Structural analysis of missense mutations in galactokinase 1 (GALK1) leading to galactosemia type-2.
Sneha PElaheh Ahmad EbrahimiSara Ahmed GhazalaThirumal Kumar DGeorge Priya Doss CGeorge Priya Doss CHatem ZayedPublished in: Journal of cellular biochemistry (2018)
Galactosemia type 2 is an autosomal recessive disorder characterized by the deficiency of galactokinase (GALK) enzyme due to missense mutations in GALK1 gene, which is associated with various manifestations such as hyper galactosemia and formation of cataracts. GALK enzyme catalyzes the adenosine triphosphate (ATP)-dependent phosphorylation of α-d-galactose to galactose-1-phosphate. We searched 4 different literature databases (Google Scholar, PubMed, PubMed Central, and Science Direct) and 3 gene-variant databases (Online Mendelian Inheritance in Man, Human Gene Mutation Database, and UniProt) to collect all the reported missense mutations associated with GALK deficiency. Our search strategy yielded 32 missense mutations. We used several computational tools (pathogenicity and stability, biophysical characterization, and physiochemical analyses) to prioritize the most significant mutations for further analyses. On the basis of the pathogenicity and stability predictions, 3 mutations (P28T, A198V, and L139P) were chosen to be tested further for physicochemical characterization, molecular docking, and simulation analyses. Molecular docking analysis revealed a decrease in interaction between the protein and ATP in all the 3 mutations, and molecular dynamic simulations of 50 ns showed a loss of stability and compactness in the mutant proteins. As the next step, comparative physicochemical changes of the native and the mutant proteins were carried out using essential dynamics. Overall, P28T and A198V were predicted to alter the structure and function of GALK protein when compared to the mutant L139P. This study demonstrates the power of computational analysis in variant classification and interpretation and provides a platform for developing targeted therapeutics.
Keyphrases
- molecular docking
- intellectual disability
- molecular dynamics simulations
- endothelial cells
- public health
- machine learning
- gene expression
- escherichia coli
- copy number
- high throughput
- binding protein
- social media
- molecular dynamics
- artificial intelligence
- deep learning
- single cell
- wild type
- protein protein
- autism spectrum disorder
- transcription factor
- replacement therapy
- amino acid
- smoking cessation
- adverse drug
- genome wide identification