Argininosuccinate

Argininosuccinic acid [2387-71-5] M 290.3, [a]p +16.4 (H2O). Likely impurity is fumaric acid. In neutral or alkaline soln it readily undergoes ring closure to the anhydride . Crystd from water by adding 1.5 vols of EtOH. Barium salt is stable at 0-5 if dry. [Westfall Biochem J 77 135 I960.]... 

Argininosuccinic anhydride [28643-94-9 M 272,3, [ct] -10" (H2O for anhydride formed at neutral pH), Crystd from water by adding two volumes of EtOH. An isomeric anhydride is formed if the free acid is allowed to stand at acid pH. In soln, the mixture of anhydrides and free acid is formed [see above entry]. 

One step in the urea cycle for ridding the body of ammonia is the conversion of argininosuccinate to the amino acid arginine plus fumarate. Propose a mechanism for the reaction, and show the structure of arginine. 

Argininosuccinate synthase links aspartate and citrulline via the amino group of aspartate (reaction 3, Figure 29-9) and provides the second nitrogen of urea. The reaction requires ATP and involves intermediate formation of citrullyl-AMP. Subsequent displacement of AMP by aspartate then forms citrulline. 

Turner MA et al Human argininosuccinate lyase a structural basis for intragenic complementation. Proc Natl Acad Sci U S A 1997 94 9063. 

Figure 32, Chromatograms of plasma and urine samples with various abnormalities, A, Phenylalaninemia B, tyrosinemia C, elevated plasma methionine seen in homocystinuria D, glycinemia E, normal urine F, argininosuccinic aciduria G, homocystinuria H, hyperglycinuria I, hyperlysinuria.

In the hepatic cytosol, citrulline reacts with aspartate to form argininosuccinate, catalyzed by argininosuccinate synthetase (AS Fig. 40-5 reaction 3). The mRNA for this enzyme is increased by starvation, corticosteroids or cyclic-AMP. Citrulline itself potently induces the mRNA. 

Argininosuccinate lyase (AL) (Fig. 40-5 reaction 4) cleaves argininosuccinate to form fumarate, which is oxidized in the tricarboxylic acid cycle, and arginine, which is hydrolyzed to urea and ornithine via hepatic arginase. Both AL and arginase are induced by starvation, dibutyryl cyclic-AMP and corticosteroids. 

Except for patients with argininosuccinic aciduria, who may demonstrate varying degrees of hepatic fibrosis, there... 

Argininosuccinic aciduria. Patients manifest high levels of argininosuccinate in urine, blood and cerebrospinal fluid. Neonates have a stormy clinical course. Almost all have died or sustained severe brain injury. A peculiar finding is trichorrhexis nodosa, or dry brittle hair with nodular protrusions that are best visible with light microscopy. The precise cause is unknown. 

Patients who survive the neonatal period can be maintained with a low-protein diet and sodium benzoate. A useful therapeutic adjunct for citrullinemia and argininosuccinic aciduria is dietary arginine supplementation, which enhances the ability to eliminate nitrogen as either citrulline or argininosuccinate. Maintaining normal arginine levels also facilitates protein synthesis. 

R. Debuchy, S. Purton, J.-D. Rochaix (1989) The argininosuccinate lyase gene of Chlamydomonas reinhardtii. An important tool for nuclear transformation and for correlating the genetic and molecular maps of the arg7 locus. EMBOJ., 8 2803-2809... 

Z. Z., Morris, S. M., )r., Coinduction of nitric oxide synthase and argininosuccinate synthetase in a murine macrophage cell line. Implications for regulation of nitric oxide production,/. Biol. Chem. 269 (1994), p. 1257-12561... 

Recently, the role of hydrazine in the mechanism of isoniazid hepatotox-icity was confirmed by Sarich et al. [181]. Using a model of isoniazid-in-duced hepatotoxicity in rabbits, they found that hydrazine plasma concentrations correlated significantly with plasma argininosuccinic acid lyase, a sensitive marker of hepatic necrosis. In contrast, no correlation was found between plasma levels of isoniazid or acetylisoniazid and the markers of induced hepatic necrosis. 

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