Disease relevance of ASL

• Melanomas and HCCs did not express argininosuccinate synthetase mRNA but did express argininosuccinate lyase mRNA, suggesting that the arginine auxotrophy of these cells was a result of an inability to produce argininosuccinate synthetase [1].
• Investigation of the urea-cycle enzyme in the leucocytes of patients with renal insufficiency, in the pre-dialytic and dialytic states, showed that in both groups the ornithine carbamoyl transferase and the argininosuccinate lyase activity was lower in both groups of patients than in normal persons [2].
• Occupational exposure to vinyl chloride causes liver angiosarcomas (ASL) and also increases the risk of several other cancers [3].
• Here, we simultaneously measured perfusion by ASL, and BOLD response in the calf muscle of 6 healthy volunteers during post-ischemic reactive hyperemia [4].
• Adenylosuccinate lyase (ASL) from Bacillus subtilis has been crystallized and structural analysis by X-ray diffraction is in progress [5].

Psychiatry related information on ASL

• A S413P mutation in ASL segregates with mental retardation in an affected family (Stone, R. L., Aimi, J., Barshop, B. A., Jaeken, J., Van den Berghe, G., Zalkin, H., and Dixon, J. E. (1992) Nature Genet. 1, 59-63) [6].
• In this study, we have preformed simultaneous near-infrared spectroscopy (NIRS) along with BOLD (blood oxygen level dependent) and ASL (arterial spin labeling)-based fMRI during an event-related motor activity in human subjects in order to compare the temporal dynamics of the hemodynamic responses recorded in each method [7].
• Outcome measures included cognitive tests (FePsy neuropsychological test battery), mood scales (ASL; mood-rating scale), and a scale for subjective complaints (ABNAS Neurotoxicity scale) [8].

High impact information on ASL

• Sustained engraftment and tissue enzyme activity after liver cell transplantation for argininosuccinate lyase deficiency [9].
• Moreover, argininosuccinate lyase activity, originally absent, became measurable in 2 different biopsy samples at 8 months, reaching 3% of control activity, indicating in situ metabolic effect and supporting the clinical evolution to a moderate form of the disease [9].
• This index of urea cycle activity also distinguished asymptomatic heterozygous carriers of argininosuccinate synthetase deficiency (0. 22 +/- 0.03), argininosuccinate lyase deficiency (0.35 +/- 0.11), and partial ornithine transcarbamylase deficiency (0.26 +/- 0.06) from normal controls [10].
• We isolated six chlorophyll b-less mutants by insertional mutagenesis by using the nitrate reductase or argininosuccinate lyase genes as tags and examined the rearrangement of mutant genomes [11].
• The mutations involved in the most successful complementation event observed in ASL deficiency were found to be an aspartate to glycine mutation at codon 87 of one allele (D87G) coupled with a glutamine to arginine mutation at codon 286 of the other (Q286R) [12].

Chemical compound and disease context of ASL

• In a 15-month-old girl with profound hypotonia, we established the diagnosis of ASL deficiency by demonstrating succinyladenosine and SAICA riboside in urine and decreased residual activity of ASL in skin fibroblasts [13].

Biological context of ASL

• Regional location of ASL and GUS to the pter to q22 region of chromosome 7 was achieved in hybrids segregating a 7/9 translocation [14].
• The human ASL phenotype segregated concordantly with the human enzyme beta-glucoronidase (GUS; beta-D-glucoronide glucuronosohydrolase, EC 3.2.1.31) in cell hybrids, but showed discordant segregation with 32 other enzyme markers representing 23 linkage groups [14].
• Identifying human ASL, by bioautography in human-mouse somatic cell hybrids has made it possible to regionally locate the ASL gene on human chromosome 7 [14].
• The 3-dimensional structure of wild-type ASL has enabled us to propose that the complementation between two ASL active site mutant subunits, Q286R and D87G, occurs through a regeneration of functional active sites in the heteromutant protein [15].
• Amino acid sequencing of peptides prepared from purified human liver ASL showed our predicted amino acid sequence to be correct [16].

Anatomical context of ASL

• We demonstrate here that (a) human normal T and B lymphocytes did not express ASS activity, (b) however, three adult T leukemia (ATL) cell lines tested here exhibited significant elevation of ASS activity, and (c) ASL activity remained relatively constant in normal lymphocytes and various leukemia cell lines [17].
• Fibroblast strain 944 (approximately 1% of residual ASAL activity), from a late-onset patient who was the product of a consanguineous mating, had only a single base-pair change in the coding region, a C-283----T transition at a CpG dinucleotide in exon 3 [18].
• Expression in COS cells demonstrated that the R95C mutation produces normal amounts of ASAL mRNA but little protein and less than 1% ASAL activity [18].
• We observed that amplified cDNA from mutant 944 and normal cells (liver, keratinocytes, lymphoblasts, and fibroblasts) contained, in addition to the expected 5' 513-base-pair band, a prominent 318-base-pair ASAL band formed by the splicing of exon 2 from the transcript [18].
• AS and sometimes AL have been shown to be coinduced with inducible NOS (iNOS) in various cell types including activated macrophages, microglia, vascular smooth muscle cells, glial cells, neuronal PC12 cells, retinal pigment epithelial cells, and pancreatic beta-cells [19].

Associations of ASL with chemical compounds

• Argininosuccinate synthetase (ASS) is a ATP-dependent and rate-limiting enzyme of the urea cycle which catalyzes L-citrulline to L-arginine in combination with argininosuccinate lyase (ASL) [17].
• Argininosuccinic aciduria, an autosomal recessive disorder of the urea cycle in humans, is associated with a deficiency of argininosuccinate lyase (ASL; L-argininosuccinate arginine-lyase, EC 4.3.2.1) [14].
• Argininosuccinate lyase (ASL) is a homotetrameric enzyme that catalyzes the reversible cleavage of argininosuccinate to arginine and fumarate [15].
• This substitution converts Arg-95 to Cys (R95C), occurs in a stretch of 13 residues that is identical in yeast and human ASAL, and was present in both of the patient's alleles but not in 14 other mutant or 10 normal alleles [18].
• Immunoadsorption of crude human liver extracts followed by analysis of the immunoprecipitates by sodium dodecyl sulfate gel electrophoresis showed only one protein band which corresponded in mobility to purified argininosuccinate lyase, demonstrating that the antibodies were specific for argininosuccinate lyase [20].

Other interactions of ASL

• On the basis of the novel sequence data, a polymerase reaction chain system for mutation-screening in all 16 coding exons of the ASL gene was established and applied to the analysis of the ASL-deficient patients [21].
• Coinduction of endothelial NOS (eNOS), AS, and AL are observed in human umbilical vein endothelial cells [19].
• Besides 14 known mutations, we detected the novel mutation c.544delC of the N-acetylglutamate synthase gene, the novel missense mutation c.721G>A (E241K) of the argininosuccinate lyase gene, and the novel double mutated allele comprising the known mutation c.703G>A (G235R) and the novel insertion c.712ins[GGACC](2) (254X) of the arginase 1 gene [22].
• The activity of glutamine synthetase and three enzymes operating in the urea cycle (carbamyl phosphate synthetase, argininosuccinate synthetase, argininosuccinate lyase) increased significantly in hepatic and extra-hepatic tissue, such as the kidney and muscle in C. batrachus, during exposure to alkaline water [23].
• Argininosuccinate lyase: a new autoantigen in liver disease [24].

Analytical, diagnostic and therapeutic context of ASL

• ASL was mapped to human chromosome 7pter----q22 using human-mouse somatic cell hybrid DNA and further mapped by in situ hybridization to chromosome 7cen----q11.2 on human metaphase chromosomes [25].
• Cloning and sequence analysis of cDNA for human argininosuccinate lyase [26].
• cDNA sequence, interspecies comparison, and gene mapping analysis of argininosuccinate lyase [25].
• IJC was measured using metabolic cooperation in a coculture system of argininosuccinate synthetase- and argininosuccinate lyase-deficient human fibroblasts [27].
• Complementation tests after polyethylene glycol fusion have been performed between 10 citrullinemic strains with argininosuccinate synthetase deficiency and between five strains with argininosuccinate lyase deficiency [28].

References