Disease relevance of ASS

• The disease was first described in humans but was recently reported in dairy cattle in Australia. Here we report the nucleotide sequence of the normal bovine cDNA for argininosuccinate synthetase and the mutation present in animals with citrullinemia [1].
• Mice treated with adenoviral vectors expressing argininosuccinate synthase lived significantly longer than untreated animals (11 days vs 1 day; however, the animals did not exhibit normal weight gain during the experiment, indicating that the therapeutic effectiveness of the transducing virus was suboptimal [2].

High impact information on ASS

• The binding of ATP and PPi at the same site is mutually exclusive; this exclusion is in accord with the finding that argininosuccinate synthetase has one reactive arginine residue per active site per subunit [3].
• Four cysteine residues, one per subunit, are shown by enzymatic assay to be required for catalytic activity, suggesting that a reactive cysteine lies within the active site of argininosuccinate synthetase [3].
• Argininosuccinate synthetase: essential role of cysteine and arginine residues in relation to structure and mechanism of ATP activation [3].
• Argininosuccinate synthase (AS) catalyzes the rate-limiting step in the recycling of citrulline to arginine, which in endothelial cells, is tightly coupled to the production of nitric oxide (NO) [4].
• Regulation of endothelial argininosuccinate synthase expression and NO production by an upstream open reading frame [4].

Chemical compound and disease context of ASS

• Citrullinemia is an inborn error of metabolism due to deficiency of the urea cycle enzyme, argininosuccinate synthetase [L-citrulline:L-aspartate ligase (AMP-forming), EC 6.3.4.5] [1].

Biological context of ASS

• Argininosuccinate synthase expression is required to maintain nitric oxide production and cell viability in aortic endothelial cells [5].
• To support this proposal, RNA interference analysis was used to selectively reduce the expression of argininosuccinate synthase (AS), because the only known metabolic role for AS in endothelial cells is in the regeneration of l-arginine from l-citrulline [5].
• The citrullinaemia genotype of the fetus/calf was established, at birth, by estimation of citrulline concentration in plasma or by analyses of argininosuccinate synthetase exon 5 sequences in DNA from blood leucocytes [6].

Anatomical context of ASS

• To support this proposal, we showed that nitric oxide synthase, and the enzymes involved in arginine regeneration, argininosuccinate synthase and argininosuccinate lyase, cofractionated with plasmalemmal caveolae, a subcompartment of the plasma membrane [7].

Associations of ASS with chemical compounds

• We have undertaken studies to identify amino acid residues that are involved in the catalytic mechanism of argininosuccinate synthetase [L-citrulline:L-aspartate ligase (AMP-forming), EC 6.3.4.5] and have found that a cysteine residue and an arginine residue are required for activity [3].
• Biosynthesis of urea. Molecular and regulatory properties of crystalline argininosuccinate synthetase [8].
• In this report we describe the formation of canavaninosuccinate from ureidohomoserine and aspartate by a human or bovine liver extract that had high argininosuccinate synthetase (EC 6.3.4.5) activity, and the subsequent formation of guanidinosuccinate by reductive cleavage [9].
• Argininosuccinate synthetase was shown not to catalyze a positional isotope exchange reaction designed to test for the formation of citrulline adenylate as a reactive intermediate [10].
• The technique has been applied to the reactions catalyzed by acetyl-CoA synthetase and argininosuccinate synthetase [10].

Other interactions of ASS

• Urea formation from citrulline was confirmed in a continuous column reactor by the coimmobilized argininosuccinate synthetase, argininosuccinate lyase (EC 4.3.2.1), and arginase (EC 3.5.3.1) [11].
• Caveolar localization of arginine regeneration enzymes, argininosuccinate synthase, and lyase, with endothelial nitric oxide synthase [7].
• The enzymes measured were: carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (AS), argininosuccinase (AL) and arginase (A) [12].

Analytical, diagnostic and therapeutic context of ASS

• Measurement of positional isotope exchange rates in enzyme-catalyzed reactions by fast atom bombardment mass spectrometry: application to argininosuccinate synthetase [10].
• Previous studies showed short-term correction of bovine and murine argininosuccinate synthetase (ASS) deficiency after first generation adenoviral-mediated liver gene therapy [13].
• Immobilization of urea cycle enzymes. II. Characterization of immobilized argininosuccinate synthetase [11].

References