[PUR8_HUMAN] Defects in ADSL are the cause of adenylosuccinase deficiency (ADSL deficiency) [MIM:103050]. ADSL deficiency is an autosomal recessive disorder characterized by the accumulation in the body fluids of succinylaminoimidazole-carboxamide riboside (SAICA-riboside) and succinyladenosine (S-Ado). Most children display marked psychomotor delay, often accompanied by epilepsy or autistic features, or both, although some patients may be less profoundly retarded. Occasionally, growth retardation and muscular wasting are also present.
Publication Abstract from PubMed
Adenylosuccinate lyase (ADSL) deficiency is a rare autosomal recessive disorder, which causes a defect in purine metabolism resulting in neurological and physiological symptoms. ADSL executes two non-sequential steps in the de novo synthesis of AMP: the conversion of phosphoribosylsuccinyl-aminoimidazole carboxamide (SAICAR) to phosphoribosylaminoimidazole carboxamide (AICAR), which occurs in the de novo synthesis of IMP, and the conversion of adenylosuccinate (AMPS) to AMP, which occurs in the de novo synthesis of AMP and also in the purine nucleotide cycle, using the same active site. Mutation of ADSL's arginine 303 to a cysteine is known to lead to ADSL deficiency. Interestingly, unlike other mutations leading to ADSL deficiency, the R303C mutation has been suggested to more significantly affect the enzyme's ability to catalyze the conversion of SAMP than that of SAICAR to their respective products. To better understand the causation of disease due to the R303C mutation, as well as to gain insights as to why the R303C mutation potentially has a disproportional decrease in activity toward its substrates, the wild-type (WT) and the R303C mutation of ADSL were investigated enzymatically, and thermodynamically. Additionally, the X-ray structures of ADSL in its apo form as well as with the R303C mutation were elucidated, providing insight into ADSL's cooperativity. By utilizing this information a model for the interaction between ADSL and SAICAR is proposed.
Structural and Biochemical Characterization of Human Adenylosuccinate Lyase (ADSL) and the R303C ADSL Deficiency Associated Mutation.,Ray SP, Deaton MK, Capodagli GC, Calkins LA, Sawle L, Ghosh K, Patterson D, Pegan SD Biochemistry. 2012 Jul 19. PMID:22812634
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑ Ray SP, Deaton MK, Capodagli GC, Calkins LA, Sawle L, Ghosh K, Patterson D, Pegan SD. Structural and Biochemical Characterization of Human Adenylosuccinate Lyase (ADSL) and the R303C ADSL Deficiency Associated Mutation. Biochemistry. 2012 Jul 19. PMID:22812634 doi:10.1021/bi300796y