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AuthorP, Sneha
AuthorEbrahimi, Elaheh Ahmad
AuthorGhazala, Sara Ahmed
AuthorD, Thirumal Kumar
AuthorR, Siva
AuthorPriya Doss C, George
AuthorZayed, Hatem
Available date2018-12-19T06:51:44Z
Publication Date2018-09
Publication NameJournal of Cellular Biochemistryen_US
Identifierhttp://dx.doi.org/10.1002/jcb.27097
CitationEbrahimi, E. A., Ghazala, S. A., Priya, G. D. C., & Zayed, H. (2018). Structural analysis of missense mutations in galactokinase 1 (GALK1) leading to galactosemia type-2. Journal of cellular biochemistry.
ISSN0730-2312
URIhttp://hdl.handle.net/10576/11214
AbstractGalactosemia 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.
Languageen
PublisherWiley
SubjectGALK1 gene
Subjectadenosine triphosphate
Subjectgalactokinase deficiency
Subjectgalactosemia type 2
Subjectin silico predictions
Subjectmolecular dynamics simulations
Subjectvariant classification and interpretation
TitleStructural analysis of missense mutations in galactokinase 1 (GALK1) leading to galactosemia type-2.
TypeArticle
Pagination7585-7598
Issue Number9
Volume Number119
ESSN1097-4644


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