Identification of potential pharmacological chaperones that selectively stabilize mutated Aspartoacylases in Canavan disease.

Canavan disease is caused by mutations in the ASPA gene, leading to diminished catalytic activity of aspartoacylase in the brain. Clinical missense mutations are found throughout the enzyme structure, with many of these mutated enzymes having not only decreased activity but also compromised stability. High-throughput screening of a small molecule library has identified several compounds that significantly increase the thermal stability of the E285A mutant enzyme, the most predominant clinical mutation in Canavan disease, while having a negligible effect on the native enzyme. Based on the initial successes, some structural analogs of these initial hits were selected for further examination. Glutathione, NAAG and patulin were each confirmed to be competitive inhibitors, indicating the binding of these compounds at the dimer interface or near the active site of the E285A enzyme. The experimental results were theoretically examined with the help of the docking analysis method. The structure activity-guided optimization of these compounds can potentially lead to potential pharmacological chaperones that could alleviate the detrimental effect of ASPA mutations in Canavan patients.

Poddar NK ，Wijayasinghe YS ，Viola RE 《-》

Docking, molecular dynamics and free energy studies on aspartoacylase mutations involved in Canavan disease.

The disruption of aspartoacylase enzyme's catalytic activity causes fatal neurodegenerative Canavan disease. By molecular dynamics and docking methods, here we studied two deleterious mutations that have been identified in the Canavan patients' genotype E285A, F295S, and revealed the possible cause for the enzyme inhibition due to the drastic changes in active site dynamics, loss of interactions among Arg 71, Arg 168 and the substrate and pKa value of critical Glu178 residue. In addition to changes in the enzyme dynamics, free energy calculations show that the binding energy of substrate decreases dramatically up on mutations.

Kocak A ，Yildiz M 《-》

Aspartoacylase catalytic deficiency as the cause of Canavan disease: a structural perspective.

Wijayasinghe YS ，Pavlovsky AG ，Viola RE 《-》

Mutational analysis of aspartoacylase: implications for Canavan disease.

Hershfield JR ，Pattabiraman N ，Madhavarao CN ，Namboodiri MA ... -  《BRAIN RESEARCH》

Identification and expression of eight novel mutations among non-Jewish patients with Canavan disease.

Kaul R ，Gao GP ，Matalon R ，Aloya M ，Su Q ，Jin M ，Johnson AB ，Schutgens RB ，Clarke JT ... -  《-》