Residual adenylosuccinase activities in fibroblasts of adenylosuccinase‐deficient children: Parallel deficiency with adenylosuccinate and succinyl‐AICAR in profoundly retarded patients and non‐parallel deficiency in a mildly retarded girl

Abstract

Adenylosuccinase (ASase) catalyses both the conversion of succinyl-aminoimidazole carboxamide ribotide (succinyl-AICAR) into AICAR and that of adenylosuccinate into AMP in the synthesis of purine nucleotides. Its deficiency results in the accumulation in body fluids of the nucleosides corresponding to both substrates, succinyl-AICAriboside and succinyladenosine. Two main subtypes of the defect are type I with severe mental retardation and succinyladenosine/succinyl-AICAriboside ratios around 1, and type II with slight mental delay and succinyladenosine/succinyl-AICAriboside ratios around 4. We report that in fibroblasts of type I patients, the activity of ASase with both adenylosuccinate and succinyl-AICAR is about 30% of normal. In contrast, in type II fibroblasts, the activity with adenylosuccinate is only 3% of normal, whereas that with succinyl-AICAR is also 30% of normal. If also present in other tissues, this non-parallel deficiency provides an explanation for the higher concentration of succinyladenosine in type II. In type I fibroblasts, ASase is further characterized mainly by a 3-fold to 4-fold increase in Km for succinyl-AICAR, and by retarded elution from an anion exchanger. In type II fibroblasts, ASase is characterized by a similar increase in Km for succinyl-AICAR but by a potent inhibition by KCl and nucleoside triphosphates, and by a normal elution profile. These results suggest a modification of the surface charge of ASase in type I, and the addition of one or more positively charged residues in the active site in type II.

Two Novel Mutant Human Adenylosuccinate Lyases (ASLs) Associated with Autism and Characterization of the Equivalent Mutant Bacillus subtilis ASL

“…Assuming that there is equal expression and stability of the two mutant enzymes in the proband (unlikely given the decreased stability of the mutant enzymes), the residual activity in the proband would be ϳ30%. This is similar to the residual ASL activity found in many ASL patients (8,9,26).…”

The nonessentiality of essential genes in yeast provides therapeutic insights into a human disease

“…This result well supported the above substrate accumulation hypothesis for explaining the Type II essentiality of ADE13. ADE13 catalyzes two reactions with S-AMP and SAICAR as substrates, respectively (Van den Bergh et al 1993). It is unclear which one is responsible for the lethality of ADE13 deletion.…”

Mutation analysis in adenylosuccinate lyase deficiency: Eight novel mutations in the re-evaluated full ADSL coding sequence

“…Interestingly, the latter patient was heterozygous for mutation R190Q, which has also been identified heterozygously in two Czech siblings with moderately delayed development . Current evidence indicates that the more severe clinical presentations of ADSL deficiency are associated with S-Ado/ SAICA-riboside ratios around 1 in body fluids [Jaeken et al, 1988;Krijt et al, 1995;Maaswinkel-Mooij et al, 1997;Köhler et al, 1999], and with parallel loss of both ADSL activities [ Van den Bergh et al, 1991. The first mutation reported in ADSL deficiency, S438P, previously labelled S413P [Stone et al, 1992], was identified in two such profoundly affected siblings.…”

“…ADSL deficiency was diagnosed on the basis of positive Bratton-Marshall tests [Laikind et al, 1986] and confirmed by high-performance liquid chromatography (HPLC) analysis of cerebrospinal fluid (CSF) and/or urine [Jaeken and Van den Berghe, 1984;Simmonds et al, 1991]. In some patients, the diagnosis was corroborated by assay of ADSL in tissue samples [Jaeken and Van den Berghe, 1984;Van den Bergh et al, 1991]. Psychomotor retardation was profound in eight patients, intermediate in one , and mild in another [patient 8 in Jaeken et al, 1988].…”