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Title: Role of O-GlcNAc Transferase in metabolic order and disorder
Keywords: Natural Sciences
Issue Date: 2009
Abstract: The O-GlcNAc modification is, akin to phosphorylation, an abundant modification which plays an important role in cellular processes. The addition of O- GlcNAc to proteins is regulated by the O-GlcNAc transferase (OGT). This enzyme is ubiquitously expressed in mammals. The human OGT spans approximately 43 kb of genomic DNA, and to date, 3 OGT isoforms have been sequenced (two nuclear and one mitochondrial). In mammals, OGT exist as different isoforms, such as in the rat and the mouse, differing by 30 nucleotides in their N-terminal (exon 2) . In this study, the mouse OGT isoforms were investigated. In addition, the expression of the full OGT transcript and various transcripts was studied by real-time PCR in mouse tissues (liver, heart, kidney, testis, lung, spleen, ear, stomach, intestine, bone, tail and brain). The highest level of full length mouse OGT was found in spleen followed by testis and lung. The human OGT was shown to have highest expression in pancreas. Further investigations showed that mice express both isoforms (one which uses both exon 2A and 2B and one which skips exon 2A and only uses exon 2B). The first isoform showed highest expression in heart and aorta and the second one in liver and lung, suggesting that mouse OGT exists in different isoforms of varying abundance. Post-translational modifications (PTMs) are the major regulators of protein biological functions. PTMs are catalyzed by their respective enzymes which are sequence specific. Depending on the environment and signaling contexts, proteins are modified and instantly functional. In this study, the protein consensus sequences of 4 different modifications were investigated by utilizing the bio-informatic tool MAPRes. This tool mines association rules of a modified residue in peptides. Phosphorylated Ser/Thr/Tyr showed a polar sequence environment with Pro at various positions. O-GlcNAc modified Ser/Thr occured in an environment with vicinal Val (-1 position) and Pro (-2 and -3 positions), acetylated Lys occured in a basic environment with a preference for His or Tyr at +1 and Ser at +7 positions. Methylated Lys also showed a preference for basic amino acids, but compared with acetylated Lys, which have a high preference for vicinal Lys, methylated Lys showed a higher preference for Arg. Methylated Arg showed a high preference for Gly both up- and downstream the peptide chain. In addition, the Yin Yang site sequence environment was also investigated and showed that such sites were located in a polar environment with Pro at various positions. These results suggest that Pro is a very important amino acid in the vicinity of modified amino acids. Furthermore the position of Pro could be determinant in deciding whether a residue is phosphorylated, O-GlcNAc modified or both (Yin Yang site).
Appears in Collections:PhD Thesis of All Public / Private Sector Universities / DAIs.

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