The Biochemical Aspects of ASase Deficiency

Abstract

Adenylosuccinate lyase (EC 4.3.2.2; adenylosuccinase; ASase) catalyzes two steps in the synthesis of purine nucleotides: the conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) into aminoimidazole carboxamide ribotide (AICAR) along the de novo pathway, and the formation of adenosine monophosphate (AMP) from adenylosuccinate (S-AMP) in the conversion of inosine monophosphate (IMP) into adenine nucleotides (Fig. 1). Both reactions involve the cleavage of a succinyl group, yielding fumarate. ASase deficiency is the first enzyme deficiency reported in humans along the de novo pathway of purine synthesis (Jaeken and van den Berghe 1984). As reviewed in the previous chapter, the defect is transmitted as an autosomal recessive trait and results in the accumulation in body fluids of two normally undetectable compounds. SAICA riboside and succinyladenosine (S-Ado). These succinylpurines are the products of the dephosphorylation, by cytosolic 5’-nucleotidase (van den Berghe and Jaeken 1986), of the two substrates of ASase. From a clinical and biochemical investigation of eight children with ASase deficiency (Jaeken et al. 1988) two main subtypes of the defect could be distinguished: the first one, identified in seven patients and referred to as type I, is characterized by very profound psychomotor retardation, often accompanied by autistic features, and by S-Ado/SAICA riboside ratios between 1 and 2. In type II, diagnosed in one girl, mental retardation is slight, S-Ado levels are higher, and S-Ado/SAICA riboside ratios are about 4. In a third variant, neurological involvement is intermediate and higher levels of both S-Ado and SAICA riboside are found in body fluids (Jaeken et al., 1992).