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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.

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Van den Bergh, F Vincent, Marie-Françoise [UCL] Jaeken, J. Van den Berghe, Georges [UCL]

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.

Document type Article de périodique (Journal article) – Journal Article, Research Support, Non-U.S. Gov't
Publication date 1993
Journal information "Journal of inherited metabolic disease" - Vol. 16, no. 2, p. 415-24 (1993)
Peer reviewed yes
issn 0141-8955
Publication status Publié
Affiliation UCL - MD/BICL - Département de biochimie et de biologie cellulaire
MESH Subject Adenosine Monophosphate - analogs & derivatives - metabolism ; Adenylosuccinate Lyase - deficiency - metabolism ; Aminoimidazole Carboxamide - analogs & derivatives - metabolism ; Binding, Competitive ; Cells, Cultured ; Child ; Chromatography, Ion Exchange ; Female ; Fibroblasts - enzymology ; Humans ; Hydrogen-Ion Concentration ; Kinetics ; Mental Retardation - enzymology ; Nucleotides - pharmacology ; Potassium Chloride - pharmacology ; Ribonucleotides - metabolism ; Substrate Specificity
Links
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Bibliographic reference Van den Bergh, F ; Vincent, Marie-Françoise ; Jaeken, J. ; Van den Berghe, Georges. 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.. In: Journal of inherited metabolic disease, Vol. 16, no. 2, p. 415-24 (1993)
Permanent URL http://hdl.handle.net/2078.1/29337