Glucose-6-phosphate dehydrogenase in health and disease and a therapeutic strategy for glucose-6-phosphate dehydrogenase deficiency
Abstract/Contents
- Abstract
- Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, is critical for a variety of cellular processes and mutations in the G6PD gene can cause G6PD deficiency -- a genetic trait present in ~300-500 million people worldwide. Currently, G6PD deficiency is most known for causing hemolytic anemia; however, it has been associated with other chronic disorders and there are no therapeutics for G6PD deficiency. Here, the role of G6PD in health and disease, past treatment strategies, and potential pharmacological pathways and drug targets are discussed. The lack of therapeutics and drug discovery efforts for G6PD deficiency motivated our lab to conduct a high throughput screen where we identified a small molecule activator of G6PD, which works by stabilizing the structural NADP+ and dimer. My work aimed to understand how loss of structural NADP+ binding affected the homo-oligomeric properties and function of G6PD and whether oligomer stabilization could be used as a therapeutic strategy for G6PD deficiency. Here, I found that loss of structural NADP+ induces structural changes in the G6PD dimer, which prevents tetramer formation. By introducing non-native cysteines at the oligomeric interfaces of G6PD, I found that the tetramer is the more active and stable form of wild type G6PD. Furthermore, I found that stabilization of the dimer and tetramer improved activity for select G6PD variants and that favoring the tetramer stabilized the enzyme to a greater extent than the dimer. Since enzyme activity and stability are major determinants of pathogenicity, my study suggests a small molecule which stabilizes the tetramer may be beneficial for treatment of G6PD deficiency related disorders and encourages the pursuit of such novel compounds. Foreseeable challenges and future research directions pertaining to these findings conclude my dissertation.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2022; ©2022 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Garcia, Adriana Ann |
|---|---|
| Degree supervisor | Mochly-Rosen, Daria |
| Thesis advisor | Mochly-Rosen, Daria |
| Thesis advisor | Chen, James Kenneth |
| Thesis advisor | Jarosz, Daniel |
| Thesis advisor | Wakatsuki, Soichi |
| Degree committee member | Chen, James Kenneth |
| Degree committee member | Jarosz, Daniel |
| Degree committee member | Wakatsuki, Soichi |
| Associated with | Stanford University, Department of Chemical and Systems Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Adriana Ann Garcia. |
|---|---|
| Note | Submitted to the Department of Chemical and Systems Biology. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/wx065mm6183 |
Access conditions
- Copyright
- © 2022 by Adriana Ann Garcia
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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