Type I
galactosemia is a very rare autosomal recessive genetic metabolic disorder that occurs because of the mutations present in the
galactose-1-phosphate uridyl transferase (GALT) gene, resulting in a deficiency of the GALT
enzyme. The action of the GALT
enzyme is to convert
galactose-1-phosphate and
uridine diphosphate glucose into
glucose-1-phosphate (G1P) and
uridine diphosphate-galactose, a crucial second step of the Leloir pathway. A missense mutation in the GALT
enzyme leads to variable
galactosemia's clinical presentations, ranging from mild to severe. Our study aimed to employ a comprehensive computational pipeline to analyze the most prevalent missense mutations (p.S135L, p.K285 N, p.Q188R, and p.N314D) responsible for
galactosemia; these genes could serve as potential targets for chaperone
therapy. We analyzed the four mutations through different computational analyses, including
amino acid conservation, in silico pathogenicity and stability predictions, and macromolecular simulations (MMS) at 50 ns The stability and pathogenicity predictors showed that the p.Q188R and p.S135L mutants are the most pathogenic and destabilizing. In agreement with these results, MMS analysis demonstrated that the p.Q188R and p.S135L mutants possess higher deviation patterns, reduced compactness, and intramolecular H-bonds of the
protein. This could be due to the physicochemical modifications that occurred in the mutants p.S135L and p.Q188R compared to the native. Evolutionary conservation analysis revealed that the most prevalent mutations positions were conserved among different species except N314. The proposed research study is intended to provide a basis for the therapeutic development of drugs and future treatment of classical
galactosemia and possibly other
genetic diseases using chaperone
therapy.