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.