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Comparative computational assessment of the pathogenicity of mutations in the Aspartoacylase enzyme

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Abstract

Aspartoacylase (ASPA) is a zinc-dependent abundant enzyme in the brain, which catalyzes the conversion of N-acetyl aspartate (NAA) into acetate and aspartate. Mutations in the ASPA gene are associated with the development of Canavan disease (CD), leading to the deficiency of ASPA activity. Patients with CD were characterized by degeneration of the white matter of the brain. We reported earlier on two patients with severe form of CD that both had two novel missense mutations in the ASPA: c.427 A > G; p. I143V and c.557 T > A; p. V186D (Zaki et al. 2017a), patient 1 harbored both mutations (p.I143V and p.V186D) in a heterozygous form together with four other mutations, and patient 2 had both mutations in homozygous form. Wijayasinghe et al. (2014) crystallized the 3D structures of four different ASPA mutants (p.K213E, p.Y231C, p.E285A, and p.F295S). In this study, we used in silico prediction methods and molecular dynamics simulation (MDS) to understand the structural impact of all these mutations. Moreover, we used molecular docking (MD) to investigate the binding patterns of the NAA substrate to the native and mutant proteins. Among the mutations, p.E285A (crystallized mutant) was predicted to be the most deleterious for the protein function and the least deleteriousness mutant was the p.I143V (novel mutant). Among the novel mutations, p.V186D was observed to be disruptive for both the zinc binding and NAA binding than the p.I143V. This study provides practical insights on the effect of these mutations on the ASPA function and might serve as a platform for drug design for CD treatment.

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Abbreviations

ASPA:

Aspartoacylase

CD:

Canavan disease

3D:

three-dimensional

RMSD:

Root Mean Square Deviation

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Acknowledgments

Hatem Zayed is supported by the Qatar University grant QUUG-CAS-DHS-14/15-3.The authors also thank the VIT University management for their encouragement and provision of facilities.

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Authors and Affiliations

  1. Department of Integrative Biology, School of Biosciences and Technology, VIT University, Vellore, India

    C. George Priya Doss

  2. Department of Biomedical Sciences, College of Health and Sciences, Qatar University, Doha, Qatar

    Hatem Zayed

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  1. C. George Priya Doss
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  2. Hatem Zayed
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Correspondence to C. George Priya Doss or Hatem Zayed.

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George Priya Doss, C., Zayed, H. Comparative computational assessment of the pathogenicity of mutations in the Aspartoacylase enzyme. Metab Brain Dis 32, 2105–2118 (2017). https://doi.org/10.1007/s11011-017-0090-5

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