Insights into the role of d‐amino acid oxidase mutations in amyotrophic lateral sclerosis. Issue 2 (11th September 2018)

• Record Type: Journal Article
• Authors: Padhi, Aditya K.; Hazra, Saugata
• Is Part Of: Journal of cellular biochemistry. Volume 120:Issue 2(2019)
• Page Start: 2180
• Page End: 2197
• Publication Date: 2018-09-11
• Subjects: amyotrophic lateral sclerosis (ALS) -- d‐amino acid oxidase (DAO) -- enzymatic activity -- molecular dynamics (MD) -- mutations; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.27529
• Languages: English
• ISSNs: 0730-2312

Abstract

Abstract: Missense mutations in the coding region of d ‐amino acid oxidase (DAO) have been found in patients suffering from amyotrophic lateral sclerosis (ALS). Mutations primarily impair the enzymatic activity of DAO and cause neurodegeneration due to an abnormal accumulation of d ‐serine in the spinal cord. However, the structural and dynamic changes that lead to impaired enzymatic activity are not fully understood. We present here extensive molecular dynamics simulations of wild‐type, and all reported ALS‐associated DAO mutants to elucidate the plausible mechanisms of impaired enzymatic activity, a critical function needed for neuroprotection. Simulation results show that DAO mutations disrupt several key interactions with the active site residues and decrease the conformational flexibility of active site loop comprising 216 to 228 residues, necessary for substrate binding and product release. This conformational restriction of the active site loop in the mutants is mainly due to the distortion of critical salt bridge and hydrogen bond interactions compared with wild‐type. Furthermore, binding free energy calculations show that DAO mutants have a lower binding affinity toward cofactor flavin adenine dinucleotide and substrate imino‐serine than the wild‐type. A closer look at the cofactor and substrate interaction profiles further show that DAO mutants have lost several critical interactions with the neighboring residues as compared with wild‐type. Taken together, this study provides first‐hand explanation of crucial structural features that lead to the loss of enzymatic function in DAO mutants and highlights the need of further genomic scans of patients with ALS to map the association of novel DAO variants in ALS pathophysiology. Abstract : This article presents mechanistic insights into the role of D‐amino acid oxidase (DAO) mutations in Amyotrophic Lateral Sclerosis (ALS) pathophysiology‐ a fatal neurodegenerative disorder. Through extensive molecular dynamics simulations and analyses, we demonstrate for the first time that certain structural and dynamics features of the enzyme leads to the loss of enzymatic activity in DAO mutants and in turn cause ALS through a unique loss‐of‐function mechanism. (figure 1).