Liu, Jiangxia
(2010)
THE APPLICATION OF METABOLIC NETWORK ANALYSIS IN UNDERSTANDING AND TARGETING METABOLISM FOR DRUG DISCOVERY.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Metabolic networks provide a vital framework for understanding the cellular metabolism in both physiological and pathophysiological states, which will ultimately facilitate network analysis-based drug discovery. In this thesis, we aim to employ a metabolic network analysis approach to study cancer metabolism (a pathophysiological state) and the metabolism of the bacterial pathogen, S. aureus (a physiological state), in order to understand, predict, and ultimately target cell metabolism for drug discovery. Cancer cells have distinct metabolism that highly depend on glycolysis instead of mitochondrial oxidative phosphorylation alone, even in the presence of oxygen, also called aerobic glycolysis or the Warburg effect, which may offer novel therapeutic opportunities. However, the origin of the Warburg effect is only partially understood. To understand the origin of cancer metabolism, our theoretical collaborator, Prof. Alexei Vazquez, developed a reduced flux balance model of human cell metabolism incorporating the macromolecular crowding (MC) constraint and the maximum glucose uptake constraint. The simulations successfully captured the main characteristics of cancer metabolism (aerobic glycolysis), indicating that MC constraint may be a potential origin of the Warburg effect. Notably, when we experimentally tested the model with mammalian cells from low to high growth rates as a proxy of MC alteration, we find that, consistent with the model, faster growing cells indeed have increased aerobic glycolysis. Moreover, the metabolic network analysis approach has also been shown to be capable of predicting the drug targets against pathogen metabolism when completely reconstructed metabolic networks are available. We deduced common antibiotic targets in Escherichia coli and Staphylococcus aureus by identifying shared tissue-specific or uniformly essential metabolic reactions in their metabolic networks. We then predicted through virtual screening dozens of potential inhibitors for several enzymes of these reactions and demonstrated experimentally that a subset of these inhibited both enzyme activities in vitro and bacterial cell viability. Our results indicate that the metabolic network analysis approach is able to facilitate the understanding of cellular metabolism by identifying potential constraints and predicting as well as ultimately targeting the metabolism of the organisms whose complete metabolic networks are available through the seamless integration of virtual screening with experimental validation.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
9 December 2010 |
| Date Type: |
Completion |
| Defense Date: |
3 December 2010 |
| Approval Date: |
9 December 2010 |
| Submission Date: |
7 December 2010 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Drug Discovery; Flux balance analysis; Molecular crowding; Warburg effect; Antibiotics; Metabolic networks |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-12072010-100902/, etd-12072010-100902 |
| Date Deposited: |
10 Nov 2011 20:09 |
| Last Modified: |
19 Dec 2016 14:38 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/10167 |
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