Date of Award
2025
Document Type
Open Access Dissertation
Degree Name
Doctor of Philosophy in Chemistry (PhD)
Administrative Home Department
Department of Chemistry
Advisor 1
Marina Tanasova
Committee Member 1
Shiyue Fang
Committee Member 2
Tarun Dam
Committee Member 3
Smitha Rao
Abstract
Facilitated Glucose transporters (GLUTs) are membrane proteins responsible for the uptake of simple sugars and other structurally similar metabolites in all mammalian cells. One of the hallmarks of cancer is dysfunctional sugar metabolism, known as the Warburg effect, and one of the manifestations of that effect is abnormal GLUT expression. There are 14 known GLUT proteins with different expression patterns in different tissues, and tumors tend to express certain GLUTs that are not present in surrounding healthy tissue. Therefore, selective targeting of GLUTs presents a potentially powerful tool for diagnostics and treatment of cancer and other diseases. This has been an active research area since the 1950s, and recently, selective targeting of GLUT5 was achieved, due to its unique substrate preference. GLUT2 also has a distinct substrate preference, which we attempted to exploit to achieve selective targeting. First, we ran computational models of GLUT2 taking up its highest affinity substrate, glucosamine, to understand which residues play a key role in the substrate recognition and uptake. Next, we screened several fluorescent conjugated glucosamine derivatives in silico to determine the structure activity relationship. And then we synthesized those derivatives in the lab to measure their uptake on live tumor cells that overexpress GLUT2. Those measurements allowed us to verify the validity of our computational model findings and the validity of our hypothesized GLUT2 binding preference, a key step towards achieving GLUT2 selectivity. Additionally, during the glucosamine derivative synthesis process, the limited number of modifications that were possible on existing glucosamine molecules, and the prohibitive cost of other glucosamine-like amino sugars and derivatives inspired the development of a novel viii synthetic pathway to sugars and amino sugars. This synthesis builds the sugar molecule one carbon atom at a time while controlling stereochemistry and substitution, enabling the synthesis of hundreds of possible sugars with different substitution, stereochemistry, and length. The utility of this synthetic approach to sugars potentially extends far beyond the scope of this investigation into GLUT2, and combined with selective targeting of GLUT2, opens the potential for many different biochemical and biomedical applications in the field of oncology and beyond.
Recommended Citation
Ismail, Abdelrahman, "Towards Developing GLUT2 Specific Probes for Biochemical and Biomedical Applications", Open Access Dissertation, Michigan Technological University, 2025.
Included in
Analytical Chemistry Commons, Carbohydrates Commons, Computational Chemistry Commons, Medicinal-Pharmaceutical Chemistry Commons, Organic Chemicals Commons, Organic Chemistry Commons
