This ammonium ion, plus the amino groups on aspartate, is then used to make urea in the urea cycle, which operates only in the liver. First, the ammonium ion is converted to carbamoyl phosphate. This is then combined with the a-amino acid ornithine to produce citrulline. In turn, citrulline is joined with aspartate, which carries a second nitogen into the cycle, producing argininosuccinate. Argininosuc-cinate is now cleaved to release fumarate and arginine. Urea is removed from arginine to regenerate ornithine, which is now ready for another cycle. Urea can then be excreted in the urine, eliminating two nitrogen atoms per urea molecule.
The overall cycle converts two ATP to ADP and one ATP to AMP. This is energetically equivalent to a total of four ATP to ADP conversions, since a fourth ATP is required to turn the AMP into ADP in the reaction:
The fumarate can enter the Krebs cycle and be converted to malate, which is oxidized to oxaloacetate, which can (among other things) be transaminated back to aspartate to carry in another nitrogen.
Ornithine plays the same role in the urea cycle as oxaloacetate in the Krebs cycle: it accepts the incoming molecule, undergoes a series of interconversions, and is regenerated allowing the cycle to begin again. The availability of ornithine determines the rate at which the cycle can operate. Arginine is a protein amino acid and is normally present in the diet as a source of ornithine. Vice versa the urea cycle can make arginine so this is not normally considered to be an essential amino acid for adults. Arginine is, however, essential in the diet of growing children as the net protein synthesis of growth needs more of it than can be supplied from the urea cycle without draining too much and so impeding the cycle.
Since the urea cycle only occurs in the liver, liver failure results in a buildup of ammonium ions in the blood. This is toxic to nerve cells, producing first mental confusion and finally coma and death.
It is interesting to note that of the three major energy sources in the diet—carbohydrate, fat, and protein—only protein is not used as an energy store in our bodies. We make specific proteins when we need them but never simply as a way of storing amino acids. Of course, if one eats a lot of protein, one puts on weight: once the amino acids have been converted to carbon skeletons or to acetyl-CoA, these can then be used to make glucose and hence glycogen (page 298) or to make fat (page 300).
All the phenylalanine in the diet that is not required for protein synthesis is converted to tyrosine by the enzyme phenylalanine hydroxylase. If this enzyme is missing or defective through mutation, then there is a serious problem. The standard way the body deals with amino acids is for aminotransferases (page 249) to transfer the NH3+ group to aspartate or glutamate, which are then processed by the urea cycle (In Depth 13.1 on page 292). However, the product formed when phenylalanine has its NH3+ group transferred away, a phenylketone called phenylpyruvate, cannot be further metabolized. Both phenylalanine and phenylpyruvate therefore accumulate in the body. About 1 in 20,000 new-born babies have this defect, which is called phenylketonuria because the phenylpyruvate appears in the urine.
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