Argininosuccinate synthetase urea cycle

As we noted in Chapter 16, the enzymes of many metabolic pathways are clustered (p. 605), with the product of one enzyme reaction being channeled directly to the next enzyme in the pathway. In the urea cycle, the mitochondrial and cytosolic enzymes appear to be clustered in this way. The citrulline transported out of the mitochondrion is not diluted into the general pool of metabolites in the cytosol but is passed directly to the active site of argininosuccinate synthetase. This channeling between enzymes continues for argininosuccinate, arginine, and ornithine. Only urea is released into the general cytosolic pool of metabolites. 

Fig. 1. The urea cycle. The enzymes involved in this cycle are (1) carbamoyl phosphate synthetase (2) ornithine transcarbamoylase (3) argininosuccinate synthetase (4) arginosuccinase and (5) arginase.

Argininosuccinate synthetase (the second enzyme of the urea cycle) and the remaining two... 

Figure 6.10 The urea cycle. The enzymes of the urea cycle include, 1 carbamoyl phosphate synthetase-I, 2 ornithine transcarbamoylase, 3 argininosuccinate synthetase, 4 argininosuc-cinase, 5 arginase.

The enzymes that catalyze these steps are homologous to argininosuccinate synthetase and argininosuccinase, respectively. Thus, four of the five enzymes in the urea cycle were adapted from enzymes taking part in nucleotide biosynthesis. The remaining enzyme, arginase, appears to be an ancient enzyme found in all domains of life. 

Figure 24-2 The urea cycle pathway. CPS I, Carbamyl phosphate synthetase I N-acetyigiutamate as positive allosteric effector OTC, ornithine transcarbamyiase MS, argininosuccinate synthetase Ai, argininosuccinate iyase AR, arginase ADP, adenosine diphosphate, ATf adenosine triphosphate, P, inorganic phosphate.

Fig. 5. Diagrammatio representation of intracellular localization of urea cycle pathway showing diffusion pattern. CPS, carbamyl phosphate synthetase ASL, argininosuccinate lyase ASA, argininosucoinate.

The liver argininosuccinate synthetase in the patient of McMurray et al. (M5) was found to have an activity of only 5% that of normal liver. Although no estimations of urea cycle enzymes of the liver were performed in the patient of Morrow et al. (M12), argininosuccinate synthetase was assayed by Tedesco and Mellman (T3) in cultured fibroblasts from the skin of the patient. They showed that although the enzyme was present in the cells, the value for the mutant enzyme was at least 25 times greater than normal, suggesting an aberrant enzyme. 

Vidailhet et al. (VI) assayed all five enzymes involved in the urea cycle, and found no detectable activity of argininosuccinate synthetase, whereas the other enzymes were present in normal activity (Table 9). It is of interest that an appreciable synthetase activity was detectable in the kidney tissue in their patient, at a level of about 20% of that found in normal liver, despite its absence in the patient s liver (L4). This observation is similar to that of Colombo and Baumgartner (C8), who found argininosuccinate lyase in the kidney of their child with argininosuccinic aciduria, in spite of its absence from the liver. The question is again raised whether it is possible thus to account for the production of urea in these cases. However, since arginase is not present in the kidney, the arginine formed would have to be transported to the liver... 

A number of inherited diseases are associated with the urea cycle. The mutations result in changes in either Vm or Km as defective proteins are produced. These include disruptions of N- acety 1 gl utam ate synthase, carbamoyl phosphate synthetase, ornithine transcarbamoylase (the most prevalent of the urea cycle deficiencies), argininosuccinate synthetase, argininosuccinate lyase, and arginase. In these diseases, when applicable, treatments are low-protein diets, to put less strain on urea cycle flux and, when appropriate, addition of amino acids as required, such as ornithine and/or arginine. 

Urea cycle disorders Carbamylphosphate synthetase deficiency, ornithine transcarbamylase deficiency, and argininosuccinic acid synthetase deficiency Narcolepsy... 

Argininosuccinate synthetase is an enzyme of the urea cycle that catalyzes the following reaction Citrulline + Aspartate + ATP <—> Argininosuccinate + AMP + PPi... 

IMP serves as the branchpoint from which both adenine and guanine nucleotides can be produced (see Fig. 41.2). Adenosine monophosphate (AMP) is derived from IMP in two steps (Fig. 41.7). In the first step, aspartate is added to IMP to form adenylosuccinate, a reaction similar to the one catalyzed by argininosuccinate synthetase in the urea cycle. Note how this reaction requires a high-energy bond, donated by GTP Fumarate is then released from the adenylosuccinate by the enzyme adenylosuccinase to form AMP. 

The intestine contains the enzymes for the urea cycle, but the for argininosuccinate synthetase and argininosuccinate lyase are very low, suggesting that the primary role of the urea cycle enzymes in the gut is to produce citrulline from the carbons of glutamine (glutamine glutamate glutamate semialdehyde ornithine citrulline). The citrulline is released in the circulation for use by the liver. 

Amniotic fluid has limited value in prenatal diagnosis for the aminoacid-opathies. Unlike the organic acid disorders, in most amino acid disorders the metabolites do not accumulate before birth. Abnormal amino acid patterns in amniotic fluid have only been found in two of the urea cycle disorders, namely argininosuccinate lyase deficiency (argininosuccinic acidemia) and argininosuccinate synthetase deficiency (citrullinemia). 

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