Metabolic Disorders are Associated with Each Reaction of The Urea Cycle
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
32nd edition.p287-288
2025-08-18
389
Five well-documented diseases represent defects in the bio synthesis of enzymes of the urea cycle. Molecular genetic analysis has pinpointed the loci of mutations associated with each deficiency, each of which exhibits considerable genetic and phenotypic variability (Table 1).
Table1. Enzymes of Inherited Metabolic Disorders of the Urea Cycle
Urea cycle disorders are characterized by hyperammonemia, encephalopathy, and respiratory alkalosis. Four of the five metabolic diseases, deficiencies of carbamoyl phosphate synthetase I, ornithine carbamoyl transferase, argininosuccinate synthetase, and argininosuccinate lyase, result in the accumulation of precursors of urea, principally ammonia and glutamine. Ammonia intoxication is most severe when the metabolic block occurs at reactions 1 or 2 (Figure 1), for if citrulline can be synthesized, some ammonia has already been removed by being covalently linked to an organic metabolite.
Fig1. Reactions and intermediates of urea biosynthesis. The nitrogen-containing groups that contribute to the formation of urea are shaded. Reactions 1 and 2 occur in the matrix of liver mitochondria and reactions 3 , 4 , and 5 in liver cytosol. CO2 (as bicarbonate), ammonium ion, ornithine, and citrulline enter the mitochondrial matrix via specific carriers (see red dots) present in the inner membrane of liver mitochondria.
Clinical symptoms common to all urea cycle disorders include vomiting, avoidance of high-protein foods, intermit tent ataxia, irritability, lethargy, and severe mental retardation. The most dramatic clinical presentation occurs in full-term infants who initially appear normal, then exhibit progressive lethargy, hypothermia, and apnea due to high plasma ammonia levels. The clinical features and treatment of all five disorders are similar. Significant improvement and minimization of brain damage can accompany a low-protein diet ingested as frequent small meals to avoid sudden increases in blood ammonia levels. The goal of dietary therapy is to provide sufficient protein, arginine, and energy to promote growth and development while simultaneously minimizing the metabolic perturbations.
Carbamoyl Phosphate Synthetase I
N-Acetylglutamate is essential for the activity of carbamoyl phosphate synthetase I, EC 6.3.4.16 (reaction 1, Figure 1). Defects in carbamoyl phosphate synthetase I are responsible for the relatively rare (estimated frequency 1:62,000) metabolic disease termed “hyperammonemia type 1.”
N-Acetylglutamate Synthetase
N-Acetylglutamate synthetase, EC 2.3.1.1 (NAGS), catalyzes the formation from acetyl-CoA and glutamate of the N acetylglutamate essential for carbamoyl phosphate synthetase I activity.
l-Glutamate + acetyl-CoA → N-acetyl-l-glutamate + CoASH
While the clinical and biochemical features of NAGS deficiency are indistinguishable from those arising from a defect in carbamoyl phosphate synthetase I, a deficiency in NAGS may respond to administered N-acetylglutamate.
Ornithine Permease
The hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome results from mutation of the ORC1 gene that encodes the mitochondrial membrane ornithine carrier. The inability to import cytosolic ornithine into the mitochondrial matrix renders the urea cycle inoperable, with consequent hyperammonemia, and hyperornithinemia due to the accompanying accumulation of cytosolic ornithine. In the absence of its normal acceptor (ornithine), mitochondrial carbamoyl phosphate carbamoylates lysine to homocitrulline, resulting in homocitrullinuria.
Ornithine Transcarbamoylase
The X-chromosome–linked deficiency termed “hyperammo nemia type 2” reflects a defect in ornithine transcarbamoylase (reaction 2, Figure 1). The mothers also exhibit hyper ammonemia and an aversion to high-protein foods. Levels of glutamine are elevated in blood, cerebrospinal fluid, and urine, probably as a result of enhanced glutamine synthesis in response to elevated levels of tissue ammonia.
Argininosuccinate Synthetase
In addition to patients who lack detectable argininosuccinate synthetase activity (reaction 3, Figure 1), 25-fold elevations in Km for citrulline have been reported. In the resulting citrullinemia, plasma and cerebrospinal fluid citrulline levels are elevated, and 1 to 2 g of citrulline are excreted daily.
Argininosuccinate Lyase
Argininosuccinic aciduria, accompanied by elevated levels of argininosuccinate in blood, cerebrospinal fluid, and urine, is associated with friable, tufted hair (trichorrhexis nodosa). Both early- and late-onset types are known. The metabolic defect is in argininosuccinate lyase (reaction 4, Figure1). Diagnosis by the measurement of erythrocyte argininosuccinate lyase activity can be performed on umbilical cord blood or amniotic fluid cells.
Arginase
Hyperargininemia is an autosomal recessive defect in the gene for arginase (reaction 5, Figure 1). Unlike other urea cycle disorders, the first symptoms of hyperargininemia typically do not appear until age 2 to 4 years. Blood and cerebrospinal fluid levels of arginine are elevated. The urinary amino acid pattern, which resembles that of lysine-cystinuria, may reflect competition by arginine with lysine and cysteine for reabsorption in the renal tubule.
Analysis of Neonate Blood by Tandem Mass Spectrometry Can Detect Metabolic Diseases
Metabolic diseases caused by the absence or functional impairment of metabolic enzymes can be devastating. Early dietary intervention, however, can in many instances ameliorate the otherwise inevitable dire effects. The early detection of such metabolic diseases is thus is of primary importance. Since the initiation in the United States of newborn screening programs in the 1960s, all states now conduct metabolic screening of newborn infants. The powerful and sensitive technique of tandem mass spectrometry (MS) can in a few minutes detect over 40 analytes of significance in the detection of metabolic disorders. Most states employ tandem MS to screen newborns to detect metabolic disorders such as organic acidemias, aminoacidemias, disorders of fatty acid oxidation, and defects in the enzymes of the urea cycle. An article in Clinical Chemistry 2006 39:315 reviews the theory of tandem MS, its application to the detection of metabolic disorders, and situations that can yield false positives, and includes a lengthy table of detectable analytes and the relevant metabolic diseases.
Can Metabolic Disorders Be Rectified by Gene or Protein Modification
Despite results in animal models using an adenoviral vector to treat citrullinemia, at present gene therapy provides no effective solution for human subjects. However, direct CRISPR/ Cas9-based modification of a defective enzyme can restore functional enzyme activity of cultured human pluripotent stem cells.
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