Structural and Biochemical Characterization of Human Adenylosuccinate Lyase (ADSL) and the R303C ADSL Deficiency-Associated Mutation
| Autor: | Kingshuk Ghosh, Stephen P. Ray, Glenn C. Capodagli, Scott D. Pegan, Lucas Sawle, Lauren A. F. Calkins, David Patterson, Michelle K. Deaton |
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| Rok vydání: | 2012 |
| Předmět: |
Purine-Pyrimidine Metabolism
Inborn Errors Mutant Mutation Missense Biology medicine.disease_cause Biochemistry Article chemistry.chemical_compound medicine Humans Nucleotide Amino Acid Sequence Autistic Disorder Adenylosuccinate lyase Purine metabolism chemistry.chemical_classification Genetics Mutation Adenylosuccinate Lyase Purine nucleotide cycle Ribonucleotides Aminoimidazole Carboxamide Lyase Adenosine Monophosphate chemistry Adenylosuccinate Sequence Alignment |
| Zdroj: | Biochemistry. 51:6701-6713 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/bi300796y |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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