4FLC

Structural and Biochemical Characterization of Human Adenylosuccinate Lyase (ADSL) and the R303C ADSL Deficiency Associated Mutation

Summary for 4FLC

• Entry DOI: 10.2210/pdb4flc/pdb
• Related: 2J91 2VD6
• Descriptor: Adenylosuccinate lyase (2 entities in total)
• Functional Keywords: purine biosynthesis, lyase, disease mutation, purine metabolism
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 220878.03

Authors

Deaton, M.K.,Ray, S.P.,Capodagli, G.C.,Calkins, L.A.F.,Sawle, L.,Ghosh, K.,Patterson, D.,Pegan, S.D. (deposition date: 2012-06-14, release date: 2012-08-01, Last modification date: 2023-09-13)

Primary citation

Ray, S.P.,Deaton, M.K.,Capodagli, G.C.,Calkins, L.A.,Sawle, L.,Ghosh, K.,Patterson, D.,Pegan, S.D.
Structural and Biochemical Characterization of Human Adenylosuccinate Lyase (ADSL) and the R303C ADSL Deficiency-Associated Mutation.
Biochemistry, 51:6701-6713, 2012

PubMed Abstract: 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.

PubMed: 22812634
DOI: 10.1021/bi300796y

Experimental method

X-RAY DIFFRACTION (2.6 Å)