Argininosuccinate lyase, activation

Argininosuccinate Lyase Activity in Red Blood Cells of Patients with Argininosuccinic Aciduria and Their Families... 

In view of the toxicity of ammonia, complete absence of any one of the enzymes of the cycle is fatal. Nonetheless, disorders of the cycle do occur, which are caused by a low activity of one of the enzymes or carbamoyl phosphate synthetase. In addition, defects in N-acetylglutamate synthase have been reported, but they are very rare. With the exception of ornithine transcarbamoylase, the deficiencies have an autosomal recessive mode of inheritance. The transcarbamoylase deficiency is inherited as an X-linked dominant trait, usually lethal in male patients. A deficiency of carbamoyl phosphate synthetase, ornithine transcarbamoylase or argininosuccinate synthetase results in accumulation and excretion of citrulline. A deficiency of argininosuccinate lyase results in the accumulation and excretion of argininosuccinate and arginine (Table 10.5). The abbreviations CPSD, OTCD, ASD, ALD and AD stand, respectively, for the deficiencies of these enzymes, where D stands for deficiency. 

Figure 47-SO The major metabolic pathways for the use of ammonia by the hepatocyte. Solid bars indicate the sites of primary enzyme defects in various metabolic disorders associated with hyperammonemia /) carbamyl phosphate synthetase I, (2) ornithine transcarbamylase, (3) argininosuccinate synthetase, (4) argininosuccinate lyase, (5) arginase, (6) mitochondrial ornithine transport, (7) propionyi CoA carboxylase, (fi) methylmalonyl CoA mutase, (9) L-lysine dehydrogenase, and (10) N-acetyl glutamine synthetase. Dotted lines indicate the site of pathway activation (+) or inhibition ( ). (From Flannery OB, Hsia YE, Wolf 6. Current status of /lyperommofiemjo syndromes. Hepatology 1982 2 495-506,)...

Fiq. 6, Comparison of carbamyl phosphate synthetase (CPS), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), and arginase (A) activities in the human liver assayed immediately after biopsy (A), after storage at —15°C (B), and at necropsy (C). 

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... 

The levels of arginase and argininosuccinate lyase were measured only in red blood cells in these cases. In one child, no detectable activity of arginase was found in the other only 12 of the mean normal level was found (Table 10). Lyase activity was normal in both children. The two enzyme activities were also measured in the parents, and both were found to be below the lowest level found in a series of normal controls, suggesting the heterozygote state. In both the lyase activity was normal. 

Formation of urea in hepatocytes. NAGS = N-acetylglutamate synthase CPSI = carbamoylphosphate synthase I OCT = ornithine carbamoyltransferase C-OT = citrulline-omithine translocase AS = argininosuccinate synthase AL = argininosuccinate lyase A = arginase. — -> indicates the absolute requirement of N-acetylglutamate for CPSI activity. 

Liver and Red Cell. The identification by Westall (W3, W4) of the amino acid excreted in large amounts as an intermediate in the urea cycle led him to postulate a deficiency of argininbsuccinate lyase in this condition. He confirmed this in the red cells of two affected children. In all other cases of argininosuccinic aciduria in which this assay has been performed, no enzyme activity has been detected in the red cells... 

It is significant that the ornithine transcarbamylase activity in the intestinal mucosa of one patient was only 20% of the mean normal compared to a reduction to less than 5% of the mean normal in the liver of the same patient (L8) (Table 7). This manifestation of an enzyme deficiency in more than one organ in the body has a parallel in argininosuccinic aciduria, where lyase deficiency has been shown to occur both in the liver and in the red cells and, in one case, in red cells, brain, and kidney. 

---