Comprehensive analysis of non-synonymous missense SNPs of human galactose mutarotase (GALM) gene: an integrated computational approach

• Published in: Journal of biomolecular structure & dynamics Vol. ahead-of-print; no. ahead-of-print; pp. 1 - 15
• Main Authors: Murthy, T. P. Krishna, Shukla, Rohit, Durga Prasad, N., Swetha, Praveen, Shreyas, S., Singh, Tiratha Raj, Pattabiraman, Ramya, Nair, Shishira S., Mathew, Blessy B., Kumar, K. M.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 21.12.2023
• Subjects: galactosemia type 4; GALM polymorphisms; in silico protocol; leloir pathway; molecular dynamics simulations; SNPs; molecular dynamics simulations; SNPs; GALM polymorphisms; galactosemia type 4; in silico protocol; leloir pathway
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2022.2160813

Missense Non-synonymous single nucleotide polymorphisms (nsSNPs) of Galactose Mutarotase (GALM) are associated with the Novel type of Galactosemia (Galactosemia type 4) together with symptoms such as high blood galactose levels and eye cataracts. The objective of the present study was to identify deleterious nsSNPs of GALM recorded on the dbSNP database through comprehensive insilico analysis. Among the 319 missense nsSNPs reported, various insilco tools predicted R78S, R82G, A163E, P210S, Y281C, E307G and F339C as the most deleterious mutations. Structural analysis, PTM analysis and molecular dynamics simulations (MDS) were carried out to understand the effect of these mutations on the structural and physicochemical properties of the GALM protein. The residues R82G and E307G were found to be part of the binding site that resulted in decreased surface accessibility. Replacing the charged wild-type residue with a neutral mutant type affected its substrate binding. All 7 mutations were found to increase the rigidity of the protein structure, which is unfavorable during ligand binding. The mutation F339E made the protein structure more rigid than all the other mutations. Y281 is a phosphorylated site, and therefore, less significant structural changes were observed when compared to other mutations; however, it may have significant differences in the usual functioning of the protein. In summary, the structural and functional analysis of missense SNPs of GALM is important to reduce the number of potential mutations to be evaluated in vitro to understand the association with some genetic diseases. Communicated by Ramaswamy H. Sarma