Sugar-Coating Metabolism: A Comparative Analysis of Global Metabolite Profiles in C. elegans O-GlcNAcylation Mutants
Marrett, Austin Sugar-Coating Metabolism - A Comparative Analysis of Global Metabolite Profiles in C. elegans O-GlcNAcylation Mutants.pdf
AuthorMarrett, Austin J.
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In the field of molecular biology, it is becoming increasingly clear that the use of gene knock-out experiments alone is insufficient to characterize the functions of the majority of genes. Approximately 85-90% of the genes in most organisms are „silent? and cannot be explored using these traditional methods. Silent genes are particularly important in the study of posttranslational modifications of proteins, which occurs completely independently of any transcription, gene splicing, or translation. Protein modification is known to be vital to the regulation and control of enzymes, including those involved in the metabolism of sugars. In this study, I examine a specific form of cyclical protein glycosylation, O-GlcNAcylation, in the model organism Caenorhabditis elegans using a metabolomics approach. By comparing global metabolite profiles of wild type N2 C. elegans and two knock-out mutant strains oga-1 and ogt-1, which respectively possess deletions for the OGA and OGT enzymes involved in O-GlcNAcylation, I demonstrate that interruption of O-GlcNAcylation produces predictable alterations to core metabolites involved in glucose metabolism and the nutrient-sensing hexosamine biosynthetic pathway (HBP). These results suggest that O-GlcNAcylation is directly dependent on, and impacted by, several other fundamental cellular pathways and metabolites. Once identified, such metabolic systems and their intermediates may serve as therapeutic targets in the treatment of diseases that also perturb the same pathways, such as diabetes, neurodegenerative diseases, and various cancers.