Dissertation
The effect of terazosin (TZ) on the PGK1 step of glycolysis
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2022
DOI: 10.25820/etd.006757
Abstract
We begin this thesis with a discussion of how disease can be studied via metabolism and narrow the focus to glycolytic enzyme phosphoglycerate kinase 1 (PGK1), its role in glycolysis, and its role as a target for drug treatment. In particular, the drug terazosin (TZ) has been used to target PGK1 in an effort to treat metabolic stress caused by diseases such as Parkinson's, Alzheimer's, ALS, and even ulcerative colitis.
The PGK1 step of glycolysis is the first step to produce ATP and it is thought that ATP is helpful in disaggregating disease causing proteins in the aforementioned ailments via its hydrotropic properties. TZ is known to bind directly to PGK1, facilitating its ability to produce ATP. It is not known how TZ causes this increase and TZ only helps at a critical dose, meaning too high or too little TZ can be ineffective or even detrimental. In this thesis we call this non-monotone dose dependence.
To find out how TZ could be affecting the PGK1 step of glycolysis, we first build a preliminary kinetic model of the PGK1 step that only includes the reversible binding and unbinding of PGK1 to its substrates, 1,3-bisphosphoglycerate (1,3-bPG) and adenosine diphosphate (ADP). We perform a steady-state and local sensitivity analysis on the kinetic parameters to gain a feel for which parameters could play a role in increasing ATP production in the PGK1 step. Then a fully-fledged PGK1 model is built, allowing also the reversible binding and unbinding of PGK1's products, 3-phosphoglycerate (3-PG) and adenosine triphosphate (ATP). Again, steady-state and local sensitivity analyses are performed and a critical value for a kinetic parameter is shown to produce a non-monotone output in ATP when perturbed. Finally, an explicit dose of TZ is incorporated in the PGK1 step as a competitive inhibitor and, interestingly, TZ doses give a non-monotone output in ATP. Upon this finding, we analyze the detailed balance (or fluxome) of each PGK1 step interaction with a different dose of TZ. This allows us to discover a possible way TZ is boosting ATP output at the PGK1 step as a competitive inhibitor, sometimes called competitive inhibitor stimulation.
Details
- Title: Subtitle
- The effect of terazosin (TZ) on the PGK1 step of glycolysis
- Creators
- Mitchell J. Riley
- Contributors
- Colleen Mitchell (Advisor)Bruce Ayati (Committee Member)Eric Taylor (Committee Member)Michael Welsh (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Applied Mathematical and Computational Sciences
- Date degree season
- Autumn 2022
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.006757
- Number of pages
- xiii, 103 pages
- Copyright
- Copyright 2022 Mitchell J. Riley
- Language
- English
- Description illustrations
- Charts, graphs, tables
- Description bibliographic
- Includes bibliographical references (pages 100-103).
- Public Abstract (ETD)
Metabolism refers to the whole sum of reactions that occur throughout the body within each cell and that provide the body with energy. When these reactions are disturbed, several diseases can manifest in humans such as Parkinson’s, Alzheimer’s, ALS, Huntington’s, and ulcerative colitis. To help learn how to treat these diseases, scientists can target several components of metabolism, and, in particular, proteins called enzymes. In this thesis we study the enzyme phosphoglycerate kinase 1 (PGK1), which is involved in the early stages of ATP (energy) production. An FDA approved drug called terazosin (TZ) is known to target and bind directly to PGK1 and increase its ATP production. This increase in ATP is thought to help treat the aforementioned diseases. However, this increase in ATP from TZ only occurs at a “sweet spot” dose. This means too much or too little TZ is ineffective, and thus it is necessary to understand the dynamics of PGK1 with TZ so that an optimal dose can be achieved for anyone treated with the medication.
To this end, we begin the thesis with a preliminary model of the PGK1 step and then proceed to model the entire PGK1 step. After some analysis, one parameter manipulation gives a hint to how TZ could be affecting the PGK1 step. Finally, we incorporate TZ into the PGK1 step as a competitive inhibitor of PGK1. With this, we can find the approximate sweet spot dose of TZ and possibly understand the way TZ affects the enzyme at this sweet spot dose.
- Academic Unit
- Interdisciplinary Graduate Program in Applied Mathematical & Computational Sciences
- Record Identifier
- 9984362458302771
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