Glucokinase (GK) is an enzyme that catalyzes the ATP-dependent phosphorylation of glucose to form glucose-6-phosphate, and it is a tightly regulated checkpoint in glucose homeostasis. The monomeric enzyme possesses a highly exotic kinetic profile, with a sigmoidal dependence on glucose, which has been the source of vigorous investigation and debate in the last several decades. This unique regulatory behavior can be thought of as a remarkable glucose sensor, which may result in hyperglycemia when it is not active enough and hypoglycemia when it is too active. This interdisciplinary study, which draws on small angle X-ray scattering (SAXS) integrated with atomistic molecular dynamics simulations and experimental glucose binding thermodynamics, I reveal the critical regulation of the glucose sensor is due to a solvent controlled switch. Moreover, this solvent controlled switch manifests a regulatory mechanism of GK; a specific local conformational change that leads to an enzyme structure that has a much more favorable solvation energy than most of the protein ensemble. These findings have direct implications for the design of small molecule GK activators as anti- diabetes therapeutics as well as for understanding how proteins can be designed to have built-in regulatory functions via solvation energy dynamics.
| Identifer | oai:union.ndltd.org:uiowa.edu/oai:ir.uiowa.edu:etd-7961 |
| Date | 01 July 2018 |
| Creators | Li, Quinn |
| Contributors | Spies, M. Ashley |
| Publisher | University of Iowa |
| Source Sets | University of Iowa |
| Language | English |
| Detected Language | English |
| Type | dissertation |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | Copyright © 2018 Quinn Li |
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