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Structural and Biochemical Characterization of Human Adenylosuccinate Lyase (ADSL) and the R303C ADSL Deficiency-Associated Mutation
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 nonsequential
steps in the de novo synthesis of AMP: the conversion of phosphoribosylsuccinyl-aminoimidazole
carboxamide (SAICAR) to phosphoribosylaminoimidazole carboxamide,
which occurs in the de novo synthesis of IMP, and the conversion of
adenylosuccinate 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 succinyladenosine monophosphate 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 into
why the R303C mutation potentially has a disproportional decrease
in activity toward its substrates, the wild type (WT) and the R303C
mutant 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