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Chemical Tools for Studying O-GlcNAc Glycosylation at the Systems Level


Thompson, John Warren Lenzi (2020) Chemical Tools for Studying O-GlcNAc Glycosylation at the Systems Level. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/gx3z-k069.


The addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to intracellular serine and threonine residues is a ubiquitous post-translational modification (PTM) found in all higher eukaryotes. Like other PTMs, it is finely regulated in response to stimuli and dysregulated in multiple diseases. However, unlike other PTMs, methods to detect and profile the dynamics of O-GlcNAc glycosylation are still in their infancy. Herein, we discuss the background, development, and application of new chemical tools that have allowed for some of the first systems-level investigations of O-GlcNAcylation in different cells, organ systems, and disease states. We also significantly advance established techniques for the detection and monitoring of O-GlcNAc on proteins of interest. Using these new techniques, we first uncover a novel O-GlcNAcylation site on Cdk5 and show that this site can dynamically regulate Cdk5 activity in the context of neurodegenerative disease. Next, we apply novel chemical, mass spectrometric, and computational tools to, for the first time, uncover cellular networks engaged by O-GlcNAcylation in vivo. Finally, we undertake the systematic optimization of mass spectrometry based O-GlcNAcomics and use these new insights to significantly advance our understanding of O-GlcNAcylation dynamics in metabolic diseases of the liver. Overall, the techniques developed and data generated herein are closing the methodological and intellectual gaps between the study of O-GlcNAc glycosylation and that of other PTMs.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:O-linked β-N-acetylglucosamine, O-GlcNAc glycosylation, O-GlcNAcomics, proteomics, chemical biology of carbohydrates.
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Chemistry
Awards:Chen Institute Graduate Innovator Grant
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Hsieh-Wilson, Linda C.
Thesis Committee:
  • Hoelz, Andre (chair)
  • Chan, David C.
  • Pachter, Lior S.
  • Hsieh-Wilson, Linda C.
Defense Date:8 June 2020
Funding AgencyGrant Number
Tianqiao and Chrissy Chen Institute for NeuroscienceUNSPECIFIED
UCLA-Caltech Medical Scientist Training ProgramUNSPECIFIED
Record Number:CaltechTHESIS:06112020-001257003
Persistent URL:
Related URLs:
URLURL TypeDescription adapted for Chapter 2. adapted for Chapter 4.
Thompson, John Warren Lenzi0000-0003-0061-4996
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:13815
Deposited By: John Thompson
Deposited On:15 Jun 2020 16:31
Last Modified:09 Jun 2021 19:19

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