Disease relevance of OGT

• To facilitate mutational analysis of OGT in the absence of competing endogenous activity, we expressed the 103-kDa human OGT in Escherichia coli [1].
• Thus, we propose that OGT can respond rapidly to heat stress through the enhancement of nucleocytoplasmic protein O-GlcNAcylation for a rescue from the early phase of hyperthermal cytotoxicity [2].
• The diabetogenic agent streptozotocin (STZ), a UDP-GlcNAc analogue, causes beta-cell toxicity by irreversibly inhibiting O-GlcNAcase, while the diabetogenic agent alloxan (ALX), also a UDP-GlcNAc analog irreversibly inhibits OGT [3].
• As our data suggest, OGT 719 may significantly inhibit growth of metastatic colorectal tumors in the liver in vivo [4].
• O-linked N-acetylglucosaminyltransferase (OGT) catalyzes the transfer of O-linked GlcNAc to serine or threonine residues of a variety of substrate proteins, including nuclear pore proteins, transcription factors, and proteins implicated in diabetes and neurodegenerative disorders [5].

Psychiatry related information on OGT

• Since a greater understanding of brain OGT may provide new insights into the pathogenesis of Alzheimer's disease, we examined the characteristics and subcellular distribution of OGT protein and OGT activity and its relationship to O-linked glycosylation [6].

High impact information on OGT

• Here, we show that O-GlcNAc transferase (OGT), the enzyme that catalyzes this posttranslational modification, interacts with a histone deacetylase complex by binding to the corepressor mSin3A [7].
• We propose that mSin3A targets OGT to promoters to inactivate transcription factors and RNA polymerase II by O-GlcNAc modification, which acts in concert with histone deacetylation to promote gene silencing in an efficient and specific manner [7].
• Interestingly, GmaR also functions as a glycosyltransferase exhibiting O-linked N-acetylglucosamine transferase (OGT) activity for flagellin (FlaA) [8].
• These studies illustrate the necessity of conditional gene-targeting approaches in the mutagenesis and study of essential sex-linked genes, and indicate that OGT participation in intracellular glycosylation is essential for embryonic stem cell viability and for mouse ontogeny [9].
• To study OGT function in vivo, we have used gene-targeting approaches in male embryonic stem cells [9].

Chemical compound and disease context of OGT

• Several colorectal cancer cell lines express the asialoglycoprotein receptor, although no significant levels can be detected in C170HM2 cells, consistent with the observation that OGT 719 is approximately 3 log orders of magnitude less potent in vitro than 5-FU [4].
• We expressed each of these OGT isoforms in a soluble form in Escherichia coli and have used them to identify novel targets including the Src-family tyrosine kinase yes and O-GlcNAc-ase [5].
• When incubated with RBC suspension, OGT and its four constituting herbs provided strong protection for RBC membrane to hemolysis induced by 2,2-azo-bis (2-amidinopropane) dihydrochloride (AAPH), an azo free radical initiator [10].

Biological context of OGT

• We find that OGT mutagenesis requires a strategy that retains an intact OGT gene as accomplished by using Cre-loxP recombination, because a deletion in the OGT gene results in loss of embryonic stem cell viability [9].
• A single copy of the OGT gene is present in the male genome and resides on the X chromosome near the centromere in region D in the mouse spanning markers DxMit41 and DxMit95, and in humans at Xq13, a region associated with neurologic disease [9].
• Segregation of OGT alleles in the mouse germ line with ZP3-Cre recombination in oocytes reveals that intact OGT alleles are required for completion of embryogenesis [9].
• These studies support the model that the catalytic subunit of OGT achieves both high specificity and a remarkable diversity of substrates by complexing with a variety of targeting proteins via its TPR protein-protein interaction domains [11].
• Identification of viable OGT mutants may facilitate examination of its role in nutrient sensing and signal transduction cascades [12].

Anatomical context of OGT

• Unlike previously described glycosyltransferases, OGT is localized to the cytosol and nucleus [13].
• In the present study, we examined the localization of OGT mRNA and OGT protein in the rat pancreas [14].
• To investigate this further, we incubated H-411E liver cells with insulin (10,000 microU/ml) and quantified the subcellular distribution of O-GlcNAc transferase (OGT) and O-GlcNAc-modified Sp1 [15].
• O-GlcNAc transferase (OGT) modifies nuclear pore proteins and transcription factors [1].
• In the islets of Langerhans, especially in the alpha-cells, intense staining with anti-OGT antibody was observed [14].

Associations of OGT with chemical compounds

• Intracellular glycosylation by the addition of N-acetylglucosamine (GlcNAc) to serine and threonine is catalyzed by the O-GlcNAc transferase (OGT) [9].
• The abundant and dynamic post-translational modification of nuclear and cytosolic proteins by beta-O-linked N-acetylglucosamine (O-GlcNAc) is catalyzed by O-GlcNAc-transferase (OGT) [11].
• We and others have proposed that mammalian OGT is the terminal step in a glucose-sensitive signal transduction pathway that becomes disregulated in insulin resistance [1].
• O-Linked N-acetylglucosaminyltransferase (OGT) catalyzes the transfer of O-linked GlcNAc to serine/threonine residues of a variety of target proteins, many of which have been implicated in such diseases as diabetes and neurodegeneration [12].
• Kinetic parameters for the purified recombinant enzyme (K(m) = 1.2 microM for Nup 62; K(m) = 0.5 microM for UDP-GlcNAc) are nearly identical to purified mammalian OGT [1].

Physical interactions of OGT

• Both GRIF-1 and OIP106 contain coiled-coil domains and interact with the tetratricopeptide repeats of OGT [16].
• We demonstrate that SCA10 interacts with OGT in vivo and is modified by O-linked glycosylation in MIN6 cells, suggesting a novel role for the Ataxin-10 protein in pancreatic beta cells [17].
• OGT 719 has the capacity selectively to bind to asialoglycoprotein receptors that are found exclusively on hepatocytes and hepatocellular carcinoma (HCC) cells [18].

Other interactions of OGT

• GRIF-1 and OIP106 are modified by O-GlcNAc and therefore are substrates for OGT [16].
• We employed site-directed mutagenesis to target potentially important amino acid residues within the two conserved catalytic domains of OGT (CD I and CD II), followed by an in vitro glycosylation assay to evaluate N-acetylglucosaminyltransferase activity after bacterial expression [12].
• The OGT protein contains multiple tandem repeats of the tetratricopeptide repeat motif [13].
• RESULTS: Neither rectum nor sigmoid colon resection led to significant changes in the pre- and postoperative glucose responses to OGT testing, or insulin, GIP and GLP-1 release [19].
• Furthermore, direct competition between OGT and CTD kinase in vivo could generate multiple functionally distinct isoforms of RNA Pol II [20].

Analytical, diagnostic and therapeutic context of OGT

• In addition, immunofluorescence staining with antibody raised against OGT stained both the exocrine acinar cells and endocrine islet cells [14].
• The sites of OGT mRNA expression were determined by in situ hybridization histochemistry with a digoxigenin (DIG)-labeled antisense cRNA probe [14].
• Immuno-electron microscopy showed that OGT is localized to the euchromatin of the nucleus and around the secretory granules of exocrine acinar cells and endocrine islet cells [14].
• We examined the localization of OGT by immunofluorescence microscopy, subcellular fractionation and immunoblotting using highly specific affinity-purified antisera [21].
• Oral administration of 1500 mg/kg/day OGT 719 inhibited liver tumor burden by 95% compared with vehicle control, without any observable signs of toxicity [4].

References