Nitrogen Excretion and the Urea Cycle:- Genetic Defects in the Urea Cycle Can Be Life-Threatening
People with genetic defects in any enzyme in volved in urea formation cannot tolerate protein rich diets. Amino acids ingested in excess of the mini mum daily requirements for protein synthesis are deaminated in the liver, producing free ammonia that cannot be converted to urea and exported into the bloodstream, and, as we have seen, ammonia is highly toxic. The absence of a urea cycle enzyme can result in hyperammonemia or in the build-up of one or more urea cycle intermediates, depending on the enzyme that is missing. Given that most urea cycle steps are irreversible, the absent enzyme activity can often be identified by determining which cycle intermediate is present in especially elevated concentration in the blood and/or urine. Although the breakdown of amino acids can have serious health consequences in individuals with urea cycle deficiencies, a protein-free diet is not a treatment option. Humans are incapable of synthesizing half of the 20 common amino acids, and these essential amino acids (Table 18–1) must be provided in the diet.
A variety of treatments are available for individuals with urea cycle defects. Careful administration of the aromatic acids benzoate or phenylbutyrate in the diet can help lower the level of ammonia in the blood. Benzoate is converted to benzoyl-CoA, which combines with glycine to form hippurate (Fig. 18–14, left). The glycine used up in this reaction must be regenerated, and ammonia is thus taken up in the glycine synthase reaction. Phenylbutyrate is converted to phenylacetate by β oxidation. The phenylacetate is then converted to phenylacetyl-CoA, which combines with glutamine to form phenylacetylglutamine (Fig. 18–14, right). The resulting removal of glutamine triggers its further synthesis by glutamine synthetase in a reaction that takes up ammonia. Both hippurate and phenylacetyl glutamine are nontoxic compounds that are excreted in the urine. The pathways shown in Figure 18–14 make only minor contributions to normal metabolism, but they become prominent when aromatic acids are ingested. Other therapies are more specific to a particular en zyme deficiency. Deficiency of N-acetylglutamate synthase results in the absence of the normal activator of carbamoyl phosphate synthetase I (Fig. 18–13). This condition can be treated by administering carbamoyl glutamate, an analog of N-acetylglutamate that is effective in activating carbamoyl phosphate synthetase I.
Supplementing the diet with arginine is useful in treating deficiencies of ornithine transcarbamoylase, argininosuccinate synthetase, and argininosuccinase. Many of these treatments must be accompanied by strict dietary control and supplements of essential amino acids. In the rare cases of arginase deficiency, arginine, the substrate of the defective enzyme, must be excluded from the diet.
FIGURE 18–14 Treatment for deficiencies in urea cycle en zymes. The aromatic acids benzoate and phenylbutyrate, ad ministered in the diet, are metabolized and combine with glycine and glutamine, respectively. The products are excreted in the urine. Sub sequent synthesis of glycine and glutamine to replenish the pool of these intermediates removes ammonia from the bloodstream.
