An In-silico Analysis of OGT gene association with diabetes mellitus

Abstract

O-GlcNAcylation is a nutrient-sensing post-translational modification process. This cycling process involves two main proteins; the O-linked N-acetylglucosamine transferase (OGT) catalyzing the addition, and the glycoside hydrolase OGA (O-GlcNAcase) catalyzing the removal of the O-GlCNAc moiety on nucleocytoplasmic proteins. This process is necessary for various important cellular functions. The O-linked N-acetylglucosamine transferase (OGT) gene is responsible for the production of the OGT protein. Several studies have shown the overexpression of this protein to have biological implications in metabolic diseases like cancer and diabetes mellitus (DM). In this study, we retrieved a total of 159 SNPs with clinical significance from the SNPs database and we probed the functional effects, stability profile, and evolutionary conservation of these to determine their fit for this research. We then identified 7 SNPs (G103R, N196K, Y228H, R250C, G341V, L367F, and C845S) with predicted deleterious effects across the four tools used (PhD-SNPs, SNPs&Go, PROVEAN, and PolyPhen2). Proceeding with this, we used ROBETTA, a homology modeling tool, to model the proteins with these point mutations and carried out a structural bioinformatics method – molecular docking – using the Glide model of the Schrodinger Maestro suite. We used a previously reported inhibitor of OGT, OSMI-1, as the ligand for these mutated protein models, and as a result, very good binding affinities and interactions were observed between this ligand and the active site residues within 4Å of OGT. We conclude that these mutation points may be used for further downstream analysis as drug targets for the treatment of diabetes mellitus.