Urea: diverse functions of a 'waste' product

1. The urea cycle is essentially the simultaneous operation of two linear pathways, both primitive and widespread among animals; one is for arginine synthesis and the other is for arginine degradation to ornithine and urea. 2. All animals may have the genetic capacity to express a urea cycle and many diverse groups of animals, from flatworms to mammals, have a functional urea cycle. 3. Evolutionary changes in vertebrates of carbamylphosphate synthetase (CPS) are directed from glutamine-dependent (CPSIII) towards NH3-dependent (CPSI) ureagenesis. Invertebrates, cartilagenous fish and the coelacanth have CPSIII (i.e. glutamine-dependent), whereas lungfish, amphibians and amniote vertebrates have CPSI; the teleost Heteropneustes has CPSI-like activity. That the coelacanth has CPSIII and Heteropneustes has 'CPSI' suggests that the form of CPS may by physiologically related (CPSIII in a balancing solute role and CPSI in a terrestrial, air-breathing excretion role) rather than being phylogenetically constrained. 4. Urea is a major balancing osmolyte in marine cartilagenous fish, the coelacanth and a few amphibians and some aestivating terrestrial amphibians. It is a storage osmolyte in cocoon-forming aestivating lungfish and amphibians. 5. Urea contributes towards positive buoyancy in marine cartilagenous fish. 6. Urea functions for non-toxic N transport in ruminant and pseudoruminant mammals. 7. Urea is a major solute in the mammalian (but not avian) kidney, contributing to a renal medullary osmotic gradient; it is substantially reabsorbed by mammalian nephrons. 8. Urea is used as a preferred nitrogenous waste compared with ammonia at high ambient pNH3 or pH, with water restriction, or air breathing. 9. Urea synthesis maintains acid-base balance by the 1:1 stoichiometry of removal of HCO3- and NH4+.