Human Biochemistry, Volume 1 - Murray R. 1993

Protein and Amino Acid Metabolism
Catabolism of Amino Acid Nitrogen
Metabolic Disorders of the Urea Cycle

Metabolic Disorders caused by a deficiency of any of the 5 Enzymes that catalyze urea synthesis reactions in the Liver are well documented (Fig. 30.13). The rate-limiting steps are likely the Reactions Catalyzed by carbamoyl phosphate synthetase (reaction 1), Ornithine transcarbamylase (reaction 2), and arginase (reaction 5). Because The Urea Cycle converts ammonia into non-toxic urea, all defects in urea synthesis lead to ammonia intoxication. The latter is more pronounced when reaction 1 or 2 is blocked, since ammonia is already covalently bound to a carbon atom during citrulline synthesis. Clinical symptoms common to all urea cycle disorders include vomiting (in infants), aversion to protein-rich foods, ataxia, irritability, lethargy, and mental retardation.

The clinical manifestations and treatments for all the disorders discussed below are quite similar. Significant improvement is observed with a protein-restricted diet, which can prevent many neurological impairments. Meals should be frequent and in small portions to avoid rapid spikes in Blood ammonia levels.

Hyperammonemia Type I

A case of disease associated with a deficiency of carbamoyl phosphate synthetase has been described (reaction 1, Fig. 30.13). This condition is presumably inherited.

Hyperammonemia Type II

Numerous cases of disease associated with ornithine transcarbamylase deficiency have been reported (reaction 2, Fig. 30.13). This condition is X-linked genetically. The mother also exhibits hyperammonemia and an aversion to protein-rich foods. The only consistent laboratory and clinical finding is an elevation of glutamine levels in the blood, CEREBROSPINAL FLUID, and urine. This apparently reflects an increase in glutamine synthesis by Glutamine Synthetase (Fig. 30.8) driven by rising tissue ammonia levels.

Citrullinemia

This rare disorder is presumably inherited in an autosomal recessive manner. It is characterized by the urinary excretion of large amounts of citrulline (1–2 g·day^-1); citrulline levels in plasma and cerebrospinal fluid are significantly elevated. Complete absence of argininosuccinate synthetase activity (reaction 3, Fig. 30.13) was recorded in one patient. A modification of this enzyme was found in another patient. In fibroblast cultures from this patient, argininosuccinate synthetase activity exhibited a K_m value for citrullin 25 times higher than normal. This likely resulted from a mutation causing a significant, yet non-lethal, modification in The Structure of the enzyme's catalytic site.

Citrulline (as well as argininosuccinate, see below) can serve as a carrier of "waste" nitrogen, since it contains nitrogen destined for urea synthesis. Arginine supplementation increases citrulline excretion in patients with this disorder. Similarly, benzoate administration directs ammonium nitrogen into hippurate (via Glycine) (see Fig. 32.2).

Argininosuccinic Aciduria

This rare autosomal recessive disorder is characterized by elevated levels of argininosuccinate in the blood, cerebrospinal fluid, and urine, and is frequently accompanied by Hair abnormalities (trichorrhexis nodosa). Although both early and late-onset cases are known, the disease typically manifests around the age of two and leads to a fatal outcome in early childhood.

This condition is associated with a deficiency of argininosuccinase (reaction 4, Fig. 30.13). While enzyme activity can be detected in cultured Skin fibroblasts from healthy individuals, it is absent in patients with argininosuccinic aciduria. In affected patients, argininosuccinase is also missing from the Brain, liver, Kidneys, and erythrocytes. Diagnosis is relatively straightforward: two-way Paper Chromatography of the patient's urine reveals argininosuccinate. If the urine is analyzed after standing for some time, additional spots appear on the chromatogram corresponding to cyclic anhydrides formed from argininosuccinate. To confirm the diagnosis, argininosuccinase activity is measured in erythrocytes. Prenatal diagnosis can be performed using umbilical cord blood. Since argininosuccinase is also present in Amniotic Fluid Cells, the diagnosis can be established via amniocentesis. For the same reasons noted in citrullinemia, administering arginine and benzoate to these patients increases The excretion of nitrogenous metabolites.

Hyperargininemia

This urea cycle defect is characterized by elevated arginine levels in the blood and cerebrospinal fluid, low erythrocyte arginase activity (reaction 5, Fig. 30.13), and increased urinary excretion of several Amino Acids, similar to what occurs in lysinuric protein intolerance. This may reflect competition between arginine, on the one hand, and Lysine and cystine, on the other, during renal tubular reabsorption. Putting the patient on a low-protein diet results in lowered plasma ammonia levels and reduced excretion of Certain amino acids in the urine.

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