamination.
Deamination of amino acids results in the production of ammonia (NH3). Ammonia is an extremely toxic base and its accumulation in the body would quickly be fatal. However, the liver contains a system of carrier molecules and enzymes which quickly converts the ammonia (and carbon dioxide) into urea. This is called the urea cycle.
The Urea Cycle
One turn of the cycle:
- consumes 2 molecules of ammonia
- consumes 1 molecule of carbon dioxide
- creates 1 molecule of urea ((NH2)2CO
- regenerates a molecule of ornithine for another turn.
Although our bodies cannot tolerate high concentrations of urea, it is much less poisonous than ammonia. Urea is removed efficiently by the kidneys.
Problems in Urea Cycle
There are several inherited diseases of the urea cycle caused by mutations in genes encoding one or another of the necessary enzymes. The most common of these is an inherited deficiency of ornithine transcarbamylase, an enzyme needed for the conversion of ornithine to citrulline. It results in elevated levels of ammonia that may be so high as to be life-threatening. It is an X-linked disorder; therefore most commonly seen in males. It can be cured by a liver transplant. It can also be caused by a liver transplant! In 1998, an Austrian woman was given a new liver from a male cadaver who - unknown to the surgeons - had a mutation in his single ornithine transcarbamylase gene. The woman's blood level of ammonia shot up, and she died a few days later.
Humans also excrete a second nitrogenous waste, uric acid. It is the product of nucleic acid, not protein, metabolism. It is produced within peroxisomes. Uric acid is only slightly soluble in water and easily precipitates out of solution forming needlelike crystals of sodium urate. These contribute to the formation of kidney stones and produce the excruciating pain of gout when deposited in the joints.
Curiously, our kidneys reclaim most of the uric acid filtered at the glomeruli. Why, if it can cause problems?
- Uric acid is a potent antioxidant and thus can protect cells from damage by reactive oxygen species (ROS).
- The concentration of uric acid is 100-times greater in the cytosol than in the extracellular fluid. So when lethally-damaged cells release their contents, crystals of uric acid form in the vicinity. These enhance the ability of nearby dendritic cells to "present" any antigens released at the same time to T cells leading to a stronger immune response.
So the risk of kidney stones and gout may be the price we pay for these protections.
Most mammals have an enzyme - uricas - for breaking uric acid down into a soluble product. However, during the evolution of great apes and humans, the gene encoding uricase became inactive. A predisposition to gout is our legacy.
Uric acid is the chief nitrogenous waste of insects, lizards and snakes and birds. It is the whitish material that birds leave on statues. These animals convert the waste products of protein metabolism as well as nucleic acid metabolism into uric acid. Because of its low solubility in water, these animals are able to eliminate waste nitrogen with little loss of water.