The Evolution of Urea Synthesis in Vertebrates

Because proteins are 16% nitrogen by weight, the disposition of nitrogen is a significant matter when proteins are catabolized. Simple deamination of amino acids during protein breakdown leads to formation of ammonia (NH₃) as the nitrogen-containing end product of catabolism. Urea (see the structure to the right) is one of the major alternative nitrogenous end products. The synthesis of urea costs energy: Each urea molecule requires the energy from four or five ATP molecules for its synthesis. This cost is an “extra cost” that is avoided if ammonia is made instead of urea.

The biochemical pathway by which urea is synthesized from protein nitrogen in vertebrates is known as the ornithine–urea cycle. In the last 25 years, a consensus has emerged that the ornithine–urea cycle existed in the earliest vertebrates. That is, the earliest vertebrates are believed to have had genes coding for all the ornithine–urea cycle enzymes.

Despite its antiquity, urea synthesis is observed today in only a minority of modern vertebrates, which have a scattered distribution in the vertebrate phylogenetic tree. These include the elasmobranch fish, coelacanth fish, mammals, most amphibians, and some others. Two principal advantages of urea synthesis seem to account for the cases in which vertebrates invest extra energy to make urea rather than ammonia from their waste protein nitrogen. First, urea is sometimes employed as an osmolyte to raise the osmotic pressure of the blood; it is used in this way by some marine fish to render the blood hyperosmotic to seawater. Second, urea is sometimes employed as a detoxification compound for waste nitrogen. Urea is far less toxic than ammonia and therefore is far better suited to being accumulated in the body than ammonia. Box Extension 28.4 presents the phylogenetic tree in detail and discusses the evolution of urea synthesis more thoroughly.

The detailed figure presents a phylogenetic tree of the vertebrates in detail, showing which modern-day groups synthesize urea from protein nitrogen as adults.

Synthesis of urea from protein nitrogen by the ornithine–urea cycle in adult vertebrates: a phylogenetic perspective Shown is a phylogenetic tree of vertebrates that have been tested for activity of the ornithine–urea cycle. The groups in pink display urea synthesis from protein nitrogen by means of the ornithine–urea cycle when adult, whereas the others do not. Among teleost fish, such urea synthesis occurs only in unusual, isolated cases but today is known not only in the toadfish (shown) but also in an alkaline-lake tilapia and an air-breathing catfish. Two enzymes of the ornithine–urea cycle are carbamoyl phosphate synthase (CPS) and arginase. Animals below the dashed line synthesize a molecular form of CPS named CPS I and cytosolic arginase; animals above the line predominantly synthesize CPS III (or synthesize a mix of CPS III and a CPS I–like enzyme) and mitochondrial arginase. Thus the enzyme forms changed at the point in evolutionary history represented by the asterisk. (After Mommsen and Walsh 1989.)

The question immediately arises of why scattered lines of vertebrate evolution lost the ability to synthesize urea. Some groups that do not synthesize urea might have suffered deletion of one or more of the required genes. A current working hypothesis, however, is that, in general, all modern-day vertebrates have the genes for the ornithine–urea cycle, but one or more of the genes are not expressed in those vertebrate groups that fail to synthesize urea from protein nitrogen. The implication is that the genes have been present in the genomes of vertebrates continuously throughout vertebrate evolution, helping to explain the spotty pattern of occurrence of urea synthesis from protein nitrogen by the ornithine–urea pathway.

If we focus on aquatic vertebrates, as suggested earlier, two principal advantages of urea synthesis seem to account for the cases in which vertebrates express urea synthesis, thereby investing extra energy to make urea rather than ammonia from their waste protein nitrogen. First, urea is sometimes employed as an osmolyte to raise the osmotic pressure of the blood, rendering the blood hyperosmotic to seawater. The phylogenetic tree suggests that this use of urea evolved at least twice independently—because it occurs in the coelacanth fish as well as the elasmobranch and holocephalan fish—offering support for the hypothesis that urea synthesis can be evolutionarily adaptive as a mechanism of osmoregulation. Second, urea is sometimes employed as a detoxification compound for waste nitrogen in aquatic animals that can face situations during which they are temporarily unable to excrete wastes. A frog moving about on land and having become dehydrated would be an example. Urea is far less toxic than ammonia. Accordingly, urea is far better suited than ammonia to being accumulated in the body between one opportunity to excrete it and another.

Chapter 29 discusses nitrogen excretion more thoroughly.

References

Mommsen, T. P., and P. J. Walsh. 1989. Evolution of urea synthesis in vertebrates: The piscine connection. Science 243: 72–75.