Disease relevance of ARGININOSUCCINATE

• In this study, the argininosuccinate substrate was modeled into the active site of duck delta IotaIota crystallin, using the coordinates of an inhibitor-bound Escherichia coli fumarase C structure to orient the fumarate moiety of the substrate [1].
• Increased urinary excretion of argininosuccinate in type II citrullinemia [2].
• The conversion of argininosuccinate to arginine by argininosuccinate lyase was inhibited by exposure to hypoxia for 24 h but not for 4-12 h [3].
• Hybridization of various Streptomyces cattleya aerial mycelium negative (Amy-) mutants with a probe containing the gene for argininosuccinate synthetase (pTG17) has revealed the presence of two different types of mutants (stable and unstable) [4].

High impact information on ARGININOSUCCINATE

• The short transcript maintains the ASAL reading frame but removes Lys-51, a residue that may be essential for catalysis, since it binds the argininosuccinate substrate [5].
• However, L-Gln did not inhibit the conversion of L-argininosuccinic acid to L-Arg by endothelial cell homogenates [6].
• The reaction of the enzyme with the alkylating agent and the specific protection against inactivation by argininosuccinate suggest that this lysine residue has an essential role in the binding of argininosuccinate to the enzyme and, consequently, is essential for catalysis [7].
• The latter is transported to cytosol and incorporated into argininosuccinate [8].
• These results support the proposal that catalysis is facilitated in the forward reaction by a general base that abstracts a proton from C-3 of argininosuccinate and a general acid that donates a proton to the guanidinium nitrogen during carbon-nitrogen bond cleavage [9].

Chemical compound and disease context of ARGININOSUCCINATE

• The conversion of L-citrulline to L-argininosuccinate by argininosuccinate synthetase (AS) was inhibited by exposure to hypoxia for 4, 12, or 24 h [3].

Biological context of ARGININOSUCCINATE

• We used complementation analysis as a probe for the detection of genetic heterogeneity within a single locus affected in a human disease, argininosuccinate lyase (L-argininosuccinate arginine-lyase, EC 4.3.2.1) deficiency [10].
• However, unlike bovine liver argininosuccinase, human liver enzyme exhibited normal Michaelis-Menten kinetics both in phosphate and Tris buffers, and the apparent Michaelis constant for L-argininosuccinate ws 0.1 mM [11].
• Argininosuccinate was found to be bound to residues in each of the three monomers that form the active site [12].
• We suspect that relatively more mutable sites maintained unchanged during the evolution of the argininosuccinate gene are able to change in the pseudogenes, such sites being eliminated or rare in the flanking regions which have been void of strong selective constraints over a much longer period [13].
• Electroporation of strains CC3395 and CC425, cell wall-less mutants devoid of argininosuccinate lyase (encoded by ARG7), in the presence of the plasmid pJD67 (which contains ARG7) was used to optimize conditions for the introduction of exogenous DNA [14].

Anatomical context of ARGININOSUCCINATE

• The urea cycle enzymes, ornithine carbamoyltransferase and arginase, are also located in the mitochondria, whereas argininosuccinate synthetase and argininosuccinate lyase are located in the cytosol [15].
• The current study was designed using morphologic techniques to determine whether Lcitrulline is taken up into axoplasm of perivascular nerves and to explore the possibility that conversion of Lcitrulline to Larginine in these nerves is through the argininosuccinate pathway in porcine cerebral arteries [16].
• Our results indicate that argininosuccinate passes between the two cell types via intercellular junctions, and this system provides a simple and accurately quantifiable model for the study of intercellular communication [17].
• The activities of argininosuccinate synthase and arginase were increased by 4-fold and 50-100-fold, respectively, in enterocytes from post-weaning pigs compared with suckling pigs [18].
• Argininosuccinate lyase(ASL)/delta-crystallin is a prominent example of an enzyme-crystallin with roles as both a catalyst and a major structural component of the eye lens in birds and reptiles [19].

Associations of ARGININOSUCCINATE with other chemical compounds

• At 0.05 ionic strength in Tris-HCl buffer, the four enzyme sites bind argininosuccinate independently and arginine binding remains negatively cooperative [20].
• The mutant strain was also able to grow in the presence of high concentrations of argininosuccinate, but its auxotrophic phenotype could not be rescued by L-citrulline, suggesting that the DeltaargF::hyg mutation exerted a polar effect on the downstream argG gene but not on argH [21].
• Argininosuccinate lyase (ASL) is a homotetrameric enzyme that catalyzes the reversible cleavage of argininosuccinate to arginine and fumarate [22].
• The enzymic activity of duck lens delta2-crystallin in the pH range 5.5-8.5 was investigated using both protium- and deuterium-labelled argininosuccinate as the substrate [23].
• By numerous criteria including electrophoresis in sodium dodecyl sulfate containing gels, electrophoresis in nondissociating gels, and analytical ultracentrifugation, the protein is homogeneous at a specific activity of 4.2 mumol/(min mg) assayed at 37 degrees C in the direction of argininosuccinate synthesis [24].

Gene context of ARGININOSUCCINATE

• Furthermore, there was an increase in the hepatic ornithine-urea cycle (OUC) capacity, with significant increases in the activities of CPS III (3.8-fold), argininosuccinate synthetase + lyase (1.8-fold) and, more importantly, glutamine synthetase (2.2-fold) [25].
• The Saccharomyces cerevisiae ARG1 gene coding for argininosuccinate synthetase has been isolated and the nucleotide sequence of both its control region and of its amino terminal end coding region determined [26].
• The lens structural protein delta-crystallin and the metabolic enzyme argininosuccinate lyase (ASL; L-argininosuccinate arginine-lyase, EC 4.3.2.1) have striking sequence similarity [27].
• The C. jejuni argH gene shows nucleotide homology to both yeast and human argininosuccinate lyase genes, and conserved amino acid domains are evident between the corresponding proteins [28].
• Particularly noteworthy is the demonstration that argininosuccinate was totally incapable of rescuing cells that utilise citrulline efficiently, consistent with tight channelling (coupling) of argininosuccinate synthetase and argininosuccinate lyase in the urea cycle [29].

Analytical, diagnostic and therapeutic context of ARGININOSUCCINATE

• Argininosuccinate lyase (EC 4.3.2.1) was purified by (NH4)2SO4 fractionation, chromatography on DEAE-cellulose and gel filtration on Sephadex G-200 [30].
• Furthermore, binding of argininosuccinate by the DLM, as well as the ddeltac1, could not be detected by isothermal titration calorimetry (ITC) [31].
• PCR analysis of five sequenced nuclear genes present in the Chlamydomonas library revealed a range from two copies for the alpha 2- and beta 2-tubulin genes to at least seven copies for the argininosuccinate lyase gene [32].
• Prenatal diagnosis of argininosuccinic aciduria by assay of argininosuccinate in amniotic fluid at the 12th week of gestation [33].
• Recent studies using fluorescence in situ hybridization (FISH) have shown that in a subset of patients with CML, deletions of 9q34 involving the argininosuccinate synthetase region occur at the time of the Philadelphia translocation and are associated with a poor prognosis [34].

References