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Adenylosuccinate lyase deficiency, also called adenylosuccinase deficiency,[1] is a rare autosomal recessive[2] metabolic disorder characterized by the appearance of succinylaminoimidazolecarboxamide riboside (SAICAriboside) and succinyladenosine (S-Ado) in cerebrospinal fluid, urine, and to a lesser extent in plasma.[3]
These two succinylpurines are the dephosphorylated derivatives of SAICAribotide (SAICAR) and adenylosuccinate (S-AMP), the two substrates of adenylosuccinate lyase (ASL), which catalyzes an important reaction in the de novo pathway of purine biosynthesis. ASL catalyzes two distinct reactions in the synthesis of purine nucleotides, both of which involve the ß-elimination of fumarate to produce either aminoimidazole carboxamide ribotide (AICAR) from SAICAR or adenosine monophosphate (AMP) from S-AMP.
As of 2004, about 60 patients had been diagnosed with ASL deficiency, but it is thought that there may be many more that go undiagnosed, due to the heterogeneity of the disease and a paucity of general screening. Patients have been diagnosed from a number of areas around the world, although a large number of them are from the Low Countries. ASL deficiency rose to prominence in the well documented case of Michael Dignan, a developmentally challenged youth.[4]
The deficiency is responsible for a range of symptoms that involve psychomotor retardation, often accompanied by epileptic seizures, and autistic features. Most patients suffer from moderate to severe retardation, while rare patients display only mild psychomotor retardation. Two common theories were proposed to account for these effects. The first is that they result from decreased concentrations of purine nucleotides needed for purine biosynthesis. Decreased concentrations however could not be evidenced in various tissues taken from ASL-deficient patients, probably because purines are furnished via the purine salvage pathway and some residual activity of ASL.[3] The second is that the buildup of accumulating succinylpurines causes neurotoxic effects. In the severely affected patients, the concentration levels of SAICAriboside and S-Ado are comparable, whereas in patients with milder forms of the disease, the ratio of S-Ado is more than double that of those more severely affected, while SAICAriboside concentration levels remain comparable. This suggests that SAICAriboside is the major contributor, while S-Ado may protect against SAICAriboside’s toxic effects.[3]
Biochemical studies of the enzyme have focused on proteins of ASL from non-human species. The ASL structure from the crystallized protein of Thermotoga maritima has been used along with DNA sequencing data to construct homology models for a variety of other organisms, including human ASL.[4] A variety of studies have been done using the equivalent enzyme from Bacillus subtilis, which shares 27% identity along with about 17% similarity in amino acid sequence with the human enzyme.[4] Homology models overlaid on each other show a high degree of overlap between the enzymes. The family of enzymes to which ASl belongs and that catalyze ß-eliminations in which fumarate is one of the products are homotetramers with four active sites composed of amino acid residues from three distinct subunits.[5] Much is known about the active site of human ASL due to studies of the active site in the B. Subtilis ASL through affinity labeling and site-directed mutagenesis. While there is quite a bit of variability among species in the sequencing of ASL, the active site of the enzyme contains many residues that are conserved across species and have been shown to be critical to the enzyme’s function. His68 and His141 seem to serve as the general acid and general base catalysts, respectively, and are critical to the catalyzing reaction of the substrate.[6] His89 seems to enhance the binding of the substrate’s phosphoryl group and orient adenylosuccinate for catalysis.[7] All three histidines are conserved throughout the 28 species for which the structure of ASL is known. Glu275 and Lys268 have also been shown to contribute to the active site, indicating that there are four active sites, each of which is formed from regions of three subunits.[5] ASL deficiency in different patients is often caused by different mutations to the enzyme. More than 30 different mutations in the ASL gene have been discovered worldwide. The mutations resulting in this deficiency are spread throughout the enzyme, with the majority located far from the active site, suggesting that thermal instability, rather than catalytic impairment of the active site is the most frequent cause of the deficiency.[8]
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