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You searched for subject:(O GlcNAc transferase). Showing records 1 – 3 of 3 total matches.

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University of Kansas

1. Tan, Ee Phie. O-GlcNAc Regulation of Mitochondrial Function and Energy Metabolism.

Degree: PhD, Biochemistry & Molecular Biology, 2017, University of Kansas

O-GlcNAc is a post-translational modification (PTM) of a single N-acetylglucosamine sugar attachment on serine or threonine residues of nuclear, cytoplasmic, and mitochondrial proteins. Two opposing enzymes facilitate the modification; O-GlcNAc transferase (OGT) adds the modification, while O-GlcNAcase (OGA) removes it. The addition and the removal of O-GlcNAc, termed O-GlcNAc cycling, is often a dynamic process sensitive to changes in the cellular environment. Disruptions in O-GlcNAcylation contribute to diseases such as diabetes, cancer, and neurodegeneration. Accumulative chronic dysfunctional mitochondria also lead to the development of disease; and importantly, O-GlcNAcylation regulates mitochondrial function. In order to test our first hypothesis that disruptions in O-GlcNAc cycling affect mitochondrial function by changing the mitochondrial proteome, we employed a proteomics screen using SH-SY5Y neuroblastoma cells. We found that OGT and OGA overexpression severely disrupted the mitochondrial proteome, including proteins involved in the respiratory chain and TCA cycle. Furthermore, mitochondrial morphology in the over-expressing cells had disorganized cristae and altered shape and size. Both cellular respiration and glycolysis is impaired. These data support that O-GlcNAc cycling was essential for the proper regulation of mitochondrial function. We next investigated how sustained elevations in cellular O-GlcNAc levels would alter the metabolic profile of the cell. We elevated cellular O-GlcNAc levels by either treating SH-SY5Y cells with low levels of glucosamine (GlcN), the metabolic substrate of OGT, or the OGA inhibitor Thiamet-G (TMG). We found cellular respiration was altered and ATP levels were lower in these cells with sustained elevated O-GlcNAc. Additionally, these cells produce significantly less reactive oxygen species (ROS). Both GlcN and TMG treated cells have elongated mitochondria, while mitochondrial fusion/fission protein expressions were decreased. RNA-sequencing analysis showed that the transcriptome is reprogrammed and NRF2 anti-oxidant response is down-regulated. Importantly, sustained O-GlcNAcylation in mice brain and liver validated the metabolic phenotypes seen in cells, whereas liver OGT knockdown elevated ROS levels, impaired mitochondrial respiration, and increased NRF2 anti-oxidant response. Furthermore, we discovered from an indirect calorimetric study that sustained elevated O-GlcNAc promoted weight loss and lowered respiration, skewing mice toward using carbohydrates as their main energy source. Here, our results demonstrated that sustained elevation in O-GlcNAcylation, coupled with increased OGA expression, reprograms energy metabolism and can potentially impact the development of metabolic diseases. Altogether, these studies provide new evidence supporting the role of O-GlcNAc as a critical regulator of mitochondrial function and energy metabolism. Advisors/Committee Members: Slawson, Chad (advisor), Swerdlow, Russell (advisor), Carlson, Gerald (cmtemember), Artigues, Antonio (cmtemember), Zhu, Hao (cmtemember).

Subjects/Keywords: Biochemistry; Metabolism; Mitochondrial function; O-GlcNAc; O-GlcNAcase; O-GlcNAc transferase; Reactive oxygen species

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APA (6th Edition):

Tan, E. P. (2017). O-GlcNAc Regulation of Mitochondrial Function and Energy Metabolism. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/26931

Chicago Manual of Style (16th Edition):

Tan, Ee Phie. “O-GlcNAc Regulation of Mitochondrial Function and Energy Metabolism.” 2017. Doctoral Dissertation, University of Kansas. Accessed September 24, 2019. http://hdl.handle.net/1808/26931.

MLA Handbook (7th Edition):

Tan, Ee Phie. “O-GlcNAc Regulation of Mitochondrial Function and Energy Metabolism.” 2017. Web. 24 Sep 2019.

Vancouver:

Tan EP. O-GlcNAc Regulation of Mitochondrial Function and Energy Metabolism. [Internet] [Doctoral dissertation]. University of Kansas; 2017. [cited 2019 Sep 24]. Available from: http://hdl.handle.net/1808/26931.

Council of Science Editors:

Tan EP. O-GlcNAc Regulation of Mitochondrial Function and Energy Metabolism. [Doctoral Dissertation]. University of Kansas; 2017. Available from: http://hdl.handle.net/1808/26931


University of Georgia

2. Stuchlik, Olga. Using Caenorhabditis elegans to elucidate the role of O-GlcNAc in insulin signal transduction.

Degree: MS, Biochemistry and Molecular Biology, 2006, University of Georgia

O-GlcNAc is a regulatory carbohydrate post-translational modification found on serine and threonine residues on cytosolic and nuclear proteins in multicellular organisms. Global elevation of O-GlcNAc levels on intracellular proteins induces insulin resistance, the hallmark of type II diabetes, in mammalian systems. In C. elegans, attenuation of the insulin-like signal transduction pathway increases lifespan of the nematode. We demonstrate that the O-GlcNAc cycling enzymes, OGT that adds O-GlcNAc and OGA, which removes it, modulate lifespan in C. elegans. The median lifespan of the oga deletion strain increases ~25% while the median life span of the ogt deletion strain decreases ~25%. Furthermore, we demonstrate that the O-GlcNAc effect on nematode median lifespan is due to attenuation of insulin-like signal transduction above PDK1 in the pathway. These results highlight the conserved feature of the O-GlcNAc modification in attenuating insulin signaling and more finely define the point in the pathway in which elevated O-GlcNAc modification is inducing insulin resistance. Advisors/Committee Members: Lance Wells.

Subjects/Keywords: O-GlcNAc Insulin Resistance C. elegans lifespan ogt-1 oga-1 O-GlcNAc transferase O-GlcNAcase

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APA (6th Edition):

Stuchlik, O. (2006). Using Caenorhabditis elegans to elucidate the role of O-GlcNAc in insulin signal transduction. (Masters Thesis). University of Georgia. Retrieved from http://purl.galileo.usg.edu/uga_etd/stuchlik_olga_200612_ms

Chicago Manual of Style (16th Edition):

Stuchlik, Olga. “Using Caenorhabditis elegans to elucidate the role of O-GlcNAc in insulin signal transduction.” 2006. Masters Thesis, University of Georgia. Accessed September 24, 2019. http://purl.galileo.usg.edu/uga_etd/stuchlik_olga_200612_ms.

MLA Handbook (7th Edition):

Stuchlik, Olga. “Using Caenorhabditis elegans to elucidate the role of O-GlcNAc in insulin signal transduction.” 2006. Web. 24 Sep 2019.

Vancouver:

Stuchlik O. Using Caenorhabditis elegans to elucidate the role of O-GlcNAc in insulin signal transduction. [Internet] [Masters thesis]. University of Georgia; 2006. [cited 2019 Sep 24]. Available from: http://purl.galileo.usg.edu/uga_etd/stuchlik_olga_200612_ms.

Council of Science Editors:

Stuchlik O. Using Caenorhabditis elegans to elucidate the role of O-GlcNAc in insulin signal transduction. [Masters Thesis]. University of Georgia; 2006. Available from: http://purl.galileo.usg.edu/uga_etd/stuchlik_olga_200612_ms

3. Zhang, H. Inhibition of Galectins and O-GlcNAc Transferase with Di- and Multivalent Ligands.

Degree: 2018, University Utrecht

The work described in this thesis focuses on the development of inhibitors for two distinct types of proteins that act on carbohydrates: the galectins and O-GlcNAc transferase (OGT). Chapter 1 and 2 describe that these two types of protein can bind or convert certain carbohydrates to exhibit different functions in a wide variety of biological processes. Therefore, selective and potent inhibitors of these proteins would be valuable tools to investigate their biological functions. Chapter 3 describes a synthesis of multivalent ligands inhibiting Gal-3, in which multiple lysine residues of albumin were chemically conjugated with “thiodigalactoside” epitopes to make neo-glycoproteins. The neo-glycoproteins were finally evaluated in binding studies with human Gal-1 and -3 to determine the binding properties. Chapter 4 describes the synthesis of galectin inhibitors with a potential “chelate effect”, which are designed to bind to the two different binding sites on galectins simultaneously. In this chapter, a series of asymmetric “hybrid” compounds were prepared, that combine two galectin ligands, i.e., thiodigalactoside derivatives and calixarene 0118. Moreover, NMR spectroscopy was used to evaluate the interactions of these compounds with Gal-1 or -3. In addition, cellular experiments were conducted to compare the cytotoxic effects of the hybrids with those of calixarene 0118. Chapter 5 describes our progress on OGT inhibition based on substrate peptides identified by array screening. Subsequently, bisubstrate inhibitors were prepared by conjugating these peptides to uridine in various ways. In parallel, an in silico fragment screening was conducted to obtain small molecules targeting the UDP binding pocket. After evaluation of the initial hits, one of these small molecules was elaborated into a novel OGT hybrid inhibitor, as the replacement of uridine. The novel compounds inhibit OGT activity with IC50 values in the micromolar range. Advisors/Committee Members: Pieters, Roland.

Subjects/Keywords: Galectins; O-GlcNAc transferase; multivalency; neo-glycoproteins; thiodigalactoside; calixarene; bisubstrate inhibitor; fragment screening

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Zhang, H. (2018). Inhibition of Galectins and O-GlcNAc Transferase with Di- and Multivalent Ligands. (Doctoral Dissertation). University Utrecht. Retrieved from http://dspace.library.uu.nl/handle/1874/364051 ; URN:NBN:NL:UI:10-1874-364051 ; urn:isbn:978-90-393-6973-9 ; URN:NBN:NL:UI:10-1874-364051 ; http://dspace.library.uu.nl/handle/1874/364051

Chicago Manual of Style (16th Edition):

Zhang, H. “Inhibition of Galectins and O-GlcNAc Transferase with Di- and Multivalent Ligands.” 2018. Doctoral Dissertation, University Utrecht. Accessed September 24, 2019. http://dspace.library.uu.nl/handle/1874/364051 ; URN:NBN:NL:UI:10-1874-364051 ; urn:isbn:978-90-393-6973-9 ; URN:NBN:NL:UI:10-1874-364051 ; http://dspace.library.uu.nl/handle/1874/364051.

MLA Handbook (7th Edition):

Zhang, H. “Inhibition of Galectins and O-GlcNAc Transferase with Di- and Multivalent Ligands.” 2018. Web. 24 Sep 2019.

Vancouver:

Zhang H. Inhibition of Galectins and O-GlcNAc Transferase with Di- and Multivalent Ligands. [Internet] [Doctoral dissertation]. University Utrecht; 2018. [cited 2019 Sep 24]. Available from: http://dspace.library.uu.nl/handle/1874/364051 ; URN:NBN:NL:UI:10-1874-364051 ; urn:isbn:978-90-393-6973-9 ; URN:NBN:NL:UI:10-1874-364051 ; http://dspace.library.uu.nl/handle/1874/364051.

Council of Science Editors:

Zhang H. Inhibition of Galectins and O-GlcNAc Transferase with Di- and Multivalent Ligands. [Doctoral Dissertation]. University Utrecht; 2018. Available from: http://dspace.library.uu.nl/handle/1874/364051 ; URN:NBN:NL:UI:10-1874-364051 ; urn:isbn:978-90-393-6973-9 ; URN:NBN:NL:UI:10-1874-364051 ; http://dspace.library.uu.nl/handle/1874/364051

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