Adenylosuccinase Activity and Succinylpurine Production in Fibroblasts of Adenylosuccinase-Deficient Children

Abstract

Adenylosuccinase (adenylosuccinate lyase, EC 4.3.2.2, ASase) catalyzes two steps in the biosynthesis of purine nucleotides: the conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) into AICAR along the de novo pathway, and the formation of AMP from adenylosuccinate (S-AMP) in the conversion of IMP into adenine nucleotides. Both reactions involve the cleavage of a succinyl group, yielding fumarate. ASase deficiency is the first enzyme deficiency reported in man (1) along the de novo pathway of purine synthesis. The defect is transmitted as an autosomal recessive trait and results in the accumulation in cerebrospinal fluid, plasma and urine, of two normally undetectable compounds, SAICAriboside and succinyladenosine (S-Ado). These are the products of the dephosphorylation, by cytosolic 5′nucleotidase (2), of the two substrates of ASase. From a clinical and biochemical study of 8 children with ASase deficiency (3) two main subtypes of the defect can be distinguished: the first one, identified in 7 patients and hereafter referred to as type I, is characterized by very profound psychomotor retardation and by S-Ado/SAICAriboside ratios between 1 and 2. In type II, diagnosed in one girl, mental retardation is slight, and S-Ado/SAICAriboside ratios are about 4.