Role of adenylosuccinate lyase in purine biosynthesis and interconversion: molecular biology and genetic defects.

Adenylosuccinate lyase catalyses two steps in the synthesis of purine nucleotides leading to nonhydrolytic cleavage of succinyl groups to yield fumarate: the conversion of 5-aminoimidazole-4-(N-succinylocarboxamide) ribonucleotide (SAICAR) into 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) along the de novo pathway and the formation of adenosine monophosphate (AMP) from adenylosuccinate (S-AMP) in the conversion of inosine monophosphate into adenine nucleotides. In addition to its role in purine biosynthesis, the enzyme is involved, together with AMP deaminase and S-AMP synthetase, in the purine nucleotide cycle. The reaction mechanism involves a general base catalyst, removing a proton from the succinyl group of the substrate, acting in concert with a general acid catalyst that protonates the amino group left on AICAR or AMP. The enzyme shows four active-site clefts, located on the boundaries between three subunits of the tetramer, which contain two highly-conserved histidine residues and a glutamate-histidine relay that are involved in catalysis. Human adenylosuccinate lyase gene is located in chromosome 22 and spans over 23 kb with 13 exons of 146 to 4536 bp. Two adenylosuccinate lyase mRNA isoforms, which are produced by an alternative splicing of exon 12, have been identified in human tissues. Exon 12 deletion results in the translation of a protein missing 59 amino acids, which is completely inactive. The deficiency of adenylosuccinate lyase causes variable degrees of psychomotor retardation, often accompanied by epileptic seizures and/or autistic features. The existence of genetic heterogeneity for the adenylosuccinate lyase deficiency could account for variability of the clinical presentation. The defect is characterised by the appearance of succinylpurines in cerebrospinal fluid and urine. Deficiency of purine nucleotides, toxic effects, and impairment of energy metabolism are potential mechanisms of cerebral damage.